Effects of Late Administration of Pentoxifylline and Tocotrienols in an Image-Guided Rat Model of Localized Heart Irradiation

Radiation-induced heart disease (RIHD) is a long-term side effect of radiotherapy of intrathoracic, chest wall and breast tumors when radiation fields encompass all or part of the heart. Previous studies have shown that pentoxifylline (PTX) in combination with α-tocopherol reduced manifestations of RIHD in rat models of local heart irradiation. The relative contribution of PTX and α-tocopherol to these beneficial effects are not known. This study examined the effects of PTX alone or in combination with tocotrienols, forms of vitamin E with potential potent radiation mitigation properties. Rats received localized X-irradiation of the heart with an image-guided irradiation technique. At 3 months after irradiation rats received oral treatment with vehicle, PTX, or PTX in combination with a tocotrienol-enriched formulation. At 6 months after irradiation, PTX-treated rats showed arrhythmia in 5 out of 14 animals. PTX alone or in combination with tocotrienols did not alter cardiac radiation fibrosis, left ventricular protein expression of the endothelial markers von Willebrand factor and neuregulin-1, or phosphorylation of the signal mediators Akt, Erk1/2, or PKCα. On the other hand, tocotrienols reduced cardiac numbers of mast cells and macrophages, but enhanced the expression of tissue factor. While this new rat model of localized heart irradiation does not support the use of PTX alone, the effects of tocotrienols on chronic manifestations of RIHD deserve further investigation.     

A Study of the Interaction of Cr(III) Complexes and Their Selective Binding with B-DNA: A Molecular Modeling Approach

Abstract

Molecular modeling and energy minimisation calculations have been used to investigate the interaction of chromium(III) complexes in different ligand environments with various sequences of B-DNA. The complexes are [Cr(salen)(H₂O)₂]⁺; salen denotes 1, 2 bis-salicylideneaminoethane, [Cr(salprn)(H₂O)₂]⁺; salprn denotes 1, 3 bis- salicylideneamino-propane, [Cr(phen)₃]³⁺; phen denotes 1, 10 phenanthroline and [Cr(en)₃]³⁺; en denotes eth- ylenediamine. All the chromium(III) complexes are interacted with the minor groove and major groove of d(AT)₁₂, d(CGCGAATTCGCG)₂ and d(GC)₁₂ sequences of DNA. The binding energy and hydrogen bond parameters of DNA-Cr complex adduct in both the groove have been determined using molecular mechanics approach. The binding energy and formation of hydrogen bonds between chromium(III) complex and DNA has shown that all complexes of chromium(III) prefer minor groove interaction as the favourable binding mode.     

Purification of muscle enzymes by pseudoaffinity chromatography

A method based on pseudoaffinity chromatography has been developed for the separation of lactate dehydrogenase (LDH), pyruvate kinase (PK) and aldolase from rabbit muscle extract using cross-linked guar (CLG) and cross-linked pectin (CLP) as the matrices, and dyes as the ligands. Screening of several dyes revealed that dyes No. 1014 and No. 1015, immobilized on CLG and CLP displayed a higher affinity for LDH and PK. Aldolase was not retained on any of the dye columns. It was observed that 1014-CLP and 1014-CLG columns retained 90% and 55% LDH activities, respectively, whereas 1015-CLP and 1015-CLG retained 83% LDH and 72% PK. A coupled-column system comprising 1014-CLP and 1015-CLP or 1014-CLG and 1015-CLG could separate LDH, PK, and aldolase from a mixture of these enzymes, as well as from rabbit muscle extract. Enzymes were found to be homogeneous on polyacrylamide gel electrophoresis. The method has been found to be simple and economical.     

Synthesis and biological activity of selective pipecolic acid-based TNF-alpha converting enzyme (TACE) inhibitors

A series of novel, selective TNF-alpha converting enzyme inhibitors based on 4-hydroxy and 5-hydroxy pipecolate hydroxamic acid scaffolds is described. The potency and selectivity of TACE inhibition is dramatically influenced by the nature of the sulfonamide group which interacts with the S1' site of the enzyme. Substituted 4-benzyloxybenzenesulfonamides exhibit excellent TACE potency with >100x selectivity over inhibition of matrix metalloprotease-1 (MMP-1). Alkyl substituents on the ortho position of the benzyl ether moiety give the most potent inhibition of TNF-alpha release in LPS-treated human whole blood.     

