Copper(II), cobalt(II) and nickel(II) complexes of lapachol: synthesis,DNA interaction,and cytotoxicity

Three novel copper(II), cobalt(II), and nickel(II) complexes of lapachol (Lap) containing 110-phenanthroline (phen) ligand, [M(Lap)₂(phen)] (M=Cu(II), 1, Co(II), 2, and Ni(II), 3), have been synthesized and characterized using, elemental analysis and spectroscopic studies. Their interactions with calf thymus DNA (CT DNA) were investigated using viscosity, thermal denaturation, circular dichorism, fluorescence quenching, and electronic absorption spectroscopy. The DNA cleavage abilities of 1–3 have been studied, where cleavage activity of copper complex 1 is more than the complexes 2 and 3. The in vitro cytotoxic potential of the complexes 1–3 against human cervical carcinoma (HeLa), human liver hepatocellular carcinoma (HepG-2), and human colorectal adenocarcinoma (HT-29) cells indicated their promising antitumor activity with quite low IC₅₀ values in the range of .15–2.41 μM, which are lower than those of cisplatin.     

1,3-Dipropyl-8-(1-phenylacetamide-1H-pyrazol-3-yl)-xanthine derivatives as highly potent and selective human A(2B) adenosine receptor antagonists

A new series of 1,3-dipropyl-8-(1-phenylacetamide-1H-pyrazol-3-yl)-xanthine derivatives has been identified as potent A(2B) adenosine receptor antagonists. The products have been evaluated for their binding affinities for the human A(2B), A(1), A(2A), and A(3) adenosine receptors. N-(4-chloro-phenyl)-2-[3-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-5-methyl-pyrazol-1-yl] (11c) showed a high affinity for the human A(2B) adenosine receptor K(i)=7nM and good selectivity (A(1), A(2A), A(3)/A(2B)>140). Synthesis and SAR of this novel class of compounds is presented herein.     

RANTES gene mRNA expression and its -403 G/A promoter polymorphism in coronary artery disease

Objective

Increased RANTES expression has been described to have a role in atherosclerosis plaque formation. Functional polymorphisms within RANTES promoter region have shown association with increased risk of coronary atherosclerosis (CAD). The aim of this study was to examine the RANTES mRNA expression in patients with CAD compared to patients without CAD and its association with RANTES − 403 G/A polymorphism in an Iranian population.

Methods

The study was performed on 319 patients who underwent coronary artery angiography and patients with > 50% stenosis in vessels considered as case groups (CAD+) N = 191 and normal vessels group as control (CAD−) N = 128. In each group 20 patients were examined for RANTES mRNA expression.RANTES mRNA expression was examined using quantitative real-time PCR. Genotyping of − 403 polymorphism was performed using PCR-RFLP technique.

Results

We found that RANTES mRNA expression was increased to 1.37 fold in CAD patients compared to the controls but the difference was not statistically significant. Also comparing the RANTES mRNA expression in patients with different RANTES − 403 G/A polymorphism showed that in patients carrying AA genotype RANTES mRNA expression was increased to 1.74 fold compared to patients carrying GG genotype and to 1.51 fold compared to patients carrying GA genotype. No significant difference for allele and genotype frequencies of RANTES − 403 polymorphism was found between cases and controls.

Conclusion

More studies on larger number of samples are required to further evaluate role of RANTES in pathogenesis of CAD.     

Mathematical model ofLaminaria production near a British Columbian salmon sea cage farm

The technical and economical feasibility of farmingLaminaria saccharina for a food base product near a salmon sea cage farm was evaluated. Suitability of kelp for nutrient removal was also analyzed. A computer model of a conceptualized system was developed in order to make the assessments. Kelp growth was modelled as a linear function of temperature and background dissolved inorganic nitrogen concentration, and it was partially experimentally validated. Based on model simulations, aLaminaria farm containing 10,60 m ropes on each end of a salmon sea cage farm is fertilized by the salmon farm and yields annually 1600 kg of dried kelp. The payback period for the initial investment of $61 × 10³ is 6 years after which an annual net profit of 20 × 10³ Canadian dollars ($16.68 × 10³ US) can be achieved. The net present worth of the kelp farm was positive for a rate of return up to 25%. Kelp production on multiple salmon farms or at a higher kelp density could increase the overall revenue.The kelp farm does not appreciably affect background nutrient or oxygen levels. With a few modifications in the model,Nereocystis andMacrocystis farming can be substituted and evaluated for feasibility and nutrient removal efficiency.     

In silico and in vitro effects of the I30T mutation on myelin protein zero instability in the cell membrane

Charcot‐Marie‐Tooth (CMT) diseases are a heterogeneous group of genetic peripheral neuropathies caused by mutations in a variety of genes, which are involved in the development and maintenance of peripheral nerves. Myelin protein zero (MPZ) is expressed by Schwann cells, and MPZ mutations can lead to primarily demyelinating polyneuropathies including CMT type 1B. Different mutations demonstrate various forms of disease pathomechanisms, which may be beneficial in understanding the disease cellular pathology. Our molecular dynamics simulation study on the possible impacts of I30T mutation on the MPZ protein structure suggested a higher hydrophobicity and thus lower stability in the membranous structures. A study was also conducted to predict native/mutant MPZ interactions. To validate the results of the simulation study, the native and mutant forms of the MPZ protein were separately expressed in a cellular model, and the protein trafficking was chased down in a time course pattern. In vitro studies provided more evidence on the instability of the MPZ protein due to the mutation. In this study, qualitative and quantitative approaches were adopted to confirm the instability of mutant MPZ in cellular membranes.     

Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1.

SHP-1 is an SH2-containing cytoplasmic tyrosine phosphatase that is widely distributed in cells of the hematopoietic system. SHP-1 plays an important role in the signal transduction of many cytokine receptors, including the receptor for erythropoietin, by associating via its SH2 domains to the receptors and dephosphorylating key substrates. Recent studies have suggested that SHP-1 regulates the function of Jak family tyrosine kinases, as shown by its constitutive association with the Tyk2 kinase and the hyperphosphorylation of Jak kinases in the motheaten cells that lack functional SHP-1. We have examined the interactions of SHP-1 with two tyrosine kinases activated during engagement of the erythropoietin receptor, the Janus family kinase Jak-2 and the c-fps/fes kinase. Immunoblotting studies with extracts from mouse hematopoietic cells demonstrated that Jak2, but not c-fes, was present in anti-SHP-1 immunoprecipitates, suggesting that SHP-1 selectively associates with Jak2 in vivo. Consistent with this, when SHP-1 was coexpressed with these kinases in Cos-7 cells, it associated with and dephosphorylated Jak2 but not c-fes. Transient cotransfection of truncated forms of SHP-1 with Jak2 demonstrated that the SHP-1-Jak2 interaction is direct and is mediated by a novel binding activity present in the N terminus of SHP-1, independently of SH2 domain-phosphotyrosine interaction. Such SHP-1-Jak2 interaction resulted in induction of the enzymatic activity of the phosphatase in in vitro protein tyrosine phosphatase assays. Interestingly, association of the SH2n domain of SHP-1 with the tyrosine phosphorylated erythropoietin receptor modestly potentiated but was not essential for SHP-1-mediated dephosphorylation of Jak2 and had no effect on c-fes phosphorylation. These data indicate that the main mechanism for regulation of Jak2 phosphorylation by SHP-1 involves a direct, SH2-independent interaction with Jak2 and suggest the existence of similar mechanisms for other members of the Jak family of kinases. They also suggest that such interactions may provide one of the mechanisms that control SHP-1 substrate specificity.