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.

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 News about the Role of Fluid and Imaging Biomarkers in Neurodegenerative Diseases

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 252
Author(s):  
Jacopo Meldolesi
Keyword(s):  
Neurodegenerative Diseases ◽  
Imaging Techniques ◽  
Imaging Biomarkers ◽  
Positron Emission ◽  
Specific Proteins ◽  
Great Relevance ◽  
The Brain ◽  
Positive Point

Biomarkers are molecules that are variable in their origin, nature, and mechanism of action; they are of great relevance in biology and also in medicine because of their specific connection with a single or several diseases. Biomarkers are of two types, which in some cases are operative with each other. Fluid biomarkers, started around 2000, are generated in fluid from specific proteins/peptides and miRNAs accumulated within two extracellular fluids, either the central spinal fluid or blood plasma. The switch of these proteins/peptides and miRNAs, from free to segregated within extracellular vesicles, has induced certain advantages including higher levels within fluids and lower operative expenses. Imaging biomarkers, started around 2004, are identified in vivo upon their binding by radiolabeled molecules subsequently revealed in the brain by positron emission tomography and/or other imaging techniques. A positive point for the latter approach is the quantitation of results, but expenses are much higher. At present, both types of biomarker are being extensively employed to study Alzheimer’s and other neurodegenerative diseases, investigated from the presymptomatic to mature stages. In conclusion, biomarkers have revolutionized scientific and medical research and practice. Diagnosis, which is often inadequate when based on medical criteria only, has been recently improved by the multiplicity and specificity of biomarkers. Analogous results have been obtained for prognosis. In contrast, improvement of therapy has been limited or fully absent, especially for Alzheimer’s in which progress has been inadequate. An urgent need at hand is therefore the progress of a new drug trial design together with patient management in clinical practice.

Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle motility in healthy old men

2021 ◽  
Author(s):  
Masaki Igarashi ◽  
Masaomi Miura ◽  
Yoshiko Nakagawa-Nagahama ◽  
Keisuke Yaku ◽  
Kosuke Kashiwabara ◽  
...  
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
Nicotinamide Adenine ◽  
Double Blind ◽  
Oral Supplementation ◽  
Healthy Elderly ◽  
Nicotinamide Mononucleotide ◽  
Parallel Group ◽  
And Performance ◽  
Old Men ◽  
Parallel Group Trial

Abstract Preclinical studies have revealed that the elevation of nicotinamide adenine dinucleotide (NAD+) levels on administration of an NAD+ precursor, nicotinamide mononucleotide (NMN), can mitigate aging-related disorders; however, human data are sparse. Therefore, we aimed to investigate whether the chronic oral supplementation of NMN can elevate blood NAD+ levels and alter physiological dysfunctions, including muscle weakness, in healthy elderly participants. We administered 250 mg NMN per day to aged men for 6 or 12 weeks (n=21 for 6 weeks, n=10 for 12 weeks) in a placebo-controlled, randomized, double blind, parallel-group trial. Chronic supplementation with NMN was well tolerated and did not cause any significant deleterious effect. Metabolomic analysis of whole blood demonstrated that the oral supplementation of NMN significantly increased the concentrations of NAD+ and NAD+ metabolites. Moreover, NMN significantly improved muscle strength and performance, which were evaluated using the 30-second chair stand test, walking speed, and grip strength, and it showed no significant effect on body composition. Thus, our evidence indicates that chronic oral NMN supplementation can be an efficient NAD+ booster for preventing aging-related muscle dysfunctions in humans.

Ageing and the human brain

2020 ◽  
pp. 170-182
Author(s):  
Verena Heise ◽  
Enikő Zsoldos ◽  
Klaus P. Ebmeier
Keyword(s):  
In Vivo Imaging ◽  
Allostatic Load ◽  
Public Health Medicine ◽  
Causal Factors ◽  
Stress Markers ◽  
Age Related ◽  
Brain Changes ◽  
Heuristic Device ◽  
The Brain

There is little doubt that the brain changes with time, and all research in psychiatry is predicated on holding age constant in comparing groups of patients or estimating the effect sizes of causal factors. Nevertheless, relatively little is known about the mechanisms that are responsible for translating time into ageing. This chapter tries, after an overview of the principal mechanisms involved in biological ageing, to summarize the age-related changes observable in brains in vivo and to demonstrate the types of investigations that may cast light on such mechanisms in the future. A useful heuristic device to order the multiple potential causes of ageing is the chronic stress–allostatic load model, widely employed in epidemiology, public health medicine, and health psychology. In vivo imaging provides a method to test the translation of intermediate stress markers, such as vascular risk, metabolic syndrome, or allostatic load, into predictors of age-related brain changes.

scholarly journals Potential caveats of putative microglia-specific markers for assessment of age-related cerebrovascular neuroinflammation

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Pedram Honarpisheh ◽  
Juneyoung Lee ◽  
Anik Banerjee ◽  
Maria P. Blasco-Conesa ◽  
Parisa Honarpisheh ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Ex Vivo ◽  
Myeloid Cells ◽  
Amyloid Angiopathy ◽  
Future Studies ◽  
Age Related ◽  
In Vivo Animal Models ◽  
Intermediate Expression ◽  
The Brain

