Bioavailability and biotransformation of sulforaphane and erucin metabolites in different biological matrices determined by LC–MS–MS

The food-related isothiocyanate sulforaphane (SFN), a hydrolysis product of the secondary plant metabolite glucoraphanin, has been revealed to have cancer-preventive activity in experimental animals. However, these studies have often provided inconsistent results with regard to bioavailability, bioaccessibility, and outcome. This might be because the endogenous biotransformation of SFN metabolites to the structurally related erucin (ERN) metabolites has often not been taken into account. In this work, a fully validated liquid chromatography tandem mass spectrometry (LC–MS–MS) method was developed for the simultaneous determination of SFN and ERN metabolites in a variety of biological matrices. To reveal the importance of the biotransformation pathway, matrices including plasma, urine, liver, and kidney samples from mice and cell lysates derived from colon-cancer cell lines were included in this study. The LC–MS–MS method provides limits of detection from 1 nmol L^?1 to 25 nmol L^?1 and a mean recovery of 99 %. The intra and interday imprecision values are in the range 1–10 % and 2–13 %, respectively. Using LC–MS–MS, SFN and ERN metabolites were quantified in different matrices. The assay was successfully used to determine the biotransformation in all biological samples mentioned above. For a comprehensive analysis and evaluation of the potential health effects of SFN, it is necessary to consider all metabolites, including those formed by biotransformation of SFN to ERN and vice versa. Therefore, a sensitive and robust LC–MS–MS method was validated for the simultaneous quantification of mercapturic-acid-pathway metabolites of SFN and ERN.

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Graphical Abstract Biotransformation of sulforaphane and erucin metabolites in mice and cell culture

     

The Lagrange spectrum of some square-tiled surfaces

Lagrange spectra have been defined for closed submanifolds of the moduli space of translation surfaces which are invariant under the action of SL(2, R). We consider the closed orbit generated by a specific covering of degree 7 of the standard torus, which is an element of the stratum H(2). We give an explicit formula for the values in the spectrum, in terms of a cocycle over the classical continued fraction. Differently from the classical case of the modular surface, where the lowest part of the Lagrange spectrum is discrete, we find an isolated minimum, and a set with a rich structure right above it.     

Robust flows over time: models and complexity results

Mathematical Programming - The problem of finding a zero of the sum of two maximally monotone operators is of central importance in optimization. One successful method to find such a zero is the...     

Distinct methylalumoxane(MAO)-derived Me-MAO- anions in contact with a zirconocenium cation--a 13C-NMR study

Zirconocenium cations of the type [(MeC5H4)2ZrMe]+, formed by excess methylalumoxane (MAO) from (MeC5H4)2ZrCl2 or (MeC5H4)2ZrMe2 with 13C-labelled ring ligands, are found to form ion pairs with two types of anions, Me-MAO(A)- and Me-MAO(B)-, which differ in their coordinative strengths: More strongly coherent ion pairs [(MeC5H4)2ZrMe+...Me-MAO(B)-] are converted to more easily separable ion pairs [(MeC5H4)2ZrMe+...Me-MAO(A)-] by a sufficient excess of MAO. These react with Al2Me6 to form outer-sphere ion pairs containing the cationic AlMe3 adduct [(MeC5H4)2Zr(mu-Me)2AlMe2]+; formation of the more easily separable ion pairs might be required also for polymerisation catalysis.     

Copper-mediated regio- and stereoselective 12β-hydroxylation of steroids with molecular oxygen and an unexpected 12β-chlorination

It is shown, that copper(I) complexes of 17-(2-iminomethyl)pyridino steroids (17-IMPY steroids) can react with molecular oxygen followed by a regio- and stereoselective γ-hydroxylation in 12β-position. After decomplexation and hydrolysis of the IMPY group 12β-hydroxy-17-ketones are available in practical useful yields. IMPY compounds are simple to prepare by condensation of oxo compounds with (2-aminomethyl)pyridine. In the cases of 17-IMPY steroids the yields in the hydroxylation procedure of an unactivated CH₂ group are higher by starting with copper(II) complexes, reduction with benzoin/triethylamine in acetone and reaction with molecular oxygen in comparison to the direct reaction of copper(I) complexes with molecular oxygen in acetone. Employing the procedure in dichloromethane as solvent starting with copper(II) complexes surprisingly the 12β-chloro compound could be isolated next to the hydroxylation product. This regio- and stereoselective γ-chlorination takes place also in acetone, when triethylammonium chloride is added to the reaction mixture. Oxygen is necessary for this reaction. The mechanistic and stereochemical aspects of these new reactions are discussed. Comparison of the different yields of steroids with different A-ring [3-methoxy-estra-1,3,5(10)-triene and 3β-hydroxy-androst-5-ene] pointed out to a subtle influence of the molecular structure far from the reaction centre on these reactions. The successful hydroxylation of the IMPY derivative of 3β-hydroxy-androst-5-ene-17-one shows the tolerance of a homoallylic system against this oxidation procedure. By Oppenauer oxidation 12β-hydroxy-androst-4-ene-3,17-dione is available. The hydroxylation procedure opens a short way to 12β-hydroxy-17-oxo steroids, which are difficult to obtain by other routes.     

