Nicotinamide adenine dinucleotide (NAD+): essential redox metabolite, co-substrate and an anti-cancer and anti-ageing therapeutic target

2020 ◽  
Vol 48 (3) ◽  
pp. 733-744 ◽  
Author(s):  
Hollie B.S. Griffiths ◽  
Courtney Williams ◽  
Sarah J. King ◽  
Simon J. Allison
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
Tumour Microenvironment ◽  
Nicotinamide Adenine ◽  
Reduced Form ◽  
Nad Metabolism ◽  
Growth And Survival ◽  
Cell Functions ◽  
Disease States ◽  
Age Related ◽  
Redox Metabolites

Nicotinamide adenine dinucleotide (NAD+) and its reduced form NADH are essential coupled redox metabolites that primarily promote cellular oxidative (catabolic) metabolic reactions. This enables energy generation through glycolysis and mitochondrial respiration to support cell growth and survival. In addition, many key enzymes that regulate diverse cell functions ranging from gene expression to proteostasis require NAD+ as a co-substrate for their catalytic activity. This includes the NAD+-dependent sirtuin family of protein deacetylases and the PARP family of DNA repair enzymes. Whilst their vital activity consumes NAD+ which is cleaved to nicotinamide, several pathways exist for re-generating NAD+ and sustaining NAD+ homeostasis. However, there is growing evidence of perturbed NAD+ homeostasis and NAD+-regulated processes contributing to multiple disease states. NAD+ levels decline in the human brain and other organs with age and this is associated with neurodegeneration and other age-related diseases. Dietary supplementation with NAD+ precursors is being investigated to counteract this. Paradoxically, many cancers have increased dependency on NAD+. Clinical efforts to exploit this have so far shown limited success. Emerging new opportunities to exploit dysregulation of NAD+ metabolism in cancers are critically discussed. An update is also provided on other key NAD+ research including perturbation of the NAD+ salvage enzyme NAMPT in the context of the tumour microenvironment (TME), methodology to study subcellular NAD+ dynamics in real-time and the regulation of differentiation by competing NAD+ pools.

scholarly journals Oral Administration of Nicotinamide Mononucleotide Increases Nicotinamide Adenine Dinucleotide Level in an Animal Brain

Nutrients ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 300
Author(s):  
Chidambaram Ramanathan ◽  
Thomas Lackie ◽  
Drake H. Williams ◽  
Paul S. Simone ◽  
Yufeng Zhang ◽  
...  
Keyword(s):  
Oral Administration ◽  
Neurodegenerative Diseases ◽  
Nicotinamide Adenine Dinucleotide ◽  
Nicotinamide Adenine ◽  
Disease States ◽  
Nicotinamide Mononucleotide ◽  
Age Related ◽  
Mice Brain ◽  
The Brain

As a redox-sensitive coenzyme, nicotinamide adenine dinucleotide (NAD+) plays a central role in cellular energy metabolism and homeostasis. Low NAD+ levels are linked to multiple disease states, including age-related diseases, such as metabolic and neurodegenerative diseases. Consequently, restoring/increasing NAD+ levels in vivo has emerged as an important intervention targeting age-related neurodegenerative diseases. One of the widely studied approaches to increase NAD+ levels in vivo is accomplished by using NAD+ precursors, such as nicotinamide mononucleotide (NMN). Oral administration of NMN has been shown to successfully increase NAD+ levels in a variety of tissues; however, it remains unclear whether NMN can cross the blood–brain barrier to increase brain NAD+ levels. This study evaluated the effects of oral NMN administration on NAD+ levels in C57/B6J mice brain tissues. Our results demonstrate that oral gavage of 400 mg/kg NMN successfully increases brain NAD+ levels in mice after 45 min. These findings provide evidence that NMN may be used as an intervention to increase NAD+ levels in the brain.

scholarly journals Pathogen induced subversion of NAD+ metabolism mediating host cell death: a target for development of chemotherapeutics

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ayushi Chaurasiya ◽  
Swati Garg ◽  
Ashish Khanna ◽  
Chintam Narayana ◽  
Ved Prakash Dwivedi ◽  
...  
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Nicotinamide Adenine Dinucleotide ◽  
Malaria Parasite ◽  
Host Cells ◽  
Nicotinamide Adenine ◽  
Targeted Therapeutics ◽  
Nad Metabolism ◽  
Host Cell Death ◽  
Nanomolar Range

