Implications of NAD+ boosters in translational medicine Kang, Baeki E.; Choi, Jun‐Yong; Stein, Sokrates ...
European journal of clinical investigation,
October 2020, 2020-10-00, 20201001, Letnik:
50, Številka:
10
Journal Article
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Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite in energy metabolism as well as a co‐substrate in biochemical reactions such as protein deacylation, protein ADP‐ribosylation and ...cyclic ADP‐ribose synthesis mediated by sirtuins, poly (ADP‐ribose) polymerases (PARPs) and CD38. In eukaryotic cells, NAD+ is synthesized through three distinct pathways, which offer different strategies to modulate the bioavailability of NAD+. The therapeutic potential of dietarily available NAD+ boosters preserving the NAD+ pool has been attracting attention after the discovery of declining NAD+ levels in ageing model organisms as well as in several age‐related diseases, including cardiometabolic and neurodegenerative diseases. Here, we review the recent advances in the biology of NAD+, including the salubrious effects of NAD+ boosters and discuss their future translational strategies.
Reduced nicotinamide adenine dinucleotide phosphate (NADPH) is essential for biosynthetic reactions and antioxidant functions; however, detection of NADPH metabolism in living cells remains ...technically challenging. We develop and characterize ratiometric, pH-resistant, genetically encoded fluorescent indicators for NADPH (iNap sensors) with various affinities and wide dynamic range. iNap sensors enabled quantification of cytosolic and mitochondrial NADPH pools that are controlled by cytosolic NAD
kinase levels and revealed cellular NADPH dynamics under oxidative stress depending on glucose availability. We found that mammalian cells have a strong tendency to maintain physiological NADPH homeostasis, which is regulated by glucose-6-phosphate dehydrogenase and AMP kinase. Moreover, using the iNap sensors we monitor NADPH fluctuations during the activation of macrophage cells or wound response in vivo. These data demonstrate that the iNap sensors will be valuable tools for monitoring NADPH dynamics in live cells and gaining new insights into cell metabolism.
Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of the nicotinamide adenine dinucleotide (NAD+) salvage pathway. Because NAD+ plays a pivotal role in energy metabolism ...and boosting NAD+ has positive effects on metabolic regulation, activation of NAMPT is an attractive therapeutic approach for the treatment of various diseases, including type 2 diabetes and obesity. Herein we report the discovery of 1-(2-phenyl-1,3-benzoxazol-6-yl)-3-(pyridin-4-ylmethyl)urea 12c (DS68702229), which was identified as a potent NAMPT activator. Compound 12c activated NAMPT, increased cellular NAD+ levels, and exhibited an excellent pharmacokinetic profile in mice after oral administration. Oral administration of compound 12c to high-fat diet-induced obese mice decreased body weight. These observations indicate that compound 12c is a promising anti-obesity drug candidate.
Compartmentalization is a fundamental design principle of eukaryotic metabolism. Here, we review the compartmentalization of NAD+/NADH and NADP+/NADPH with a focus on the liver, an organ that ...experiences the extremes of biochemical physiology each day. Historical studies of the liver, using classical biochemical fractionation and measurements of redox-coupled metabolites, have given rise to the prevailing view that mitochondrial NAD(H) pools tend to be oxidized and important for energy homeostasis, whereas cytosolic NADP(H) pools tend to be highly reduced for reductive biosynthesis. Despite this textbook view, many questions still remain as to the relative size of these subcellular pools and their redox ratios in different physiological states, and to what extent such redox ratios are simply indicators versus drivers of metabolism. By performing a bioinformatic survey, we find that the liver expresses 352 known or predicted enzymes composing the hepatic NAD(P)ome, i.e. the union of all predicted enzymes producing or consuming NADP(H) or NAD(H) or using them as a redox co-factor. Notably, less than half are predicted to be localized within the cytosol or mitochondria, and a very large fraction of these genes exhibit gene expression patterns that vary during the time of day or in response to fasting or feeding. A future challenge lies in applying emerging new genetic tools to measure and manipulate in vivo hepatic NADP(H) and NAD(H) with subcellular and temporal resolution. Insights from such fundamental studies will be crucial in deciphering the pathogenesis of very common diseases known to involve alterations in hepatic NAD(P)H, such as diabetes and fatty liver disease.
•Static magnetic field can improve the TN removal efficiency of A/O SBR process.•PHB and EPS synthesis can be enhanced by static magnetic field.•Electron transport is more active when static magnetic ...field is applied.•SMF can reduce the microorganism community diversity.
