Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205: Towards tetraoxane scaffolds with potential for single dose cure of malaria

A series of aryl carboxamide and benzylamino dispiro 1,2,4,5-tetraoxane analogues have been designed and synthesized in a short synthetic sequence from readily available starting materials. From this series of endoperoxides, molecules with in vitro IC50s versus Plasmodium falciparum (3D7) as low as 0.84?nM were identified. Based on an assessment of blood stability and in vitro microsomal stability, N205 (10a) was selected for rodent pharmacokinetic and in vivo antimalarial efficacy studies in the mouse Plasmodium berghei and Plasmodium falciparum Pf3D70087/N9 severe combined immunodeficiency (SCID) mouse models. The results indicate that the 4-benzylamino derivatives have excellent profiles with a representative of this series, N205, an excellent starting point for further lead optimization studies.     

Bioavailability and dosing strategies of mineral in anaerobic mono‐digestion of maize straw

The influence of the bonding form distribution of Fe, Ni, Co and Mn and their potential bioavailability during the anaerobic degradation of maize straw was investigated. Two reactors were operated over 117 days at 37°C and different dosage strategies of mineral were studied in reactor (R2). Control reactor (R1) was metal‐limited over time. mineral supplementation (1 g L^?1) once a week reported the highest methane yield (257 mL g^?1 VS) with 30% of increment. Ni and Co predominated in their oxidizable bonding forms and Fe mainly existed as residual and oxidizable fractions. The potential bioavailability (Mn ?? Co ≈ Ni ? Fe) of R2 was higher comparing to R1. Metal deprivation in R1 led to depletion of both sequential extraction fractions and total metal concentrations until the end of the process. This study confirmed that the dosage strategy of mineral has a stimulatory effect on methane production from crop maize waste.     

An improved understanding of soil Cd risk to humans and low cost methods to phytoextract Cd from contaminated soils to prevent soil Cd risks

We believe greater consideration should be given the agronomic and nutritional/bioavailability factors that influence risk from Cd-contaminated soils. We have argued that the ability of rice to accumulate soil Cd in grain while excluding Fe, Zn and Ca (even though the soil contains 100-times more Zn than Cd) was important in adverse effects of soil Cd is farm families in Asia. Further, polished rice grain is deficient in Fe, Zn and Ca for humans, which promotes Cd absorption into duodenal cells. New kinetic studies clarified that dietary Cd is absorbed into duodenum enterocytes; 109Cd from a single meal remained in the duodenum for up to 16 days; part of the turnover pool 109Cd moved to the liver and kidneys by the end of the 64-day 'chase' period. Thus malnutrition induced by subsistence rice diets caused a higher absorption of dietary Cd and much higher potential risk from soil Cd than other crops. Because rice-induced Fe-Zn-Ca-malnutrition is so important in soil Cd risk, it seems evident that providing nutritional supplements to populations of exposed subsistence rice farmers could protect them against soil Cd during a period of soil remediation. In the long term, high Cd rice soils need to be remediated. Remediation by removal and replacement of contaminated soil is very expensive (on the order of $3 million/ha); while phytoextraction using the high Cd accumulating ecotypes of the Zn-Cd hyperaccumulator, Thlaspi caerulescens, should provide low cost soil Cd remediation.     

Microbial Factors Rather Than Bioavailability Limit the Rate and Extent of PAH Biodegradation in Aged Crude Oil Contaminated Model Soils

The rate and extent of polynuclear aromatic hydrocarbons (PAH) biodegradation in a set of aged model soils that had been contaminated with crude oil at the high concentrations (i.e.,>20,000?mg/kg) normally found in the environment were measured in 90-week slurry bioremediation experiments. Soil properties such as organic matter content, mineral type, particle diameter, surface area, and porosity did not significantly influence the PAH biodegradation kinetics among the 10 different model soils. A comparison of aged and freshly spiked soils indicates that aging affects the biodegradation rate and extent only for higher-molecular-weight PAHs, while the effects of aging are insignificant for 4-ring PAHs and total PAHs. In all model soils with the exception of kaolinite clay, the rate of abiotic desorption was faster than the rate of biodegradation during the initial phase of bioremediation treatment, indicating that PAH biodegradation was limited by microbial factors. Similarly, any of the higher-molecular-weight PAHs that were still present after 90 weeks of treatment were released rapidly during abiotic desorption tests, which demonstrates that bioavailability limitations were not responsible for the recalcitrance of these hydrocarbons. Indeed, an analysis of microbial counts indicates that a severe reduction in hydrocarbon degrader populations may be responsible for the observed incomplete PAH biodegradation. Therefore, it can be concluded that the recalcitrance of PAHs during bioremediation is not necessarily due to bioavailability limitations and that these residual contaminants therefore might pose a greater risk to environmental receptors than previously thought.     

