Editorial [Hot Topic:Nicotinamide Adenine Dinucleotide Biology and Disease(Executive Editor: W. Todd Penberthy)]

Nicotinamide adenine dinucleotide (NAD) research has progressed from the initial vitamin discovery phase in 1937 with the cure for the NAD deficiency disease pellagra [1], to discoveries in the 1950s of activities observed after application at pharmacological doses. These latter applications include benefits to mental health [2, 3] and lipodystrophy [4], where nicotinic acid remains the most effective means of elevating HDL levels to this current day. Basic research reveals that NAD functions as a co-factor in over 200 redox reactions and as a substrate for three categorical classes of enzymes: NAD-dependent deacetylases (Sirtuins), ADP-ribosyl transferases (most prominently, PARP-1), and ADP cyclases (e.g. CD38). The effects of NAD deficiency are made evident as the symptoms of the dreaded disease pellagra the symptoms of which are often generalized and easily remembered by the four D's: dermatitis, diarrhea, dementia, and death. These symptoms represent the wide range of functions of NAD spanning from auto-immunity to mental function. Modern molecular biology has revealed undeniably profound trophic neuronal benefits afforded by maintaining NAD levels working through SIRT-1 in studies of Slow Wallerian Degeneration mouse [5]. These benefits extend to a wide range of neurodegenerative disease models [6]. Two NAD-utilizing enzymes have emerged as tremendous focus areas of pharmaceutical drug target investment: PARP-1 (e.g. Inotek Pharmaceuticals bought by Genentech last year) and SIRT-1 (e.g. Sirtris Pharmaceuticals, bought by GSK). However, there are now known to be up to 18 potential ADP-ribosyl transferase related genes and seven Sirtuin related genes, some with specific nuclear or mitochondrial restricted subcellular locations. While SIRT- 1 and PARP-1 have mostly been studied for their roles in cancer biology to date, the role of NAD in auto-immune, neurodegenerative, and infectious disease is rapidly increasing. Looking to the future, this issue of Current Pharmaceutical Design features leaders in the field relating NAD biology to specific disease states. Focus is given to cancer, cardiovascular disease, diabetes, multiple sclerosis, and tuberculosis-schizophrenia. James B. Kirkland presents detailed analysis of endogenous and pharmacological concentrations for respective NAD precursors with emphasis on relevant pathway signaling, while Weihai Ying et al. present a mechanisms of action regulating NADPH oxidase and apoptosis. Shin-ichiro Imai covers the rate-limiting enzyme controlling NAD recycling, NAMPT [7]. As the only known extracellular enzyme in the NAD salvage pathway nicotinamide mononucleotide working through NAMPT has unique potential for regulating the immune system and beta cell function. Cancer research has led the way in NAD experimental investigations for many years. In this issue, Claudia Benavente with Elaine and Myron Jacobson highlight increasingly appreciated NAD-centric pathways including niacin-deficient activation of NADPH oxidase, utilization of glutamine as an energy source during loss of glycolysis, and the potential importance of Sirtuins in UV damage responses. Meanwhile, Jo Milner brings to light the importance of increased SIRT1 concentrations in cancer with new insight on regulatory mechanisms involving micro-RNAs.