Augmentation Of NAD Research Articles

Elevation of NAD+ by nicotinamide riboside spares spinal cord tissue from injury and promotes locomotor recovery

Spinal cord injury (SCI)-induced tissue damage spreads to neighboring spared cells in the hours, days, and weeks following injury, leading to exacerbation of tissue damage and functional deficits. Among the biochemical changes is the rapid reduction of cellular nicotinamide adenine dinucleotide (NAD+), an essential coenzyme for energy metabolism and an essential cofactor for non-redox NAD+-dependent enzymes with critical functions in sensing and repairing damaged tissue. NAD+ depletion propagates tissue damage. Augmenting NAD+ by exogenous application of NAD+, its synthesizing enzymes, or its cellular precursors mitigates tissue damage. Nicotinamide riboside (NR) is considered to be one of the most promising NAD+ precursors for clinical application due to its ability to safely and effectively boost cellular NAD+ synthesis in rats and humans. Moreover, various preclinical studies have demonstrated that NR can provide tissue protection. Despite these promising findings, little is known about the potential benefits of NR in the context of SCI. In the current study, we tested whether NR administration could effectively increase NAD+ levels in the injured spinal cord and whether this augmentation of NAD+ would promote spinal cord tissue protection and ultimately lead to improvements in locomotor function. Our findings indicate that administering NR (500 mg/kg) intraperitoneally from four days before to two weeks after a mid-thoracic contusion-SCI injury, effectively doubles NAD+ levels in the spinal cord of Long-Evans rats. Moreover, NR administration plays a protective role in preserving spinal cord tissue post-injury, particularly in neurons and axons, as evident from the observed gray and white matter sparing. Additionally, it enhances motor function, as evaluated through the BBB subscore and missteps on the horizontal ladderwalk. Collectively, these findings demonstrate that administering NR, a precursor of NAD+, increases NAD+ within the injured spinal cord and effectively mitigates the tissue damage and functional decline that occurs following SCI.

Augmentation of NAD+ by Dunnione Ameliorates Imiquimod-Induced Psoriasis-Like Dermatitis in Mice.

BackgroundDunnione has anti-inflammatory properties arising from its ability to alter the ratio of NAD+/NADH through NAD(P)H quinone oxidoreductase 1 (NQO1) enzymatic action, followed by subsequent inhibition of NF-κB and inflammatory cytokines. Psoriasis is a chronic, inflammatory skin disorder in which the IL-23/Th17 axis plays an important role in inflammation. However, it is unclear whether modulation of NAD+ levels affects psoriasis, such as skin inflammation. Therefore, in this study, we investigated the effect of NAD+/NADH ratio modulation on imiquimod (IMQ)-induced, psoriasis-like skin inflammation in mice.MethodsPsoriasis-like skin inflammation was generated by daily topical application of IMQ cream. The severity of dermatitis was assessed using the Psoriasis Area Severity Index (PASI) and histochemistry. Expression of inflammatory cytokines was detected by enzyme-linked immunosorbent assay and quantitative PCR. Acetylation of NF-κB p65 and STAT3 was determined by Western blotting.ResultsDunnione improved IMQ-induced epidermal hyperplasia and inflammation, consistent with decreased levels of inflammatory cytokines (IL-17, IL-22, and IL-23) in skin lesions. Moreover, we found that an increase in the NAD+/NADH ratio by dunnione restored SIRT1 activity, thereby reduced imiquimod-induced STAT3 acetylation, which modulates the expression of psoriasis-promoting inflammatory cytokines, such as IL-17, IL-22, and IL-23.ConclusionPharmacological modulation of cellular NAD+ levels could be a promising therapeutic approach for psoriasis-like skin disease.

Turning up the NAD+-mitophagy axis to treat Alzheimer's disease.

Turning up the NAD+-mitophagy axis to treat Alzheimer's disease.

Modulation of cGAS-STING Pathway by Nicotinamide Riboside in Alzheimer's Disease.