Characterization of the antioxidant activity of aglycone and glycosylated derivatives of hesperetin: an in vitro and in vivo study

The flavonoids are mainly present in Citrus fruits as their glycosyl derivatives. This study was conducted comparing in vitro xanthine oxidase inhibitory activity of the aglycone hesperetin and its glycosylated forms (hesperidin and G‐hesperidin) and their effects on the plasma lipid profile and the oxidative–antioxidative system (TBARS and antioxidant enzymes) in rats. The concentrations of the major conjugated metabolites in rat plasma after oral administration of these compounds were also determined. Wistar male rats were randomly assigned to three groups (n = 6) supplemented for 30 days with 1 mmol/kg body mass of hesperetin, hesperidin or G‐hesperidin. Hesperetin was a stronger xanthine oxidase inhibitor (IC₅₀ = 53 μM and K_i = 17.3 μM) than the glycosylate derivatives. Supplementation with the three compounds led to a lower (more favorable) atherogenic index, and an antioxidant preventive effect from the increase of hepatic superoxide dismutase was observed associated to HT supplementation, possibly because of the higher level of hesperetin‐glucuronide in rat plasma. Copyright © 2015 John Wiley & Sons, Ltd.     

Root-induced modifications of the exchange of phosphate ion between soil solution and soil solid phase

The uptake of phosphorus (P) by roots results in a depletion of phosphate ions (PO₄) in the rhizosphere. The corresponding decrease in PO₄ concentration in the soil solution (C_P) gives rise to a replenishment of P from the solid phase which is time- and C_P-dependent. This PO₄ exchange which reflects the buffer power of the soil for PO₄ also varies with the composition and the physico-chemical conditions of the soil. As root activity can modify these physico-chemical conditions in the rhizosphere, the question arises whether these modifications affect the ability of PO₄ bound to the soil solid phase to exchange with PO₄ in soil solution. The aim of the present work was to measure and compare the parameters which describe the amount of PO₄ bound to soil solid phase that is capable to replenish solution P for both rhizosphere and bulk soils. The soil sample was a P-enriched, calcareous topsoil collected from a long-term fertiliser trial. Rhizosphere soil samples were obtained by growing dense mats of roots at the surface of 3 mm thick soil layer for one week. Three plant species were compared: oilseed rape (Brassica napus L., cv Goeland) pea (Pisum sativum L., cv. Solara) and maize ( Zea mays L., cv. Volga). The time- and C_P-dependence of the PO₄ exchange from soil to solution were described using an isotopic dilution method. The measured C_P values were 0.165 mg P L⁻¹ for bulk soil and 0.111, 0.101 and 0.081 mg P L⁻¹ for rhizosphere soils of maize, pea and rape, respectively. The kinetics of the PO₄ exchange between liquid and solid phases of soil were significantly different between rhizosphere and bulk soils. However, when changes in C_P were accounted for, the parameters describing the PO₄ exchange with time and C_P between soil solution and soil solid phase were found to be very close for bulk and rhizosphere soils. For this calcareous and P-enriched soil, plant species differed in their ability to deplete PO₄ in solution. The resulting changes in the ability of the soil solid phase to replenish solution PO₄ were almost fully explained by the depletion of soil solution P. This revised version was published online in June 2006 with corrections to the Cover Date.     

Two-liquid-phase bioreactors for enhanced degradation of hydrophobic/toxic compounds

Two-liquid-phase culture systems involve the addition of a water-immiscible, biocompatible and non-biodegradable solvent to enhance a biocatalytic process. Two-liquid-phase bioreactors have been used since the mid-seventies for the microbial and enzymatic bioconversion of hydrophobic/toxic substrates into products of commercial interest. The increasing popularity of bioremediation technologies suggests a new area of application for this type of bioreactor. The toxicity and the limited bioavailability of many pollutants are important obstacles that must first be overcome in order to improve biodegradation processes. Two-liquid-phase bioreactors have the potential to resolve both limitations of biotreatment technologies by the enhancement of the mass-transfer rate of compounds with low bioavailability, and by the controlled delivery of apolar toxic compounds. This technology can also be useful in accelerating the enrichment of microorganisms degrading problematic pollutants. In this paper, we discuss the application of two-liquid-phase bioreactors to enhance the biodegradation of toxic/poorly bioavailable contaminants. Important microbial mechanisms involved in this type of system are described. Uptake of the substrates can be achieved by microorganisms freely dispersed in the aqueous phase and/or bound at the interface between the aqueous and the immiscible phases. Production of surface-active compounds and adhesion abilities are microbial features involved in the process. General guidelines for the design of two-liquid-phase bioreactors for biodegradation purposes are presented. Solvent selection should be established on specific criteria, which depend on the characteristics of target compound(s) and the microorganism(s) implicated in the biodegradation process. The central importance of maximizing the interfacial surface area is highlighted. The potential of this approach as an alternative to current biotreatment technologies is also discussed.     

