Identification of novel small molecules that inhibit protein-protein interactions between MAGE and KAP-1

The Class I MAGE proteins are normally expressed only in developing germ cells but are often aberrantly expressed in malignancies, particularly melanoma, making them good therapeutic targets. MAGE proteins promote tumor survival by binding to the RBCC region of KAP-1 and suppressing p53. Although, suppression of MAGE expression, by RNA interference, relieves p53 suppression and inhibits tumor growth, its therapeutic uses are limited by lack of methods for systemic delivery of small interfering RNA. To overcome this barrier, we sought to discover chemical compounds that inhibit binding between MAGE and KAP-1 proteins. Based on previously published effects of MAGE suppression, we developed a strategy for screening a small molecule library based on selective death of MAGE positive cells, activation of p53 and lack of caspase activity. We screened the Maybridge HitFinder library of compounds and eight compounds fulfilled these criteria. Seven of these compounds interfered with co-precipitation of MAGE and KAP-1, and three interfered with binding of MAGE and KAP-1 in a mammalian two hybrid assay. We now report identification of three potential compounds that interfere with MAGE/KAP-1 binding and can be developed as novel chemo-therapeutic agents for treatment of advanced melanoma and other cancers.     

On photoprotective mechanisms of carotenoids in light harvesting complex

Carotenoids in light harvesting complex (LHC) play an important role in preventing plants photodamage caused by excess light. Non-photochemical quenching (NPQ) is an important mechanism adopted by plants to deal with high light intensity and the major component is referred to as energy dependent quenching (qE). Despite numerous studies have been devoted to investigating the site and mechanism of qE, there are still much debate on these topics. In this article, we discussed the possible site and underlying mechanism of qE based on the structural similarity of carotenoids. Moreover, being as good antioxidants, carotenoids’ potential protective effects against LHC photo-oxidation by quenching active oxygen species or triplet excited state chlorophyll are also discussed.     

Synthesis and characterization of cationic rhodium(I) dicarbonyl complexes

Treatment of Rh(acac)(CO)₂ (acac = acetoacetonate) with perchloric acid followed by addition of an α-diimine (α-diimine = 1,4-bis(Ar)-2,3-dimethyl-1,4-diaza-1,3-butadiene, Ar = 3,5-dimethylphenyl, 1; 3,5-di-tert-butylphenyl, 2; and 3,4,5-trimethoxyphenyl, 3; phenyl, 4; and 4-chlorophenyl, 5) generates a series of complexes of the type [Rh(α-diimine)(CO)₂][ClO₄] 6-10 with varying electronic properties of the supporting diimine ligand. X-ray crystal structures have been determined for the α-diimine ligands 1-5, and complexes 6, 8, and 10.     

Synthesis, characterization, fluorescence and computational studies of new Cu, Ni and Hg complexes with emissive thienylbenzoxazolyl-alanine ligands

The interaction of four fluorescent compounds containing thiophene and benzoxazole moieties combined with an alanine residue with alkaline, alkaline-earth, transition and post-transition metal ions was explored. The highly fluorescent heterocyclic alanine derivatives are strongly quenched in the solid state after complexation with the paramagnetic metal ions Cu²⁺ and Ni²⁺, and with the diamagnetic Hg²⁺. Absorption and steady-state fluorescence titrations reveal a selective interaction with Cu²⁺, Ni²⁺ and Hg²⁺. In all cases the formation of mononuclear or dinuclear metal complexes in solid state and in solution are postulated. DFT calculations on the mercury(II) complexes confirm the formation of dinuclear species. Our results suggest that one metal ion is coordinated by the chelate group formed by the amine and the protonated carboxylic groups present in the amino acid residue while a second metal ion is directly linked to the chromophore. As parent compound, L4 shows no interaction with Cu²⁺ and Ni²⁺ salts. However, the interaction with Hg²⁺ induces a strong quenching and a red shift of the fluorescence emission.     

