The effect of pH, electrolytes and temperature on the rhizosphere geochemistry of phytosiderophores

Background and aims: Graminaceous plants are grown worldwide as staple crops under a variety of climatic and soil conditions. They release phytosiderophores for Fe acquisition (Strategy II). Aim of the present study was to uncover how the rhizosphere pH, background electrolyte and temperature affect the mobilization of Fe and other metals from soil by phytosiderophores. Methods: For this purpose a series of kinetic batch interaction experiments with the phytosiderophore 2′-deoxymugineic acid (DMA), a calcareous clay soil and a mildly acidic sandy soil were performed. The temperature, electrolyte concentration and applied electrolyte cation were varied. The effect of pH was examined by applying two levels of lime and Cu to the acidic soil. Results: Fe mobilization by DMA increased by lime application, and was negatively affected by Cu amendment. Mobilization of Fe and other metals decreased with increasing ionic strength, and was lower for divalent than for monovalent electrolyte cations at equal ionic strength, due to higher adsorption of metal-DMA complexes to the soil. Metal mobilization rates increased with increasing temperature leading to a faster onset of competition; Fe was mobilized faster, but also became depleted faster at higher temperature. Temperature also affected biodegradation rates of metal-DMA complexes. Conclusion: Rhizosphere pH, electrolyte type and concentration and temperature can have a pronounced effect on Strategy II Fe acquisition by affecting the time and concentration ‘window of Fe uptake’ in which plants can benefit from phytosiderophore-mediated Fe uptake.© The Author(s) 201

Serum-binding properties of isosteric ruthenium and osmium anticancer agents elucidated by SEC–ICP–MS

Size-exclusion chromatography–inductively coupled plasma–mass spectrometry (SEC–ICP–MS) was used to study the serum-binding preferences of two metallodrugs with anticancer activities in vivo, namely the organoruthenium compound plecstatin-1 and its isosteric osmium analog. The complexes were administered intraperitoneally into mice bearing a CT-26 tumor. Comparing the total metal content of mouse whole blood and serum underlined that the metallodrugs are mainly located in serum and not in the cellular fraction of the blood samples. In mouse serum, both compounds were not only found to bind extensively to the serum albumin/transferrin fraction but also to immunoglobulins. Free drug was not observed in any of the samples indicating rapid protein binding of the metallodrugs. These findings were validated by spiking human serum with the respective compounds ex vivo. An NCI-60 screen is reported for the osmium analog, which revealed a relative selectivity for cancer cell lines of the ovary and the central nervous system with respect to plecstatin-1. Finally, a COMPARE 170 analysis revealed disruption of DNA synthesis as a possible treatment effect of the osmium-based drug candidate.© The Author(s) 201

Teichospora and the Teichosporaceae

A multigene analysis of a combined ITS, LSU, SSU, rpb2 and tef1 sequence data matrix was applied to infer the phylogenetic position of the genus Teichospora in the Pleosporales, based on isolates from freshly collected material of the generic type T. trabicola and several additional species. Phylogenetic analyses revealed that Misturatosphaeria and Floricola are synonyms of Teichospora. All species of these genera and several species recently described in the genus Curreya belong to Teichospora and are thus combined in this genus. Also, Melanomma radicans and Ramusculicola thailandica are combined in Teichospora. The new name Teichospora parva is established for Misturatosphaeria minima. Three new species, T. melanommoides, T. pusilla and T. rubriostiolata, are described, and an expanded description of T. mariae is given. The family Teichosporaceae is currently confined to Teichospora, which can be phylogenetically clearly separated from Lophiostoma, the type genus of the Lophiostomataceae. The family name Floricolaceae is a synonym of Teichosporaceae. All species described here form apically free paraphyses among immature asci. This finding contradicts the current general dogma that apically free paraphyses are absent in the Pleosporales and questions the wide use of the term pseudoparaphysis

EGFR-targeting peptide-coupled platinum(IV) complexes

The high mortality rate of lung cancer patients and the frequent occurrence of side effects during cancer therapy demonstrate the need for more selective and targeted drugs. An important and well-established target for lung cancer treatment is the occasionally mutated epidermal growth factor receptor (EGFR). As platinum(II) drugs are still the most important therapeutics against lung cancer, we synthesized in this study the first platinum(IV) complexes coupled to the EGFR-targeting peptide LARLLT (and the shuffled RTALLL as reference). Notably, HPLC–MS measurements revealed two different peaks with the same molecular mass, which turned out to be a transcyclization reaction in the linker between maleimide and the coupled cysteine moiety. With regard to the EGFR specificity, subsequent biological investigations (3-day viability, 14-day clonogenic assays and platinum uptake) on four different cell lines with different verified EGFR expression levels were performed. Unexpectedly, the results showed neither an enhanced activity nor an EGFR expression-dependent uptake of our new compounds. Consequently, fluorophore-coupled peptides were synthesized to re-evaluate the targeting ability of LARLLT itself. However, also with these molecules, flow cytometry measurements showed no correlation of drug uptake with the EGFR expression levels. Taken together, we successfully synthesized the first platinum(IV) complexes coupled to an EGFR-targeting peptide; however, the biological investigations revealed that LARLLT is not an appropriate peptide for enhancing the specific uptake of small-molecule drugs into EGFR-overexpressing cancer cells.© The Author(s) 201

Multiple-dose pharmacokinetics of anidulafungin during continuous venovenous haemofiltration

