Abstract
NAD+ plays crucial roles in a variety of biological processes including energy metabolism, aging, and calcium homeostasis. Multiple studies have also shown that NAD+ administration can profoundly decrease oxidative cell death and ischemic brain injury. A number of recent studies have further indicated that NAD+ administration can decrease ischemic brain damage, traumatic brain damage and synchrotron radiation X-ray-induced tissue injury by such mechanisms as inhibiting inflammation, decreasing autophagy, and reducing DNA damage. Our latest study that applies nano-particles as a NAD+ carrier has also provided first direct evidence demonstrating a key role of NAD+ depletion in oxidative stress-induced ATP depletion. Poly(ADP-ribose) polymerase-1 (PARP-1) and sirtuins are key NAD+-consuming enzymes that mediate multiple biological processes. Recent studies have provided new information regarding PARP-1 and sirtuins in cell death, ischemic brain damage and synchrotron radiation X-ray-induced tissue damage. These findings have collectively supported the hypothesis that NAD+ metabolism, PARP-1 and sirtuins play fundamental roles in oxidative stress-induced cell death, ischemic brain injury, and radiation injury. The findings have also supported “the Central Regulatory Network Hypothesis”, which proposes that a fundamental network that consists of ATP, NAD+ and Ca2+ as its key components is the essential network regulating various biological processes.
Highlights
Increasing evidence has indicated that NAD+ plays important roles in energy metabolism and mitochondrial functions and in aging, gene expression, calcium homeostasis, and immune functions [1,2,3]
Our study showed that Synchrotron Radiation (SR) X-ray irradiation produced dose-dependent increases in poly(ADPribose) (PAR) formation—an index of poly(ADP-ribose) polymerase (PARP) activation, which can be prevented by the administration of the antioxidant N-acetyl cysteine (NAC), suggesting that oxidative stress mediates the SR X-ray-induced PARP activation
As stated above, increasing evidence has indicated crucial roles of NAD+ and Poly(ADP-ribose) polymerase-1 (PARP-1) in cell survival under such pathological conditions as cerebral ischemia and SR X-ray exposures. These pieces of evidence have suggested that NAD+ metabolism as well as PARP-1 may become promising therapeutic targets for multiple diseases
Summary
Increasing evidence has indicated that NAD+ plays important roles in energy metabolism and mitochondrial functions and in aging, gene expression, calcium homeostasis, and immune functions [1,2,3]. Our study showed that SR X-ray irradiation produced dose-dependent increases in poly(ADPribose) (PAR) formation—an index of PARP activation, which can be prevented by the administration of the antioxidant N-acetyl cysteine (NAC), suggesting that oxidative stress mediates the SR X-ray-induced PARP activation This finding is consistent with our previous observation suggesting that oxidative stress plays a key role in SR X-ray-induced tissue damage [70]. Our study has provided the first evidence suggesting that SR X-ray can induce PARP activation by generating oxidative stress, leading to various tissue injuries at least partially by inducing DNA damage and apoptotic changes. A latest study has suggested a mechanism underlying the effects of PARP-1 activation on inflammation: PARP-1 activation leads to decreased NAD+ levels and subsequent decreases in SIRT1 activity, resulting in reduced deacetylation of p65 subunit of NFκB, increased NFκB activation, and increased inflammatory responses in primary murine astrocytes [76]. Because PARP-1 activation plays a significant role in HMGB1 translocation [77], PARP1 inhibition may decrease inflammation by blocking translocation of HMGB1 out of the nucleus
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