AbstractHijacking of host metabolic status by a pathogen for its regulated dissemination from the host is prerequisite for the propagation of infection. M. tuberculosis secretes an NAD+-glycohydrolase, TNT, to induce host necroptosis by hydrolyzing Nicotinamide adenine dinucleotide (NAD+). Herein, we expressed TNT in macrophages and erythrocytes; the host cells for M. tuberculosis and the malaria parasite respectively, and found that it reduced the NAD+ levels and thereby induced necroptosis and eryptosis resulting in premature dissemination of pathogen. Targeting TNT in M. tuberculosis or induced eryptosis in malaria parasite interferes with pathogen dissemination and reduction in the propagation of infection. Building upon our discovery that inhibition of pathogen-mediated host NAD+ modulation is a way forward for regulation of infection, we synthesized and screened some novel compounds that showed inhibition of NAD+-glycohydrolase activity and pathogen infection in the nanomolar range. Overall this study highlights the fundamental importance of pathogen-mediated modulation of host NAD+ homeostasis for its infection propagation and novel inhibitors as leads for host-targeted therapeutics.

scholarly journals Cesium Treatment Depresses Glycolysis Pathway in HeLa Cell

2021 ◽  
Vol 55 (4) ◽  
pp. 477-488
Keyword(s):  
Hela Cell ◽  
Nicotinamide Adenine Dinucleotide ◽  
Aerobic Glycolysis ◽  
Biological Effects ◽  
Glycolytic Enzyme ◽  
Nicotinamide Adenine ◽  
Reduced Form ◽  
Dependent Manner ◽  
Nadh Ratio ◽  
Glycolysis Pathway

Background/Aims: Cesium (Cs) is an alkali metal element that is of no essential use for humans; it has no known beneficial function that is verified by clinical research. When used as an alternative cancer therapy, it even causes toxicity in high doses. Thus, before using Cs as treatment in clinical settings, it is important to clearly determine its biological effects on cells. However, Cs was found to suppress the proliferation of human cervical cancer cells in a dose-dependent manner, and it was assumed that Cs inhibits the glycolysis pathway. In this study, we clearly determined the step of the glycolysis pathway that is affected by Cs. Methods: The glycolytic enzyme expressions, activities, and metabolite concentrations in HeLa cells were measured by PCR, western blotting, and enzymatic methods, after treating the cells with Cs for 3 days. Results: Cs treatment decreased transcriptional and expression levels of hexokinase, glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase (PK), and lactate dehydrogenase and the activity of PK. Analysis of glycolysis pathway metabolites revealed that Cs treatment reduces lactate level and increases the level of nicotinamide adenine dinucleotide (oxidized form, NAD+); however, it did not affect the levels of pyruvate and nicotinamide adenine dinucleotide (reduced form, NADH). Increase of the [NAD+]/[NADH] ratio and decrease of the [lactate]/[pyruvate] ratio indicate that Cs treatment inhibits the aerobic glycolysis pathway. Conclusion: Cs treatment inhibits PK activity and increases the [NAD+]/[NADH] ratio. Hence, Cs has been determined to inhibit glycolysis, especially the aerobic glycolysis pathway. These results suggest that suppression of HeLa cell proliferation following Cs treatment was caused by inhibition of aerobic glycolysis by Cs.

Acyl-CoA-binding domain containing 3 modulates NAD+ metabolism through activating poly(ADP-ribose) polymerase 1

2015 ◽  
Vol 469 (2) ◽  
pp. 189-198 ◽  
Author(s):  
Yong Chen ◽  
Sookhee Bang ◽  
Soohyun Park ◽  
Hanyuan Shi ◽  
Sangwon F. Kim
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
Cell Metabolism ◽  
Living Cells ◽  
Binding Domain ◽  
Nicotinamide Adenine ◽  
Cellular Functions ◽  
Nad Metabolism ◽  
Domain 3 ◽  
And Function

Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells and plays a fundamental role is basic cellular functions. Our findings revealed that acyl-CoA binding domain 3 (ACBD3) has prominent impacts on the cellular NAD+ metabolism via regulating PARP1 activation-dependent automodification and thus cell metabolism and function.

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