Niobium-substituted arsenotungstates: Controllable transformation between monomers and tetramer

Three niobium-containing arsenotungstates have been synthesized for the first time: peroxoniobium-containing Cs₅K[AsW₉(NbO₂)₃O₃₇]·7H₂O (1), peroxo-free Cs_5.5Na_0.5[AsW₉Nb₃O₄₀]·17H₂O (2), and tetramer Cs₁₀K₃H₃[As₄W₃₆Nb₁₆O₁₆₆]·28H₂O (3). Both monomers 1 and 2 can assemble into tetramer 3 in acidic conditions, and 3 can transform to 1 or 2 by adding H₂O₂ or adjusting the pH value. Comparing the Nb-containing POM systems of A-α-XW₉ (X = Si, Ge, As), although they are different only in heteroatoms, there are remarkable differences in reaction conditions and reactivity. The ¹⁸³W NMR spectra of 1, the UV-Vis spectra of 1-2 along with the IR spectra and thermal stability of 1-3 have been studied and compared with their Ge or Si analogs. The electrochemical properties of 1-3 have also been investigated and the cyclic voltammograms of 3 indicate good electrocatalytic activity towards the reduction of nitrite.     

Synthesis and supramolecular structures of iso- and heteropolymetallates assisted by organoamino phosphonium cations

Polyoxometallate (POM) clusters represent an interesting choice of building blocks for the construction of inorganic-organic hybrid materials. The supramolecular aggregation of several iso- and heteropolymetallate anions in presence of various organoamino phosphonium cations is described. The phosphonium POM salts 4-8 were prepared by the reaction of [P(NHR)₄]Cl {1 (R = cyclohexyl), 2 (R = iso-butyl) and 3 (R = iso-propyl)} with Na₂MoO₄·2H₂O/Na₂WO₄·2H₂O. The compound 9, [P(NHCy)₄]₃[AsMo₁₂O₄₀], was prepared in a three component reaction involving 1, Na₂MoO₄·2H₂O and Na₂HAsO₄. Formation of the Keggin clusters in 7 and 8 was achieved by a facile P-N bond cleavage of 3 under the acidic conditions of the reaction. X-ray structure analyses of the title compounds show an interesting range of hydrogen bonded supramolecular structures with topologies resembling from 2D-sheets to 3D-networks.     

A pyridine adduct of bis(di-iso-butyldithiocarbamato-S,S′)cadmium(II): Multinuclear (C, N, Cd) CP/MAS NMR spectroscopy, crystal and molecular structure, and thermal behaviour

Crystalline bis(N,N-di-iso-butyldithiocarbamato-S,S′)(pyridine)cadmium(II) - adduct 1 was prepared and studied by means of multinuclear ¹³C, ¹⁵N, ¹¹³Cd CP/MAS NMR spectroscopy, single-crystal X-ray diffraction and simultaneous thermal analysis (STA). In molecular structure 1, the cadmium atom coordinates with four sulphur atoms and one nitrogen atom of pyridine, forming a coordination polyhedron [CdS₄N], whose geometry is an almost ideal tetragonal pyramidal (C_4v). The coordinated py molecule is in the apical position, while two structurally non-equivalent di-iso-butyldithiocarbamate ligands, playing the same terminal S,S′-chelating function, define the basal plane. To characterise additionally the structural state of the cadmium atom in this fivefold coordination, ¹¹³Cd chemical shift anisotropy (CSA) parameters, δ_aniso and η, were calculated from experimental MAS NMR spectra that revealed an almost axially symmetric ¹¹³Cd chemical shift tensor. From a combination of TG and DSC measurements taken under an argon atmosphere, we found that the mass of adduct 1 is lost in two steps involving initial desorption of coordinated py molecules with subsequent thermal destruction of liberated cadmium(II) di-iso-butyldithiocarbamate, with yellow-orange, fine-powdered solid CdS as the final product.     

