High-throughput screening

Quantitative high-throughput screening: A titration-based approach that efficiently identifies biological activities in large chemical libraries. Inglese, J. et al. Proc. Natl Acad. Sci. USA 103, 11473–11478 (2006)

Traditional high-throughput screening (HTS), which tests compounds at a single concentration, is often burdened by false-positives and -negatives, and requires extensive follow-up testing. Now, Inglese and colleagues from the NIH Chemical Genomics Center have developed a quantitative HTS method to generate concentration–response curves for >60,000 compounds in a single experiment. From the primary screen, pyruvate kinase activators and inhibitors with a variety of potencies and efficacies were identified, and structure–activity relationships were determined.

Therapeutic angiogenesis

Netrins promote developmental and therapeutic angiogenesis. Wilson, D. W. et al. Science 313, 640–644 (2006)

Wilson and colleagues have further added to the role of netrins — prototypical axonal attractants — by showing that they stimulate the proliferation, migration and tube formation of human endothelial cells, independently of known netrin receptors. In addition, netrins accelerated neovascularization in a murine model of ischaemia and reversed neuropathy and vasculopathy in a murine diabetic model. The dual vascular and neuronal regenerative functions of netrins could make them a therapeutic target in the control of diabetic complications.

Metabolic disorders

NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism. Pei, L. et al. Nature Med. 12, 1048–1055 (2006)

Dysregulation of hepatic glucose production contributes to the pathogenesis of diabetes. Pei and colleagues have shown that NR4A orphan nuclear receptors are downstream mediators of cAMP action in the control of hepatic glucose metabolism. Hepatic expression of NR4A receptors is elevated in diabetic mice, contributing to hyperglycaemia. Inactivation of the NR4A pathway in mice compromised hepatic glucose production. These results demonstrate a previously unrecognized role for NR4A receptors in glucose homeostasis, which makes them potential targets for the treatment of metabolic disease.

Cancer

Mutations that increase the life-span of C. elegans inhibit tumour growth. Pinkston, J. M. et al. Science 313, 971–975 (2006)

Understanding how youthful animals resist tumours could provide new insights into tumour cell biology. Pinkston and colleagues demonstrated that a variety of mutations that extend the lifespan of the nematode C. elegans confer resistance to tumours induced by mutations in the gld-1 gene. Mutations that increased lifespan by restricting food intake or inhibiting respiration reduced tumour cell division, without effects on apoptosis. Longevity mutations did not alter mitosis, suggesting that cellular changes leading to longevity preferentially antagonize tumour cell growth.