Abstract Background The ability to distinguish resident microglia from infiltrating myeloid cells by flow cytometry-based surface phenotyping is an important technique for examining age-related neuroinflammation. The most commonly used surface markers for the identification of microglia include CD45 (low-intermediate expression), CD11b, Tmem119, and P2RY12. Methods In this study, we examined changes in expression levels of these putative microglia markers in in vivo animal models of stroke, cerebral amyloid angiopathy (CAA), and aging as well as in an ex vivo LPS-induced inflammation model. Results We demonstrate that Tmem119 and P2RY12 expression is evident within both CD45int and CD45high myeloid populations in models of stroke, CAA, and aging. Interestingly, LPS stimulation of FACS-sorted adult microglia suggested that these brain-resident myeloid cells can upregulate CD45 and downregulate Tmem119 and P2RY12, making them indistinguishable from peripherally derived myeloid populations. Importantly, our findings show that these changes in the molecular signatures of microglia can occur without a contribution from the other brain-resident or peripherally sourced immune cells. Conclusion We recommend future studies approach microglia identification by flow cytometry with caution, particularly in the absence of the use of a combination of markers validated for the specific neuroinflammation model of interest. The subpopulation of resident microglia residing within the “infiltrating myeloid” population, albeit small, may be functionally important in maintaining immune vigilance in the brain thus should not be overlooked in neuroimmunological studies.

Acute administration of a tryptophan-free amino acid mixture decreases 5-HT release in rat hippocampus in vivo

1997 ◽  
Vol 272 (3) ◽  
pp. R991-R994 ◽  
Author(s):  
R. Stancampiano ◽  
F. Melis ◽  
L. Sarais ◽  
S. Cocco ◽  
C. Cugusi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Oral Administration ◽  
Free Amino Acid ◽  
Free Amino ◽  
Dorsal Hippocampus ◽  
Amino Acid Mixture ◽  
Acid Mixture ◽  
Acute Administration ◽  
The Brain

The effect of oral administration of a tryptophan-free amino acid mixture or the same mixture containing tryptophan (Trp) on hippocampal serotonin (5-HT) extracellular levels was studied using in vivo brain microdialysis of freely moving rats. During chloral hydrate anesthesia rats were implanted with dialysis probes in the dorsal hippocampus, and experiments were performed 24 h later. In vehicle-treated rats, the extracellular levels of 5-hydroxyindolacetic acid (5-HIAA) and 5-HT did not change during 240 min after ingestion. Oral administration of the Trp-free amino acid mixture significantly decreased basal 5-HT and 5-HIAA output 100 min after ingestion (65 and 81% of basal value, respectively) and remained at this level for another 140 min. The amino acid mixture containing Trp failed to significantly change basal extracellular levels of 5-HT, but enhanced that of 5-HIAA by approximately 134%. Moreover, in rats receiving the Trp-free amino acid mixture, the increase of hippocampal 5-HT release induced by d-fenfluramine (206%) was smaller than that released by the same drug in rats receiving the nutritionally balanced amino acid mixture (271%). Thus these results show that removal of Trp from the balanced amino acid mixture decreases spontaneous and d-fenfluramine-induced release of 5-HT in the hippocampus. In conclusion, our study supports the hypothesis that the mood-lowering effect observed in man after ingestion of a Trp-free amino acid mixture is associated with diminished 5-HT release in the brain.

scholarly journals New Chemical Probe Targeting Bacterial NAD Kinase

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 4893
Author(s):  
David A. Clément ◽  
Clarisse Leseigneur ◽  
Muriel Gelin ◽  
Dylan Coelho ◽  
Valérie Huteau ◽  
...  
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
Kinase Inhibitors ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Nicotinamide Adenine ◽  
Infection Model ◽  
Detailed Knowledge ◽  
Nad Kinase ◽  
Chemical Probe ◽  
Covalent Coupling

Nicotinamide adenine dinucleotide (NAD) kinases are essential and ubiquitous enzymes involved in the tight regulation of NAD/nicotinamide adenine dinucleotide phosphate (NADP) levels in many metabolic pathways. Consequently, they represent promising therapeutic targets in cancer and antibacterial treatments. We previously reported diadenosine derivatives as NAD kinase inhibitors with bactericidal activities on Staphylococcus aureus. Among them, one compound (namely NKI1) was found effective in vivo in a mouse infection model. With the aim to gain detailed knowledge about the selectivity and mechanism of action of this lead compound, we planned to develop a chemical probe that could be used in affinity-based chemoproteomic approaches. Here, we describe the first functionalized chemical probe targeting a bacterial NAD kinase. Aminoalkyl functional groups were introduced on NKI1 for further covalent coupling to an activated SepharoseTM matrix. Inhibitory properties of functionalized NKI1 derivatives together with X-ray characterization of their complexes with the NAD kinase led to identify candidate compounds that are amenable to covalent coupling to a matrix.

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