Simulations of SIN Mutations and Histone Variants in Human Nucleosomes Reveal Altered Protein-DNA and Core Histone Interactions

Abstract Alterations in the stability of a nucleosome exert predominant influence on chromatin structure and eukaryotic gene expression. In an attempt to investigate the mononucleosome stability using computational approaches, we have simulated the structure of a human mononucleosome and have compared their energies under the influence of core mutations, tail substitutions, variant histones, and orthologs. We observe that mutant nucleosomes carrying SIN (SWI Independent) mutations do not alter the overall nucleosomal structure but cause local structural changes leading to significant changes in energy and hence the stability. We observe that the nucleosome stability is altered by the substitution of only certain critical lysine residues on the H3 tails. Interestingly, the incorporation of variants H2A.Z and H3.3 lower nucleosome stability as evidenced by small energy changes. However, the substitution of histone orthologs did not alter structural stability. Our simulations to determine the nucleosome stability using energy trends emphasize the role of mutations, variants, and orthologs as determinants of chromatin structure at the nucleosome core particle level. The de-stabilization we observe on the human nucleosome with core mutations show similar trends of instability as validated experimentally in yeast.     

Knapsack - TOPSIS Technique for Vertical Handover in Heterogeneous Wireless Network

In a heterogeneous wireless network, handover techniques are designed to facilitate anywhere/anytime service continuity for mobile users. Consistent best-possible access to a network with widely varying network characteristics requires seamless mobility management techniques. Hence, the vertical handover process imposes important technical challenges. Handover decisions are triggered for continuous connectivity of mobile terminals. However, bad network selection and overload conditions in the chosen network can cause fallout in the form of handover failure. In order to maintain the required Quality of Service during the handover process, decision algorithms should incorporate intelligent techniques. In this paper, a new and efficient vertical handover mechanism is implemented using a dynamic programming method from the operation research discipline. This dynamic programming approach, which is integrated with the Technique to Order Preference by Similarity to Ideal Solution (TOPSIS) method, provides the mobile user with the best handover decisions. Moreover, in this proposed handover algorithm a deterministic approach which divides the network into zones is incorporated into the network server in order to derive an optimal solution. The study revealed that this method is found to achieve better performance and QoS support to users and greatly reduce the handover failures when compared to the traditional TOPSIS method. The decision arrived at the zone gateway using this operational research analytical method (known as the dynamic programming knapsack approach together with Technique to Order Preference by Similarity to Ideal Solution) yields remarkably better results in terms of the network performance measures such as throughput and delay.     

Locus dependence in epigenetic chromatin silencing

Current biological models of epigenetic switches built on chromatin modifications lead to strong constraints on the repertoire of dynamic behaviors for the system. We use the structure of the bifurcation diagram of the underlying dynamical system to explain the existing single cell data in silencing by the SIR system in yeast.     

Downregulation of glutaredoxin but not glutathione loss leads to mitochondrial dysfunction in female mice CNS: implications in excitotoxicity

Oxidative stress, excitotoxicity and mitochondrial dysfunction play synergistic roles in neurodegeneration. Maintenance of thiol homeostasis is important for normal mitochondrial function and dysregulation of protein thiol homeostasis by oxidative stress leads to mitochondrial dysfunction and neurodegeneration. We examined the critical roles played by the antioxidant, non-protein thiol, glutathione and related enzyme, glutaredoxin in maintaining mitochondrial function during excitotoxicity caused by beta-N-oxalyl amino-L-alanine (L-BOAA), the causative factor of neurolathyrism, a motor neuron disease involving the pyramidal system. L-BOAA causes loss of GSH and inhibition of mitochondrial complex I in lumbosacral cord of male mice through oxidation of thiol groups, while female mice are resistant. Reducing GSH levels in female mice CNS by pretreatment with diethyl maleate or L-propargyl glycine did not result in inhibition of complex I activity, unlike male mice. Further, treatment of female mice depleted of GSH with L-BOAA did not induce inhibition of complex I indicating that GSH levels were not critical for maintaining complex I activity in female mice unlike their male counterpart. Glutaredoxin, a thiol disulfide oxidoreductase helps maintain redox status of proteins and downregulation of glutaredoxin results in loss of mitochondrial complex I activity. Female mice express higher levels of glutaredoxin in certain CNS regions and downregulation of glutaredoxin using antisense oligonucleotides sensitizes them to L-BOAA toxicity seen as mitochondrial complex I loss. Ovariectomy downregulates glutaredoxin and renders female mice vulnerable to L-BOAA toxicity as evidenced by activation of AP1, loss of GSH and complex I activity indicating the important role of glutaredoxin in neuroprotection. Estrogen protects against mitochondrial dysfunction caused by excitotoxicity by maintaining cellular redox status through higher constitutive expression of glutaredoxin in the CNS. Therapeutic interventions designed to upregulate glutaredoxin may offer neuroprotection against excitotoxicity in motor neurons.