Potent antiobesity effect of a short-length peptide YY-analogue continuously administered in mice

The gastrointestinal peptide, peptide YY_3–36 (PYY_3–36) and its shorter peptide analogues have been reported to reduce appetite by activating the neuropeptide Y2 receptor (Y2R), which is associated with obesity and other metabolic diseases. A 14-amino acid PYY analogue, Ac-[d-Pro²⁴,Cha^27,28,36,Aib³¹]PYY(23–36) (3), showed high binding affinity and agonist activity for the Y2R, similar to that of PYY_3–36, but had weak anorectic activity upon continuous administration in lean mice. Three amino acid substitutions [Pya(4)²⁶, Aib²⁸, Lys³⁰], which contributed to the decreased hydrophobicity of 3, efficiently increased its anorectic activity. The compound containing these three amino acids, Ac-[d-Pro²⁴,Pya(4)²⁶,Cha^27,36,Aib^28,31,Lys³⁰]PYY(23–36) (22), exerted more potent and durable food intake suppression than that by PYY_3–36 in lean mice, as well as excellent Y2R agonist activity (EC₅₀: 0.20 nM) and good subcutaneous bioavailability (66.6%). The 11-day continuous administration of 22 at 1 mg/kg/day successfully produced antiobese and antidiabetic effects, with more than 20% body weight loss in obese and Type 2 diabetes ob/ob model mice.     

Changes in Hg fractionation in soil induced by willow

This study investigated the effect of willow (Salix viminalis ×  S. schwerinii) on soil characteristics, including changes in Hg fractionation in the soil solid phase, and Hg accumulation and distribution in pot-grown plants cultivated for 32 and 76 days in aged Hg-contaminated soil (30 mg Hg kg⁻¹DW). Changes in soil pH and organic carbon content as well as in Hg fractionation were monitored in both rhizospheric soil and in soil without plants. Mercury fractionation was performed by a 5-step sequential soil extraction procedure. Organic carbon content increased while pH decreased in the rhizospheric soil. Both chemically defined exchangeable Hg (0.1) and Hg bound to humic and fulvic acids (1.1) decreased in the rhizospheric soil, whereas plant accumulation of Hg increased with cultivation time. The sum of the decrease of these two soil Hg fractions after 76 days of cultivation was approximately equal to the amount of Hg accumulated in plants. Furthermore, the major Hg fractions (Hg bound to residual organic matter (53), sulphides (43), and the residual fraction (2.5)) remained stable. Neither whole plant accumulation of Hg from the soil, approximately 0.2 of total Hg in soil after 76 days cultivation, nor the fraction of total plant Hg in the shoots, which accounted for about 3 of the total plant Hg pool regardless of the cultivation time, were high. The overall results suggest that plants might be suitable for phytostabilization of aged Hg-contaminated soil, where root systems trap bioavailable Hg and help to control both leaching of Hg and re-entrainment of Hg-containing particulates from a contaminated site.     

Relevance of Rhizosphere Research to the Ecological Risk Assessment of Trace Metals in Soils

The chemical, mineralogical, and microbial properties of the rhizosphere of a range of forested ecosystems were studied to identify the key processes controlling the distribution and fate of trace metals at the soil–root interface. The results of our research indicate that: (1) the rhizosphere is a soil microenvironment where properties (e.g., pH, organic matter, microbes) and processes (nutrient and water absorption, exudation) differ markedly from those of the adjacent bulk soil; (2) the rhizosphere is a corrosive medium where the weathering and neoformation of soil solid phases are enhanced; (3) the concentrations of solid-phase and water-soluble trace metals like Cd, Cu, Ni, Pb, and Zn are generally higher in the rhizosphere as shown by both macroscopic and microscopic approaches; (4) a larger fraction of water-soluble metals is complexed by dissolved organic substances in the rhizosphere; and (5) soil microorganisms play, either directly or indirectly, a distinct role on metal speciation, in particular Cu and Zn, in the rhizosphere. These results improve our capacity to estimate metal speciation and bioavailability at the soil–root interface. Furthermore, the research emphasizes the crucial physical position occupied by the rhizosphere with respect to the process of elemental uptake by plants and its key functional role in the transfer of trace metals along the food chain. We conclude that the properties and processes of the rhizosphere should be viewed as key components of assessments of the ecological risks associated with the presence of trace metals in soils.