Two anoxic/oxic (A/O) sequencing batch reactor (SBR) processes were utilized to study the effects of static magnetic field (SMF) on biological wastewater treatment process. Except for conventional indices, the reduced nicotinamide adenine dinucleotide (NADH)/oxidized nicotinamide adenine dinucleotide (NAD+) ratio and electron transport system activity (ETSA), as well as poly-beta-hydroxybutyrate (PHB) and extracellular polymetric substance (EPS) contents in two reactors which were with and without SMF under two cyclic times (12 h and 8 h) were monitored. When the process was enhanced by SMF, the total nitrogen removal efficiency can be improved (>80%), and the NADN/NAD+ ratio, ESTA, the maximum EPS content and the maximum PHB content in the reactor with SMF were higher. Besides, SMF can reduce the microorganism community diversity and make species distribute more even and abundant. SMF can promote the performance of A/O SBR process via improving electron transport and microbial community.
Acetaminophen (APAP) overdose induces acute liver injury (ALI), even acute liver failure (ALF). There is a significant unmet need to furtherly elucidate the mechanisms and find new therapeutic ...target. Recently, emerging evidence indicates that nicotinamide adenine dinucleotide (NAD+) plays a crucial role in APAP-induced ALI. Herein, we firstly investigated the protein expression of NAD kinase (NADK), as the rate-limiting enzyme converting NAD+ to nicotinamide adenine dinucleotide phosphate (NADP+), and found it was positively correlated with APAP-induced ALI in a dose- and time-dependent manner. Additionally, supplementation of N-acetylcysteine (NAC), known as an antidote of APAP, mitigated the ALI and downregulated the expression of NADK which was also in a dose-dependent manner. Moreover, pretreatment with methotrexate (MTX), the inhibitor of NADK, attenuated the levels of transaminases, alleviated morphological abnormalities, and improved oxidative stress triggered by APAP overdose, which was attributed to elevated hepatic NAD+ pool. Subsequently, the increased NAD+ upregulated the expression of Sirt1, SOD2 and attenuated DNA damage. Collectively, elevated expression of NADK is related to APAP-induced ALI, and inhibition of NADK alleviates the ALI through elevating liver NAD+ level and improving antioxidant capacity.
•The expression of NADK was positively correlated with APAP-induced ALI.•Inhibition of NADK alleviated APAP-induced ALI.•Inhibition of NADK increased the level of NAD+ and activated Sirt1/SOD2.
Interest in pharmacological agents capable of increasing cellular NAD+ concentrations has stimulated investigations of nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). NR and NMN ...require large dosages for effect. Herein, we describe synthesis of dihydronicotinamide riboside (NRH) and the discovery that NRH is a potent NAD+ concentration-enhancing agent, which acts within as little as 1 h after administration to mammalian cells to increase NAD+ concentrations by 2.5–10-fold over control values. Comparisons with NR and NMN show that in every instance, NRH provides greater NAD+ increases at equivalent concentrations. NRH also provides substantial NAD+ increases in tissues when administered by intraperitoneal injection to C57BL/6J mice. NRH substantially increases NAD+/NADH ratio in cultured cells and in liver and no induction of apoptotic markers or significant increases in lactate levels in cells. Cells treated with NRH are resistant to cell death caused by NAD+-depleting genotoxins such as hydrogen peroxide and methylmethane sulfonate. Studies to identify its biochemical mechanism of action showed that it does not inhibit NAD+ consumption, suggesting that it acts as a biochemical precursor to NAD+. Cell lysates possess an ATP-dependent kinase activity that efficiently converts NRH to the compound NMNH, but independent of Nrk1 or Nrk2. These studies identify a putative new metabolic pathway to NAD+ and a potent pharmacologic agent for NAD+ concentration enhancement in cells and tissues.
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.
•Nicotinamide Riboside augments spinal cord nicotinamide adenine dinucleotide (NAD+).•Elevating NAD+ protects spinal cord tissue from spinal cord injury (SCI).•Elevating NAD+ enhances motor recovery following SCI.
Reactive oxygen species (ROS) and oxidative stress have long been linked to aging and diseases prominent in the elderly such as hypertension, atherosclerosis, diabetes and atrial fibrillation (AF). ...NADPH oxidases (Nox) are a major source of ROS in the vasculature and are key players in mediating redox signalling under physiological and pathophysiological conditions. In this review, we focus on the Nox-mediated ROS signalling pathways involved in the regulation of 'longevity genes' and recapitulate their role in age-associated vascular changes and in the development of age-related cardiovascular diseases (CVDs). This review is predicated on burgeoning knowledge that Nox-derived ROS propagate tightly regulated yet varied signalling pathways, which, at the cellular level, may lead to diminished repair, the aging process and predisposition to CVDs. In addition, we briefly describe emerging Nox therapies and their potential in improving the health of the elderly population.
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