Speciation analysis of arsenic in groundwater from Inner Mongolia with an emphasis on acid-leachable particulate arsenic

Arsenic in drinking water affects millions of people around the world. While soluble arsenic is commonly measured, the amount of particulate arsenic in drinking water has often been overlooked. We report here determination of the acid-leachable particulate arsenic and soluble arsenicals in well water from an arsenic-poisoning endemic area in Inner Mongolia, China. Water samples (583) were collected from 120 wells in Ba Men, Inner Mongolia, where well water was the primary drinking water source. Two methods were demonstrated for the determination of soluble arsenic species (primarily inorganic arsenate and arsenite) and total particulate arsenic. The first method used solid phase extraction cartridges and membrane filters to separate arsenic species on-site, followed by analysis of the individual arsenic species eluted from the cartridges and filters. The other method uses liquid chromatography separation with hydride generation atomic fluorescence detection to determine soluble arsenic species. Analysis of acidified water samples using inductively coupled plasma mass spectrometry provided the total arsenic concentration. Arsenic concentrations in water samples from the 120 wells ranged from <1 to ∼1000 μg L⁻¹. On average, particulate arsenic accounted for 39 ± 38% (median 36%) of the total arsenic. In some wells, particulate arsenic was six times higher than the soluble arsenic concentration. Particulate arsenic can be effectively removed using membrane filtration. The information on particulate and soluble arsenic in water is useful for optimizing treatment options and for understanding the geochemical behavior of arsenic in groundwater.     

Zur Dimorphie von Nd3Cl[SiO4]2

On the Dimorphism of Nd₃Cl[SiO₄]₂ On reacting NdCl₃, Nd₂O₃, and SiO₂ (molar ratio: 1 : 4 : 6) at 850 °C in evacuated silica tubes, pale violet, hydrolysis resistant neodymium(III) chloride ortho‐silicate Nd₃Cl[SiO₄]₂ can be obtained within seven days. If equimolar amounts of NaCl are added as flux, rod‐ or platelet‐shaped, transparent single crystals of two modifications accumulate simultaneously. The one with the higher density (A‐Nd₃Cl[SiO₄]₂) crystallizes monoclinically (C2/c, no. 15; a = 1416.6(1), b = 638.79(6), c = 872.21(9) pm, β = 98.403(7)°; V_m = 117.55 cm³/mol, Z = 4), whereas the one with the lower density (B‐Nd₃Cl[SiO₄]₂) exhibits orthorhombic symmetry (Pnma, no. 62; a = 709.36(7), b = 1815.7(2), c = 631.48(6) pm; V_m = 122.45 cm³/mol, Z = 4). Two crystallographically independent Nd³⁺ cations exist in each of both crystal structures, which in the A type are surrounded by nine (1 Cl^– + 8 O^2–) and ten (2 Cl^– + 8 O^2–), whilst those in the B type by only two times eight (1 Cl^– + 7 O^2– and 2 Cl^– + 6 O^2–) anions, respectively. Thereby all oxygen atoms of both forms represent members of discrete ortho‐silicate tetrahedra ([SiO₄]^4–). Although both crystal structures are built of alternating anionic double layers {(Nd1)₂[SiO₄]₂}^2– and cationic single layers {(Nd2)Cl}²⁺, there is a higher cross‐linkage of the building units in the A‐type lattice, where the cations are coordinated by three and four tetrahedra edges of ortho‐silicate anions, compared to only two times two of them in the B type. From this an about 4% higher density of Nd₃Cl[SiO₄]₂ results for the A‐type structure (D_x = 5.55 g/cm³) in comparison with B‐type Nd₃Cl[SiO₄]₂ (D_x = 5.33 g/cm³).     

Epigenetic Anti-Cancer Treatment With a Stabilized Carbocyclic Decitabine Analogue

5-Aza-2’-deoxycytidine (Decitabine, AzadC) is a nucleoside analogue, which is in clinical use to treat patients with myelodysplastic syndrome or acute myeloid leukemia. Its mode of action is unusual because the compound is one of the few drugs that act at the epigenetic level of the genetic code. AzadC is incorporated as an antimetabolite into the genome and creates covalent, inhibitory links to DNA methyltransferases (DNMTs) that methylate 2’-deoxycytidine (dC) to 5-methyl-dC (mdC). Consequently, AzadC treatment leads to a global loss of mdC, which presumably results in a reactivation of silenced genes, among them tumor suppressor and DNA damage response genes. Because AzadC suffers from severe instability, which limits its use in the clinic, a more sophisticated AzadC derivative would be highly valuable. Here, we report that a recently developed carbocyclic AzadC analogue (cAzadC) blocks DNMT1 in the AML cell line MOLM-13 as efficient as AzadC. Moreover, cAzadC has a surprisingly strong anti-proliferative effect and leads to a significantly higher number of double strand breaks compared to AzadC, while showing less off-target toxicity. These results show that cAzadC triggers more deleterious repair and apoptotic pathways in cancer cells than AzadC, which makes cAzadC a promising next generation epigenetic drug.