268 research outputs found

    A powerful mitochondria-targeted iron chelator affords high photoprotection against solar ultraviolet A radiation

    Get PDF
    Mitochondria are the principal destination for labile iron, making these organelles particularly susceptible to oxidative damage on exposure to ultraviolet A (UVA, 320–400 nm), the oxidizing component of sunlight. The labile iron-mediated oxidative damage caused by UVA to mitochondria leads to necrotic cell death via adenosine triphosphate depletion. Therefore, targeted removal of mitochondrial labile iron via highly specific tools from these organelles may be an effective approach to protect the skin cells against the harmful effects of UVA. In this work, we designed a mitochondria-targeted hexadentate (tricatechol-based) iron chelator linked to mitochondria-homing SS-like peptides. The photoprotective potential of this compound against UVA-induced oxidative damage and cell death was evaluated in cultured primary skin fibroblasts. Our results show that this compound provides unprecedented protection against UVA-induced mitochondrial damage, adenosine triphosphate depletion, and the ensuing necrotic cell death in skin fibroblasts, and this effect is fully related to its potent iron-chelating property in the organelle. This mitochondria-targeted iron chelator has therefore promising potential for skin photoprotection against the deleterious effects of the UVA component of sunlight

    Dual selective iron chelating probes for the monitoring of mitochondrial labile iron pools

    Get PDF
    Mitochondria-targeted peptides incorporating dual fluorescent and selective iron chelators have been designed as novel biosensors for the mitochondrial labile iron pool.</p

    Solid-Phase Synthesis and In-Silico Analysis of Iron-Binding Catecholato Chelators

    Get PDF
    Siderophores are iron-complexing compounds synthesized by bacteria and fungi. They are low molecular weight compounds (500-1500 Daltons) possessing high affinity for iron(III). Since 1970 a large number of siderophores have been characterized, the majority using hydroxamate or catecholate as functional groups. The biosynthesis of siderophores is typically regulated by the iron levels of the environment where the organism is located. Because of their exclusive affinity and specificity for iron(III), natural siderophores and their synthetic derivatives have been exploited in the treatment of human iron-overload diseases, as both diagnostic and therapeutic agents. Here, solid-phase approach for the preparation of hexadentate, peptide-based tricatecholato containing peptides is described. The versatility of the synthetic method allows for the design of a common scaffolding structure whereby diverse ligands can be conjugated. With so many possibilities, a computational approach has been developed which will facilitate the identification of those peptides which are capable of providing a high affinity iron(III) binding site. This study reports an integrated computational/synthetic approach towards a rational development of peptide-based siderophores

    Design of novel fluorescent mitochondria-targeted peptides with iron-selective sensing activity

    Get PDF
    Mitochondrial labile iron (LI) plays a crucial role in oxidative injuries and pathologies. At present, there is no organelle-specific sensitive iron sensor which can reside exclusively in the mitochondria and reliably monitor levels of LI in this organelle. In the present study, we describe the development of novel fluorescent and highly specific mitochondria iron sensors, using the family of mitochondria-homing ‘SS-peptides’ (short cell-permeant signal peptides mimicking mitochondrial import sequence) as carriers of highly specific iron chelators for sensitive evaluation of the mitochondrial LI. Microscopic analysis of subcellular localization of a small library of fluorescently labelled SS-like peptides identified dansyl (DNS) as the lead fluorophore for the subsequent synthesis of chimaeric iron chelator-peptides of either catechol (compounds 10 and 11) or hydroxypyridinone (compounds 13 and 14) type. The iron-sensing ability of these chimaeric compounds was confirmed by fluorescent quenching and dequenching studies both in solution and in cells, with compound 13 exhibiting the highest sensitivity towards iron modulation. The intramolecular fluorophore–chelator distance and the iron affinity both influence probe sensitivity towards iron. These probes represent the first example of highly sensitive mitochondria-directed fluorescent iron chelators with potential to monitor mitochondrial LI levels.</jats:p

    Targeting integrin αvβ6 with gallium-68 tris (hydroxypyridinone) based PET probes

    Get PDF
    Expression of the cellular transmembrane receptor αvβ6 integrin is mostly restricted to malignant epithelial cells in a wide variety of carcinomas, including pancreatic and others derived from epithelial tissues. Thus, this protein is considered an attractive target for tumour imaging and therapy. Two different (68)Ga hexadentate tris (3,4-hydroxypyridinone) (THP) chelators were produced in this study and coupled to the αvβ6 integrin–selective peptide cyclo(FRGDLAFp(NMe)K) via NHS chemistry. Radiolabelling experiments confirmed a high radiochemical yield of the two PET probes. In addition, cellular binding studies showed high binding affinities in the nanomolar range. The two integrin αvβ6-peptide-THP synthesized and radiolabeled in this study will facilitate in vivo monitoring of transmembrane receptor αvβ6 integrin by using the advantage of THP chemistry for rapid, efficient and stable gallium chelation

    Auditing the office for learning and teaching resource library

    Get PDF
    The Australian government Office for Learning and Teaching\u27s (OLT) Resource Library is a key means of disseminating the outcomes from projects funded by itself and its predecessor organisations, the Australian Learning and Teaching Council (ALTC) and the Carrick Institute. In order to apply the recommendations and resources emanating from these projects, it is vital that educators and other stakeholders are aware of, and effectively able to use, the Resource Library. Based on anecdotal evidence indicating a lack of awareness of the Resource Library and problems with consistently being able to search for and retrieve relevant resources from the database, the OLT commissioned a project to formally evaluate the Library and redesign it to improve access and usability. This paper reports on the project\u27s progress, including the results from a questionnaire completed by 117 higher education stakeholders
    • …
    corecore