Tissue transglutaminase (TG2) - a wound response enzyme

Repair of tissue after injury depends on a series of concerted but overlapping events including, inflammation, re-epithelialization, neovascularization and synthesis and stabilization of a fibrous extracellular matrix (ECM) that is remodeled to emulate normal tissue over time. Particular members of the transglutaminase (TG) family are upregulated during wound healing and act as a novel class of wound-healing mediators during the repair process. This group of enzymes which crosslink proteins via epsilon(gamma-glutamyl) lysine bridges are involved in wound healing through their ability to stabilize proteins and also by regulating the behavior of a wide variety of cell types that are recruited to the damaged area in order to carry out tissue repair. In this article we discuss the function of the most widely expressed member of the TG family "tissue transglutaminase" (TG2) in wound repair. Using both early and recent evidence from the literature we demonstrate how the multifunctional TG2 affects the stability of the ECM, cell-ECM interactions and as a consequence cell behavior within the different phases of wound healing, and highlight how TG2 itself might be exploited for therapeutic use.

Carbon monoxide inhibits sprouting angiogenesis and vascular endothelial growth factor receptor-2 phosphorylation

Carbon monoxide (CO) is a gaseous autacoid known to positively regulate vascular tone; however, its role in angiogenesis is unknown. The aim of this study was to investigate the effect of CO on angiogenesis and vascular endothelial growth factor (VEGF) receptor-2 phosphorylation. Human umbilical vein endothelial cells (HUVECs) were cultured on growth factor- reduced Matrigel and treated with a CO-releasing molecule (CORM-2) or exposed to CO gas (250 ppm). Here, we report the surprising finding that exposure to CO inhibits vascular endothelial growth factor (VEGF)-induced endothelial cell actin reorganisation, cell proliferation, migration and capillary-like tube formation. Similarly, CO suppressed VEGF-mediated phosphorylation of VEGFR-2 at tyrosine residue 1175 and 1214 and basic fibroblast growth factor- (FGF-2) and VEGF-mediated Akt phosphorylation. Consistent with these data, mice exposed to 250 ppm CO (1h/day for 14 days) exhibited a marked decrease in FGF-2-induced Matrigel plug angiogenesis (p<0.05). These data establish a new biological function for CO in angiogenesis and point to a potential therapeutic use for CO as an anti-angiogenic agent in tumour suppression.

Towards a 21st-century roadmap for biomedical research and drug discovery: consensus report and recommendations

Decades of costly failures in translating drug candidates from preclinical disease models to human therapeutic use warrant reconsideration of the priority placed on animal models in biomedical research. Following an international workshop attended by experts from academia, government institutions, research funding bodies, and the corporate and nongovernmental organisation (NGO) sectors, in this consensus report, we analyse, as case studies, five disease areas with major unmet needs for new treatments. In view of the scientifically driven transition towards a human pathway-based paradigm in toxicology, a similar paradigm shift appears to be justified in biomedical research. There is a pressing need for an approach that strategically implements advanced, human biology-based models and tools to understand disease pathways at multiple biological scales. We present recommendations to help achieve this.

Use of peptide nucleic acids as therapeutic agents

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