Biomedical subjects

A J Mendonca

Publications and source records attributed to A J Mendonca.

4 recordsLinked to original sources

PubMed2000

Oxidative stress is involved in seizure-induced neurodegeneration in the kindling model of epilepsy.

Reactive oxygen species have been implicated in the development of seizures under pathological conditions and linked to seizure-induced neurodegeneration. There has been little direct evidence, however, of free radical production resulting from seizures. Using amygdala-kindled rats, we have examined the generation of reactive oxygen species following seizures, and their possible contribution to seizure development and seizure-induced neuronal loss. The concentrations of two products of free radical-induced lipid peroxidation, malonaldehyde and 4-hydroxy-2(E)-nonenal, were measured using colorimetric assays. Lipid peroxidation was increased in both hemispheres of kindled rats as compared to sham-operated controls. Cell death was also significantly increased in all hippocampal areas. Antioxidants (vitamin E and glutathione) prevented the rise in lipid peroxides and hippocampal neuronal death during kindling, but did not arrest the development of seizures.Thus, epileptiform activity can result in free radical production which may be one of the factors leading to cell death.

Animals↗

PubMed1999

Optimization of solid supports for combinatorial chemical synthesis.

Until recently, resins were used primarily for peptide and oligonucleotide synthesis. Recent advances in combinatorial chemistry have fostered increased acceptance of resins as supports for the synthesis of small molecule libraries. The methodology for selecting a resin bead that is ideal for the solid phase synthesis of small molecules is described in this review. The process of manufacturing a typical resin, the UniSphere-200, is also explained. Furthermore, a new approach is proposed for the solid phase synthesis of analogs which are traditionally done in solution phase. This new procedure involves the use of building blocks attached to an activated resin. These building blocks are displaced by a functional group on the scaffold around which the analogs are built. Use of an excess of resin-linked building blocks drives the reaction to completion. Additionally, a newly developed, grafted surface solid support, is described. This support, the MicroTube, can be used for the synthesis of large numbers of discrete molecules by a patented directed sorting method.

Chemical Phenomena↗

PubMed1995

Structurally defined synthetic cancer vaccines: analysis of structure, glycosylation and recognition of cancer associated mucin, MUC-1 derived peptides.

Translation of an immune response into therapy is probably the toughest task in designing vaccines for cancer due to the heterogeneity of the cell surface antigens which display tremendous variations in glycoforms. Consequently, a small segment (antigen) of cancer-associated mucin, in spite of generating antigen-specific immune responses, may be limited in therapeutic value. It is important that the synthetic segment resembles the native cancer-associated mucin in both structure and conformation. Synthetic cancer associated mucin derived 16 amino acid peptide GVTSAPDTRPAPGSTA and its partially glycosylated forms have demonstrated specific binding to two monoclonal antibodies, B27.29 and BCP8, raised against the native cancer associated mucin, MUC-1 and a MUC-1 derived synthetic peptide, respectively. In spite of the structural similarities at the core peptide level of both glycosylated and unglycosylated peptides, it appears that partial glycosylation does not inhibit and even slightly enhances binding to the MAb B27.29 indicating that the glycosylated synthetic peptide more closely resembles the native mucin epitope recognized by MAb B27.29. From molecular dynamic simulations using NMR derived distance constraints, both glycosylated and unglycosylated peptides have shown a type 1 beta turn involving the same amino acids in both glycosylated and unglycosylated peptides. The alpha GalNAc attached to the threonine (T3) and serine (S4) in the 16 amino acid sequence has not imposed any conformational changes to the peptide backbone nor has offered severe steric resistance to the binding of either antibody to the glycopeptides as indicated by hapten inhibition studies. Nevertheless, all peptides have displayed glycosylation dependent specificities in binding to these antibodies, i.e. the glycosylated peptides demonstrated relative higher affinities to the native mucin antibody B27.29 while the unglycosylated peptide is more specific to the MAb BCP8. Immune responses generated by these synthetic glycopeptides are highly specific in recognizing the native cancer associated mucin.

Acetylgalactosamine↗

PubMed1992

Photosensitization by anticancer agents. 11. Mechanisms of photosensitization of human leukemic cells by diaminoanthraquinones: singlet oxygen and radical reactions.

The synthesis of several aminoanthraquinone derivatives (AAQs), designed to suppress the dark toxicity and to promote more efficient cancer cell photosensitization for potential use in photodynamic therapy (PDT), is described. The following AAQs were synthesized: 1-NH2-4,5-(MeO)2-AQ (1), 1,5-(NH2)2-4,8-(MeO)2-AQ (2), 1,8-(NH2)2-4,5-(MeO)2-AQ (3), and 1,5-(NHPhMe)2-4,8-(MeO)2-AQ (8). The agents exhibit strong absorption in the region 480-620 nm. Possible mechanisms of photosensitization were studied by measuring 1O2 phosphorescence at 1270 nm, detecting superoxide radicals employing an electron paramagnetic resonance (EPR)-spin trapping technique, and measuring oxygen consumption during the photo-oxidation of a representative biological electron donor, NADH. Strong phosphorescence from 1O2 was observed upon illumination of 2 and 3 in C6H6 (quantum yield of 0.25 and 0.5 respectively), and in EtOH (quantum yield of 0.23 and 0.34). The 1-amino-AQ (1) was the weakest 1O2 sensitizer, with quantum yield of 0.13 in benzene. No phosphorescence was observed in EtOH. A superoxide radical was detected as a spin adduct of 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) in irradiated benzene solutions of 1, 2 or 3 and DMPO. AAQs 2 and 3 sensitized photo-oxidation of NADH in H2O/EtOH mixture with the intermediacy of singlet oxygen as judged by the effect of sodium azide on the photostimulated oxygen consumption. Evolution of O2 upon addition of catalase to the illuminated solution confirmed the ultimate formation of hydrogen peroxide. These findings suggested that the (di)amino-dimethoxyanthraquinones might exert photosensitization via both Type I and Type II mechanisms. The AAQs were tested for their ability to photosensitize K562 human chronic myeloid leukemic cells in culture. Viability was measured using the 3,4,5-diethylthiazol-2,5-diphenyl tetrazolium blue assay, and DNA and possible membrane damage were assessed. The results from illuminating cells with light > 475 nm show that for the 1,5-compounds, the presence of methoxy substituents at 4,8 positions reduces the dark toxicity from ID50 of 23 to 250 microM and for the 1,8-compounds correspondingly from ID50 of 53 to > 300 microM. In the 1,5-series this decrease of the dark toxicity is accompanied by an increase in light-induced dose modification from 8.85 to 14.4. Differences exist in the mechanisms of cytotoxicity between the prototype phenolic AAQs and their methoxy counterparts. It appears that the cytotoxic action of the latter causes cell damage by the formation of a high proportion of alkali labile sites in addition to frank strand breaks.(ABSTRACT TRUNCATED AT 400 WORDS)

Anthraquinones↗