Numerous studies demonstrate a global decrease in nicotinamide adenine dinucleotide (NAD+) with aging. This decline is associated with the development of several of the hallmarks of aging such as reduced mitophagy and neuroinflammation, processes thought to play a significant role in the progression of Alzheimer's disease (AD). Augmentation of NAD+ by oral administration of a precursor, nicotinamide riboside (NR), reduces senescence of affected cells, attenuates DNA damage and neuroinflammation in the transgenic APP/PS1 murine model of AD. Inflammation mediated by microglial cells plays an important role in progression of AD and other neurodegenerative diseases. The cytoplasmic DNA sensor, cyclic GMP-AMP synthase (cGAS) and downstream stimulator of interferon genes (STING), generates an interferon signature characteristic of senescence and inflammaging in the brain of AD mice. Elevated cGAS-STING observed in the AD mouse brains and human AD fibroblasts was normalized by NR. This intervention also increased mitophagy with improved cognition and behavior in the APP/PS1 mice. These studies suggest that modulation of the cGAS-STING pathway may benefit AD patients and possibly other disorders characterized by compromised mitophagy and excessive neuroinflammation.

Effect of NAD+ boosting on kidney ischemia-reperfusion injury.

Acute kidney injury (AKI) is associated with a very high mortality and an increased risk for progression to chronic kidney disease (CKD). Ischemia-reperfusion injury (IRI) is a model for AKI, which results in tubular damage, dysfunction of the mitochondria and autophagy, and in decreased cellular nicotinamide adenine dinucleotide (NAD+) with progressing fibrosis resulting in CKD. NAD+ is a co-enzyme for several proteins, including the NAD+ dependent sirtuins. NAD+ augmentation, e.g. by use of its precursor nicotinamide riboside (NR), improves mitochondrial homeostasis and organismal metabolism in many species. In the present investigation the effects of prophylactic administration of NR on IRI-induced AKI were studied in the rat. Bilateral IRI reduced kidney tissue NAD+, caused tubular damage, reduced α-Klotho (klotho), and altered autophagy flux. AKI initiated progression to CKD, as shown by induced profibrotic Periostin (postn) and Inhibin subunit beta-A, (activin A / Inhba), both 24 hours and 14 days after surgery. NR restored tissue NAD+ to that of the sham group, increased autophagy (reduced p62) and sirtuin1 (Sirt1) but did not ameliorate renal tubular damage and profibrotic genes in the 24 hours and 14 days IRI models. AKI induced NAD+ depletion and impaired autophagy, while augmentation of NAD+ by NR restored tissue NAD+ and increased autophagy, possibly serving as a protective response. However, prophylactic administration of NR did not ameliorate tubular damage of the IRI rats nor rescued the initiation of fibrosis in the long-term AKI to CKD model, which is a pivotal event in CKD pathogenesis.

NAD+ homeostasis in renal health and disease.

The mammalian kidney relies on abundant mitochondria in the renal tubule to generate sufficient ATP to provide the energy required for constant reclamation of solutes from crude blood filtrate. The highly metabolically active cells of the renal tubule also pair their energetic needs to the regulation of diverse cellular processes, including energy generation, antioxidant responses, autophagy and mitochondrial quality control. Nicotinamide adenine dinucleotide (NAD+) is essential not only for the harvesting of energy from substrates but also for an array of regulatory reactions that determine cellular health. In acute kidney injury (AKI), substantial decreases in the levels of NAD+ impair energy generation and, ultimately, the core kidney function of selective solute transport. Conversely, augmentation of NAD+ may protect the kidney tubule against diverse acute stressors. For example, NAD+ augmentation can ameliorate experimental AKI triggered by ischaemia–reperfusion, toxic injury and systemic inflammation. NAD+-dependent maintenance of renal tubular metabolic health may also attenuate long-term profibrotic responses that could lead to chronic kidney disease. Further understanding of the genetic, environmental and nutritional factors that influence NAD+ biosynthesis and renal resilience may lead to novel approaches for the prevention and treatment of kidney disease.

Augmentation of cellular NAD+ by NQO1 enzymatic action improves age-related hearing impairment.