Background: Clinical studies support a role for anidulafungin as first-line treatment of invasive candidiasis in critically ill patients and postulate no need for dose adjustments in mild to severe renal failure. Although intensive care patients requiring renal replacement therapy are at particular risk of invasive fungal infection, no pharmacokinetic data on anidulafungin during continuous venovenous haemofiltration (CVVHF) are available. Patients and methods: Ten patients with CVVHF due to acute renal failure were included. Anidulafungin was infused on 3 consecutive days starting with a loading dose of 200 mg on day 1, followed by doses of 100 mg on each of days 2 and 3. During the 72 h study phase of CVVHF, blood and ultrafiltrate samples were collected at corresponding times. Anidulafungin concentrations were determined by HPLC. Results: Peak plasma concentrations were reached 3 h after the start of infusion and were 8.5 +/- 3.6 mg/L at the pre-filter port. The mean arterial area under the curve (AUC(0-24)) of the study population was 109.9 +/- 49.82 mg.h/L, the total clearance was 1.08 +/- 0.41 L/h, the volume of distribution was 41.97 +/- 22.64 L and the elimination half-life was 28.78 +/- 10.40 h. Anidulafungin was not filtered, but CVVHF resulted in a substance loss of similar to 20%, due to adherence to synthetic surfaces. Conclusions: Pharmacokinetics of anidulafungin during CVVHF resembled findings in healthy adults and adults with fungal infections. Therefore we recommend a loading dose of 200 mg intravenous anidulafungin on the first day and 100 mg on consecutive treatment days in patients during CVVHF

Synthesis and in vivo anticancer evaluation of poly(organo)phosphazene-based metallodrug conjugates

Within this work we aimed to improve the pharmacodynamics and toxicity profile of organoruthenium and -rhodium complexes which had previously been found to be highly potent in vitro but showed unselective activity in vivo. Different organometallic complexes were attached to a degradable poly(organo)phosphazene macromolecule, prepared via controlled polymerization techniques. The conjugation to hydrophilic polymers was designed to increase the aqueous solubility of the typically poorly soluble metal-based half-sandwich compounds with the aim of a controlled, pH-triggered release of the active metallodrug. The synthesized conjugates and their characteristics have been thoroughly studied by means of 31P NMR and UV-Vis spectroscopy, ICP-MS analyses and SEC coupled to ICP-MS. In order to assess their potential as possible anticancer drug candidates, the complexes, as well as their respective macromolecular prodrug formulations were tested against three different cancer cell lines in cell culture. Subsequently, the anticancer activity and organ distribution of the poly(organo)phosphazene drug conjugates were explored in vivo in mice bearing CT-26 colon carcinoma. Our investigations revealed a beneficial influence of this macromolecular prodrug by a significant reduction of adverse effects compared to the free metallodrugs

Retention of phytosiderophores by the soil solid phase – adsorption and desorption

Background and aims: Graminaceous plants exude phytosiderophores (PS) for acquiring Fe. Adsorption of PS and its metal complexes to the soil solid phase reduces the FePS solution concentration and hence Fe uptake. In this study we aimed to quantify adsorption, and to determine to what extent adsorption depends on the complexed metal and on soil properties. Furthermore, we examined if adsorption is a reversible process. Methods: Adsorption and desorption of PS and metal-PS complexes were examined in batch experiments in which the PS 2′-deoxymugineic acid (DMA) and its metal-complexes (FeDMA, CuDMA, NiDMA and ZnDMA) interacted with several calcareous soils. Results: Adsorption of DMA ligand (0–1000 μM) and metal-DMA complexes (0–100 μM) was linear in the concentration range examined. Adsorption varied by a factor ≈2 depending on the complexed metal and by up to a factor 3.5 depending on the soil. Under field-like conditions (50 % water holding capacity), 50–84 % of the DMA was predicted to be retained to the soil solid phase. Alike adsorption, desorption of metal-DMA complexes is fast (approximate equilibrium within 1 hour). However, only a small fraction of the adsorbed FeDMA (28–35 %) could be desorbed. Conclusions: Despite this small fraction, the desorbed FeDMA still exceeded the amount in solution, indicating that desorption of FeDMA from soil reactive compounds can be an important process buffering the solution concentration

Diagnostic Performance of Urinary Resveratrol Metabolites as a Biomarker of Moderate Wine Consumption

Background: Nutritional biomarkers may be better measures of dietary exposure than self-reported dietary data. We evaluated resveratrol metabolites, potential biomarkers of wine consumption, in humans after moderate consumption of sparkling, white, or red wines. Methods: We performed 2 randomized, crossover trials and a cohort study. In the first study, 10 healthy men consumed 30 g of ethanol/day as sparkling wine or gin for 28 days. In the second trial, 10 healthy women consumed 20 g of ethanol/day as white or red wine for 28 days. We also evaluated 52 participants in a study on the effects of a Mediterranean diet on primary prevention of cardiovascular disease (the PREDIMED Study). We used liquid chromatography-tandem mass spectrometry to analyze urinary total resveratrol metabolites (TRMs) and predictive values and ROC curve analyses to assess the diagnostic accuracy. Results: We observed significant increases in TRMs [72.4 (95% confidence interval, 48.5-96.2; P = 0.005), 211.5 (166.6-256.3; P = 0.005), and 560.5 nmol/g creatinine (244.9-876.1; P = 0.005)] after consumption of sparkling, white, or red wine, respectively, but no changes after the washout or gin periods. In the cohort study, the reported daily dose of wine consumption correlated directly with TRMs (r = 0.654; P <0.001). Using a cutoff of 90 nmol/g, we were able to use TRMs to differentiate wine consumers from abstainers with a sensitivity of 72% (60%-84%); and a specificity of 94% (87%-100%). Conclusions: Resveratrol metabolites in urine may be useful biomarkers of wine intake in epidemiologic and intervention studies. 2006 American Association for Clinical Chemistry