3. I. Based on the above discussion, it appears that the classical paradigm regarding the biological functions of NAD and NADP is too narrow to generalize the growing functions of these molecules. It is tempting to propose that a novel paradigm about the biological functions of NAD and NADP may be emerging. From: Ying W. (2008) Antioxidants & Redox Signaling Two of my major new thoughts about NAD
4. II. NAD, together with ATP and Ca 2+ , may be the most fundamental components in life which mediate nearly all of the key biological processes. The close interactions among these components may constitute a â Central Regulatory Network â in life. From: Ying W. (2008) Antioxidants & Redox Signaling
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6. NADPH NADP + NAD + NADH NAADP Antioxidation Oxidative Stress Reductive biosynthesis Calcium homeostasis Mitochondrial function Energy metabolism Oxidative stress Calcium homeostasis Gene expression Mitochondrial function Energy metabolism Calcium homeostasis Gene expression Cell death Aging Dehydrogenases PARPs Sirtuins ARCs ARTs NADK Dehydrogenases/Oxidases GRx NADPH oxidase G6PDH 6GPDH IDP MEP TDH de novo pathway Salvage pathway L-Trp NMN/NaMN ARCs ETC Oxidases From: Ying W. (2007) Antioxidants & Redox Signaling
7. 1. Roles of NAD+ and NADH in cellular functions 1.1. NAD+ and NADH in energy metabolism (a) Glycolysis (GAPDH); (b) pyruvate / lactate conversion; (c) TCA cycle; (d) electron transport chain; and (e) energy metabolism affected by NAD-dependent SIR2 / PARPs.
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9. 1.3. NAD+ and NADH in calcium homeostasis From: Ying W. (2008) Antioxidants & Redox Signaling
11. 1.5. NAD + and NADH in aging From: Ying W. (2007) Antioxidants & Redox Signaling
12. Summary NAD + and NADH have emerged as one of the most influential couples in nearly all of the major biological processes in life, including calcium homeostasis, mitochondrial functions, energy metabolism, gene expression, immunological functions, aging and cell death.
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14. NAD + Dehydrogenases PARP Poly(ADP-ribosyl)ated proteins + Nam ARTs cADPR + Nam NAD + kinase NADP + sirtuins Deacylated proteins + Nam + O-acetyl-ADP-ribose (ADP-ribosyl)ated proteins + Nam ADP-ribosyl cyclases Salvage pathway Nam / NA de novo pathway NaMN L-Trp L-Kyn Qa Energy metabolism / Mitochondrial functions NADH DNA repair Cell death Gene expression Genomic stability Gene silencing Aging Cell death Calcium homeostasis Antioxidation Calcium homeostasis Signal transduction Immunological regulation Ying W. (2006)
26. Ying W. et al. (2003) BBRC 308:809-813. NAD + treatment can restore the intracellular NAD + levels in astrocytes treated with the PARP activator MNNG
31. * We have further found that NAD + treatment can abolish MNNG-induced mitochondrial permeability transition and mitochondrial depolarization (Alano, Ying and Swanson JBC (2004).
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35. Can NAD + be used in vivo to decrease brain injury in cerebral ischemia and other PARP-1 related diseases? We used a rat model of transient focal ischemia to test our hypothesis that NAD + administration can decrease ischemic brain damage. 3. Therapeutic potential of NAD +
36. A key problem for treatment of CNS diseases: William M. Pardridge. (2005) The Blood-Brain Barrier: Bottleneck in Brain Drug Development. NeuroRx. 2: 3â14. A key challenge in establishing effective strategies for neuroprotection: Searching for drug delivery approaches that can overcome the limitations of BBB.
37. The Nose May Help the Brain --- Intranasal Drug Delivery for Treating Neurological Diseases Ying W. (Editorial) Future Neurology
38. Intranasal administration, but not intravenous administration, with the PARG inhibitor gallotannin, decreased ischemic brain injury
39. NAD + treatment can increase intracellular NAD + in a brain slice model
40. Ischemia Ischemia + 10 mg / kg NAD + Intranasal administration with 10 mg / kg NAD + at 2 hrs after ischemic onset can profoundly decreased infarct formation. This treatment did not affect multiple major physiological parameters including temperature, blood pressure, pH etc.
45. Ischemia Ischemia + GT AIF Nucleus Merge Ischemia-reperfusion induced AIF translocation in rat brains
46. Can NAD + be used for treating other PARP-1-associated diseases ? Our latest study: Intranasal NAD + delivery could decrease traumatic brain injury. TBI TBI + NAD +