Age‐related hearing loss (ARHL) is a major neurodegenerative disorder and the leading cause of communication deficit in the elderly population, which remains largely untreated. The development of ARHL is a multifactorial event that includes both intrinsic and extrinsic factors. Recent studies suggest that NAD+/NADH ratio may play a critical role in cellular senescence by regulating sirtuins, PARP‐1, and PGC‐1α. Nonetheless, the beneficial effect of direct modulation of cellular NAD+ levels on aging and age‐related diseases has not been studied, and the underlying mechanisms remain obscure. Herein, we investigated the effect of β‐lapachone (β‐lap), a known plant‐derived metabolite that modulates cellular NAD+ by conversion of NADH to NAD+ via the enzymatic action of NADH: quinone oxidoreductase 1 (NQO1) on ARHL in C57BL/6 mice. We elucidated that the reduction of cellular NAD+ during the aging process was an important contributor for ARHL; it facilitated oxidative stress and pro‐inflammatory responses in the cochlear tissue through regulating sirtuins that alter various signaling pathways, such as NF‐κB, p53, and IDH2. However, augmentation of NAD+ by β‐lap effectively prevented ARHL and accompanying deleterious effects through reducing inflammation and oxidative stress, sustaining mitochondrial function, and promoting mitochondrial biogenesis in rodents. These results suggest that direct regulation of cellular NAD+ levels by pharmacological agents may be a tangible therapeutic option for treating various age‐related diseases, including ARHL.

Augmentation of NAD+ levels by enzymatic action of NAD(P)H quinone oxidoreductase 1 attenuates adriamycin-induced cardiac dysfunction in mice

BackgroundAdriamycin (ADR) is a powerful chemotherapeutic agent extensively used to treat various human neoplasms. However, its clinical utility is hampered due to severe adverse side effects i.e. cardiotoxicity and heart failure. ADR-induced cardiomyopathy (AIC) has been reported to be caused by myocardial damage and dysfunction through oxidative stress, DNA damage, and inflammatory responses. Nonetheless, the remedies for AIC are even not established. Therefore, we illustrate the role of NAD+/NADH modulation by NAD(P)H quinone oxidoreductase 1 (NQO1) enzymatic action on AIC. Methods and resultsAIC was established by intraperitoneal injection of ADR in C57BL/6 wild-type (WT) and NQO1 knockout (NQO1−/−) mice. All Mice were orally administered dunnione (named NQO1 substrate) before and after exposure to ADR. Cardiac biomarker levels in the plasma, cardiac dysfunction, oxidative biomarkers, and mRNA and protein levels of pro-inflammatory mediators were determined compared the cardiac toxicity of each experimental group. All biomarkers of Cardiac damage and oxidative stress, and mRNA levels of pro-inflammatory cytokines including cardiac dysfunction were increased in ADR-treated both WT and NQO1−/− mice. However, this increase was significantly reduced by dunnione in WT, but not in NQO1−/− mice. In addition, a decrease in SIRT1 activity due to a reduction in the NAD+/NADH ratio by PARP-1 hyperactivation was associated with AIC through increased nuclear factor (NF)-κB p65 and p53 acetylation in both WT and NQO1−/− mice. While an elevation in NAD+/NADH ratio via NQO1 enzymatic action using dunnione recovered SIRT1 activity and subsequently deacetylated NF-κB p65 and p53, however not in NQO1−/− mice, thereby attenuating AIC. ConclusionThus, modulation of NAD+/NADH by NQO1 may be a novel therapeutic approach to prevent chemotherapy-associated heart failure, including AIC.

PO-463 Augmentation of NAD+BY NQO1 activation attenuates cisplatin-mediated hearing impairment

