Effect of novel dinuclear platinum(II) complexes on redox status of MOLT-4 leukemic cells

Abstract

As the alkylating agents metabolism is accompanied by reactive oxygen species (ROS) generation, the aim of this study has been to compare the effect of cisplatin and novel platinum(II) complexes, Pt₂(isopropylamine)₄(berenil)₂, Pt₂(piperazine)₄(berenil)_2, Pt₂(2-picoline)₄(berenil)₂, Pt₂(3-picoline)₄(berenil)₂, Pt₂(4-picoline)₄(berenil)₂, on the redox state of human leukemic T-cells line Molt-4. Treatment of Molt-4 with the novel complexes has shown that all compounds enhance total ROS and superoxide anion generation as well as change the activity of antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. Moreover, all the above-mentioned compounds cause a decrease in the level of non-enzymatic antioxidants such as GSH as well as vitamin C, E and A. Such a situation is conducive to oxidative stress formation and oxidative modifications of cellular macromolecules. DNA damage of MOLT-4 leukemic cells is connected with 8-hydroxy-2′-deoxyguanosine and N7-methyldeoxyguanosine generation. The increased level of protein carbonyl groups and dityrosine indicates enhanced protein oxidative modifications, while an increase in the level of lipid peroxidation products, MDA, 4-HNE and isoprostanes proves the significant lipid peroxidation after treatment of Molt-4 cells with the complexes. Moreover, the complexes enhance expression of Bax and cytochrome c as well as decrease the expression of Bcl-2 and p53 protein. The novel platinum(II) complexes in comparison with cisplatin disturb redox status more intensively and lead to oxidative stress in Molt-4 cells. The enhanced oxidative modifications of macromolecules of human leukemic cancer cells lead to a shift in the proapoptotic–antiapoptotic balance into the proapoptotic direction.     

C1q Precipitins in Human Seminal Plasma

Seminal plasma was tested against purified C_1q by double diffusion. Precipitation reactions were frequently observed in the seminal plasma of patients with normozoospermia and patients with azoospermia; most of these reactions were not due to soluble immune complexes binding to C_1q. A factor resistant to DNAse and RNAse (mol wt: 25,000-150,000 daltons) was found to precipitate C_1q. It's discovery adds to the list of substances which may interfere in C_1q precipitation tests.     

Towards a phylogenetic approach to the composition of species complexes in the North and Central American Triatoma,vectors of Chagas disease

Phylogenetic relationships of insect vectors of parasitic diseases are important for understanding the evolution of epidemiologically relevant traits, and may be useful in vector control. The sub-family Triatominae (Hemiptera:Reduviidae) includes ∼140 extant species arranged in five tribes comprised of 15 genera. The genus Triatoma is the most species-rich and contains important vectors of Trypanosoma cruzi, the causative agent of Chagas disease. Triatoma species were grouped into complexes originally by morphology and more recently with the addition of information from molecular phylogenetics (the four-complex hypothesis); however, without a strict adherence to monophyly. To date, the validity of proposed species complexes has not been tested by statistical tests of topology. The goal of this study was to clarify the systematics of 19 Triatoma species from North and Central America. We inferred their evolutionary relatedness using two independent data sets: the complete nuclear internal transcribed spacer-2 ribosomal DNA (ITS-2 rDNA) and head morphometrics. In addition, we used the Shimodaira–Hasegawa statistical test of topology to assess the fit of the data to a set of competing systematic hypotheses (topologies). An unconstrained topology inferred from the ITS-2 data was compared to topologies constrained based on the four-complex hypothesis or one inferred from our morphometry results. The unconstrained topology represents a statistically significant better fit of the molecular data than either the four-complex or the morphometric topology. We propose an update to the composition of species complexes in the North and Central American Triatoma, based on a phylogeny inferred from ITS-2 as a first step towards updating the phylogeny of the complexes based on monophyly and statistical tests of topologies.     

Osteoclasts in RA: Diverse origins and functions

Osteoclasts were recognized in the late 1990s as the cells responsible for generalized and focal bone loss in rheumatoid arthritis (RA). Concepts about osteoclast biology have changed radically based on recent evidence of considerable diversity in both the origins and the functions of osteoclasts. In addition, the role for osteoclasts is not confined to bone resorption but may also include active contributions to inflammatory and autoimmune responses. Thus, in RA, osteoclast progenitors may arise from both circulating cells and cells developed within the rheumatoid synovium or subchondral bone. Within the inflamed synovium, osteoclasts are activated by factors such as cytokines, immune complexes, or activators of the toll-like receptors, which are not found in healthy bone tissue. Finally, recent data suggest that osteoclasts may be capable of antigen presentation to T cells via major histocompatibility complex class I and class II molecules. Confirmation of this suggestion by future studies would indicate that osteoclasts might be involved not only in bone resorption, but also in autoimmune responses and antigen presentation. These data highlight the considerable complexity of interactions between bone tissue and the immune system. Research into these interactions may identify new targets for treatments against the bone abnormalities associated with chronic inflammatory disease.     

Nucleoside analogue delivery systems in cancer therapy

Nucleoside analogues (NAs) are important agents in the treatment of hematological malignancies. They are prodrugs that require activation by phosphorylation. Their rapid catabolism, cell resistance and overdistribution in the body jeopardize nucleoside analogue chemotherapy. Accordingly, therapeutic doses of NAs are particularly high and regularly have to be increased, resulting in severe toxicity and narrow therapeutic index. The major challenge is to concentrate the drug at the tumour site, avoiding its distribution to normal tissues. New drug carriers and biomaterials are being developed to overcome some of these obstacles. This review highlights novel NA delivery systems and discusses new technologies that could improve NA cancer therapy.     

Electrochemical and homogeneous electron transfers to the Alzheimer amyloid-β copper complex follow a preorganization mechanism

Deciphering the electron transfer reactivity characteristics of amyloid β-peptide copper complexes is an important task in connection with the role they are assumed to play in Alzheimer’s disease. A systematic analysis of this question with the example of the amyloid β-peptide copper complex by means of its electrochemical current–potential responses and of its homogenous reactions with electrogenerated fast electron exchanging osmium complexes revealed a quite peculiar mechanism: The reaction proceeds through a small fraction of the complex molecules in which the peptide complex is “preorganized” so as the distances and angles in the coordination sphere to vary minimally upon electron transfer, thus involving a remarkably small reorganization energy (0.3 eV). This preorganization mechanism and its consequences on the reactivity should be taken into account for reactions involving dioxygen and hydrogen peroxide that are considered to be important in Alzheimer’s disease through the production of harmful reactive oxygen species.     

Mitochondrial dysfunction in CA1 hippocampal neurons of the UBE3A deficient mouse model for Angelman syndrome

Angelman syndrome (AS) is a severe neurological disorder caused by a deficiency of ubiquitin protein ligase E3A (UBE3A), but the pathophysiology of the disease remains unknown. We now report that in the brains of AS mice in which the maternal UBE3A allele is mutated (m−) and the paternal allele is potentially inactivated by imprinting (p+) (UBE3A m−\p+), the mitochondria are abnormal and exhibit a partial oxidative phosphorylation (OXPHOS) defect. Electron microscopy of the hippocampal region of the UBE3A m−\p+ mice (n = 6) reveals small, dense mitochondria with altered cristae, relative to wild-type littermates (n = 6) and reduced synaptic vesicle density. The specific activity of OXPHOS complex III is reduced in whole brain mitochondria in UBE3A m−\p+ (n = 5) mice versus wild-type littermates (n = 5). Therefore, mitochondrial dysfunction may contribute to the pathophysiology of Angelman syndrome.