Perinatal supplementation with thymoquinone improves diabetic complications and T cell immune responses in rat offspring

Background

Epidemiological studies have shown that the offspring of mothers who experience diabetes mellitus during pregnancy are seven times more likely to develop health complications later in life compared to offspring born to nondiabetic mothers.

Aim of the study

We investigated whether supplementation with a natural antioxidant (thymoquinone; TQ) in female rats with streptozotocin (STZ)-induced gestational diabetes (GD) improved diabetic complications and T cell immune responses in their offspring.

Methods

Three groups of female rats were tested: nondiabetics, diabetics treated with TQ during pregnancy and lactation periods and diabetics that were not treated with TQ (n = 10 female rats in each group).

Results

Our data demonstrated a significant decrease in the numbers of neonates born to diabetic rats compared with those born to control rats. GD led to macrosomic pups with several postpartum complications, such as a significant increase in plasma levels of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α (but not of IL-10); a marked decrease in the plasma level of IL-2; a marked reduction in the proliferative capacity of superantigen (SEB)-stimulated T-lymphocytes; and an obvious reduction in the number of circulating and thymus homing T cells. TQ supplementation of diabetic mothers during pregnancy and lactation periods had an obvious and significant effect on the number and mean body weight of neonates. Furthermore, TQ significantly restored the IL-2 level and T cell proliferation and subsequently rescued both circulating and thymus homing T cells in the offspring.

Conclusions

Our data suggest that nutritional supplementation of GD mothers with the natural antioxidant TQ during pregnancy and lactation periods improves diabetic complications and maintains an efficient T cell immune response in their offspring, providing a protective effect in later life.     

Beneficial role of naringin, a flavanoid on nickel induced nephrotoxicity in rats

This study was conducted to investigate the beneficial role of naringin on nickel induced nephrotoxicity. Nickel (Ni) (20 mg/kg body weight (b.w.) was administered intraperitoneally (i.p.) for 20 days. Naringin was administered orally (20, 40 and 80 mg/kg b.w.) with i.p. administration of Ni. Ni administration increased the levels of serum urea, uric acid and creatinine with a significant decrease in creatinine clearance and decreased levels of urea, uric acid and creatinine in urine. The levels of lipid peroxidation markers and nickel concentration in blood and kidney were also increased. While, the activities of enzymic and non-enzymic antioxidants were decreased. Treatment with naringin attenuated the alterations in the renal and urine markers, decreasing lipid peroxidation markers, increasing the antioxidant cascade and decreasing the nickel concentration in blood and kidney. All these changes were supported by histopathological observations. These findings demonstrate that naringin exerts a protective effect against nickel toxicity.     

Reduced glutathione content in human sperm is decreased after cryopreservation: Effect of the addition of reduced glutathione to the freezing and thawing extenders

In this study, total glutathione content was determined in human spermatozoa before and after cryopreservation. Total GSH in fresh semen was 4.47 ± 0.46 nmol/10⁸ cells. Following semen cryopreservation, GSH decreased to 1.62 ± 0.13 nmol/10⁸ cells, a 64% reduction (p < 0.01). This decrease in GSH content was associated with a decrease in sperm progressive motility (68% of reduction, p < 0.01). Addition of 1 mM GSH to the freezing extender increased the percentage of total motility and sperm viability. It also modified the motility pattern measured by CASA with changes in the straight-line and average path velocities and wobble of the curvilinear trajectory. Addition of GSH to the freezing media reduced spermatozoa ROS levels and increased the level of sulfhydryl groups on membrane proteins. Nevertheless, no effect of GSH addition on lipid membrane disorder or chromatin condensation was detected. Addition of 1 or 5 mM GSH to the thawing media increased the percentage of motile and progressively motile spermatozoa, but no effect on viability was detected. In conclusion, the antioxidant defensive capacity of the GSH is severely altered by the freeze–thawing process. The addition of GSH to the freezing and thawing extender could be of partial and limited benefit in improving the function of frozen human spermatozoa.