IntroductionCisplatin [cis-diaminedichloroplatinum-II] is an extensively used chemotherapeutic agent, and one of its most adverse effects is ototoxicity. A number of studies have demonstrated that these effects are related to oxidative stress and DNA damage. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. The cofactor nicotinamide adenine dinucleotide (NAD+) has emerged as a key regulator of cellular energy metabolism and homeostasis. Although a link between NAD+-dependent molecular events and cellular metabolism is evident, it remains unclear whether modulation of NAD+ levels has an impact on cisplatin-induced hearing impairment.Material and methodsTo investigate whether augmentation of NAD+ by NQO1 activation using b-Lapachone (b-Lap) attenuates cisplatin-mediated hearing impairment, male C57BL/6 mice and NQO1 knockout mice on a C57BL/6 background were used. For analysis of the auditory threshold, auditory brainstem response (ABR) was recorded. For biochemical analysis, we measured the enzymatic activity of SIRT1, PARP1, ROS production, NAD+/NADH ratio, mRNA levels of miR-34a and pro-inflammatory cytokines. Immunohistochemistry and western blot analysis were also performed.Results and discussionsWe have demonstrated for the first time that both the protein expression level and the activity of SIRT1 were suppressed by the reduction of intracellular NAD+ levels in cisplatin-treated cochlear tissue. We also found that the decrease in SIRT1 protein expression and its activity after cisplatin exposure were mediated by the increase in transcriptional activity of p53 for miR-34a expression and PARP-1 activation causing NAD+-depletion, respectively. However, the increase in cellular NAD+ levels by NQO1 activation using b-Lap prevented mice from cisplatin-induced cochlear damage and hearing impairment through the modulation of PARP-1, SIRT1, p53, and NF-kB.ConclusionConsidering that b-Lap itself did not attenuate the tumoricidal effect of cisplatin, these results suggest that the direct modulation of the cellular NAD+ level by pharmacological agents could be a promising therapeutic strategy for enhancing the efficacy of cisplatin chemotherapy without its adverse effects.

104P - Augmentation of NAD+ levels by enzymatic action of NAD(P)H quinone oxidoreductase 1 attenuates adriamycin-induced cardiomyopathy

104P - Augmentation of NAD+ levels by enzymatic action of NAD(P)H quinone oxidoreductase 1 attenuates adriamycin-induced cardiomyopathy

164 Augmentation of NAD+ by NQO1 activation attenuates cisplatin-mediated hearing impairment

164 Augmentation of NAD+ by NQO1 activation attenuates cisplatin-mediated hearing impairment

720: Augmentation of NAD+ by NQO1 activation attenuates cisplatin-mediated hearing impairment

720: Augmentation of NAD+ by NQO1 activation attenuates cisplatin-mediated hearing impairment

Augmentation of NAD(+) by NQO1 attenuates cisplatin-mediated hearing impairment.

Cisplatin (cis-diaminedichloroplatinum-II) is an extensively used chemotherapeutic agent, and one of its most adverse effects is ototoxicity. A number of studies have demonstrated that these effects are related to oxidative stress and DNA damage. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. The cofactor nicotinamide adenine dinucleotide (NAD+) has emerged as a key regulator of cellular energy metabolism and homeostasis. Here, we demonstrate for the first time that, in cisplatin-mediated ototoxicity, the levels and activities of SIRT1 are suppressed by the reduction of intracellular NAD+ levels. We provide evidence that the decrease in SIRT1 activity and expression facilitated by increasing poly(ADP-ribose) transferase (PARP)-1 activation and microRNA-34a through p53 activation aggravates cisplatin-mediated ototoxicity. Moreover, we show that the induction of cellular NAD+ levels using β-lapachone (β-Lap), whose intracellular target is NQO1, prevents the toxic effects of cisplatin through the regulation of PARP-1 and SIRT1 activity. These results suggest that direct modulation of cellular NAD+ levels by pharmacological agents could be a promising therapeutic approach for protection from cisplatin-induced ototoxicity.

Specific ablation of Nampt in adult neural stem cells recapitulates their functional defects during aging

Neural stem/progenitor cell (NSPC) proliferation and self-renewal, as well as insult-induced differentiation, decrease markedly with age. The molecular mechanisms responsible for these declines remain unclear. Here, we show that levels of NAD(+) and nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in mammalian NAD(+) biosynthesis, decrease with age in the hippocampus. Ablation of Nampt in adult NSPCs reduced their pool and proliferation in vivo. The decrease in the NSPC pool during aging can be rescued by enhancing hippocampal NAD(+) levels. Nampt is the main source of NSPC NAD(+) levels and required for G1/S progression of the NSPC cell cycle. Nampt is also critical in oligodendrocytic lineage fate decisions through a mechanism mediated redundantly by Sirt1 and Sirt2. Ablation of Nampt in the adult NSPCs in vivo reduced NSPC-mediated oligodendrogenesis upon insult. These phenotypes recapitulate defects in NSPCs during aging, giving rise to the possibility that Nampt-mediated NAD(+) biosynthesis is a mediator of age-associated functional declines in NSPCs.