NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

Xie, Na; Zhang, Lu; Gao, Wei; Huang, Canhua; Huber, Peter E.; Zhou, Xiao‐Bo; Li, Changlong; Shen, Guobo; Zou, Bingwen

doi:10.1038/s41392-020-00311-7

Cited by 551 publications

(473 citation statements)

References 680 publications

(1,043 reference statements)

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“…As described in a previous published review, the salvage pathway occupied 85% of all the NAD+ and thus regarded as a key metabolism pathway. 13 NAD+ would be transformed to nicotinamide (NAM) through NAD+ consuming enzymes, and then became nicotinamide dinucleotide (NMN) after being catalyzed by nicotinamide phosphoribosyl transferase (NAMPT). NMN would then be catalyzed by nicotinamide mononucleotide adenylyl transferase 1–3 (NMNAT1-3).…”

Section: Resultsmentioning

confidence: 99%

“…NAD+, as a coenzyme that exists in human body and is closely related to thousands of enzymes involved in cellular life activities, 13 has the potential of delaying senescence and prolonging life with its direct precursor substance, nicotinamide mononucleotide (NMN). As aging is a risk factor of DED based on the TFOS DEWS II, 14 the application of NMN, which is a potential anti-aging drug might help in the management of DED.…”

Section: Introductionmentioning

confidence: 99%

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Nicotinamide Mononucleotide Alleviates Hyperosmolarity-Induced IL-17a Secretion and Macrophage Activation in Corneal Epithelial Cells/Macrophage Co-Culture System

Yu¹,

Pu²,

Dai³

et al. 2021

JIR

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Background Hyperosmosis stress (HS) was a key pathological factor in the development of dry eye disease (DED). Nicotinamide mononucleotide (NMN) demonstrated protective effects in the corneal damage, however, its role in the HS-induced DED remained unclear. Methods A NaCl based HS in-vitro model (500 mOsm) was generated and used in a co-culture system including corneal epithelial cells (CEC) and macrophage cell line RAW264.7. The effect of NMN on NAD+ metabolism and the expression of HS biomarker, tonicity-responsive element binding protein (TonEBP), was studied in the CEC. The cellular activity, including cell viability, apoptosis status and lactate dehydrogenase (LDH) release through trypan blue staining, flow cytometry and LDH assay, respectively. The mitochondrial membrane potential (MMP) assay would be conducted using the JC1 kit. The expression of IL-17a were detected using RT-PCR, ELISA and Western blot. After co-culture with the CEC in different group for 24 h, the phagocytosis ability and macrophage polarization were assessed in RAW264.7 cells co-cultured with CEC with or without HS or NMN treatment. Besides, the involvement of Notch pathway in the RAW264.7 would be analyzed. The potential involvement of Sirtuin 1 (SIRT1) and IL-17a in the crosstalk between CEC and macrophage was studied with SIRT1 inhibitor EX 527 and anti-IL-17a monoclonal antibody, respectively. Results NMN treatment increased NAD+ concentration and thus improved cell viability, reduced apoptotic rate and decreased the LDH release in HS-treated CEC. Besides, NMN alleviated HS-induced MMP, intracellular ROS and LDH release. Besides, it was confirmed NMN improve SIRT1 function and decreased the HS related IL-17a expression in CEC and then alleviated macrophage phagocytosis ability and M1 polarization based on a CEC-macrophage co-culture system. Moreover, NMN treatment of CEC in the CEC could moderate the subsequent macrophage activation through Notch pathway. SIRT1 activation and IL-17a inhibition was regarded as key progress in the function of NMN based on the application of EX 527 and anti-IL-17a antibody in the CEC-macrophage co-culture system. Conclusion The findings demonstrated that NMN could alleviated HS-induced DED status through regulating the CEC/macrophage interaction. Our data pointed to the role of SIRT1, IL-17a and Notch pathway in the function of NMN and then provided updated knowledge of potential NMN application in the management of DED.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nicotinamide Mononucleotide Alleviates Hyperosmolarity-Induced IL-17a Secretion and Macrophage Activation in Corneal Epithelial Cells/Macrophage Co-Culture System

Yu¹,

Pu²,

Dai³

et al. 2021

JIR

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“…De novo NAD + synthesis or increased availability of NAD + precursors may thus support cognitive functions and lead to a decrease of Aβ amyloid fibrils [ 221 , 222 , 223 , 224 , 225 ]. Nicotinamide treatment preserved mitochondrial integrity in mouse models of AD [ 220 ] in cells with a functional NAD + salvage pathway.…”

Section: Nad + Boosters and Therapeutic Role Inmentioning

confidence: 99%

Mono(ADP-ribosyl)ation Enzymes and NAD+ Metabolism: A Focus on Diseases and Therapeutic Perspectives

Poltronieri

Celetti

Palazzo

2021

Cells

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Mono(ADP-ribose) transferases and mono(ADP-ribosyl)ating sirtuins use NAD+ to perform the mono(ADP-ribosyl)ation, a simple form of post-translational modification of proteins and, in some cases, of nucleic acids. The availability of NAD+ is a limiting step and an essential requisite for NAD+ consuming enzymes. The synthesis and degradation of NAD+, as well as the transport of its key intermediates among cell compartments, play a vital role in the maintenance of optimal NAD+ levels, which are essential for the regulation of NAD+-utilizing enzymes. In this review, we provide an overview of the current knowledge of NAD+ metabolism, highlighting the functional liaison with mono(ADP-ribosyl)ating enzymes, such as the well-known ARTD10 (also named PARP10), SIRT6, and SIRT7. To this aim, we discuss the link of these enzymes with NAD+ metabolism and chronic diseases, such as cancer, degenerative disorders and aging.

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“…NAD + is essential for glycolysis as well as oxidative phosphorylation (OXPHOS) as an electron transmitter. NAD + also serves as a co-substrate for poly (ADP-ribose) polymerases (PARPs) and the sirtuin family ( 26 – 28 ). The intracellular NAD + level is one of the critical determinants of differentiation and functions in macrophages.…”

Section: The Impact Of Dietary Intervention On Immune Responsesmentioning

confidence: 99%

Dietary Intervention Impacts Immune Cell Functions and Dynamics by Inducing Metabolic Rewiring

2021

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Accumulating evidence has shown that nutrient metabolism is closely associated with the differentiation and functions of various immune cells. Cellular metabolism, including aerobic glycolysis, fatty acid oxidation, and oxidative phosphorylation, plays a key role in germinal center (GC) reaction, B-cell trafficking, and T-cell-fate decision. Furthermore, a quiescent metabolic status consolidates T-cell-dependent immunological memory. Therefore, dietary interventions such as calorie restriction, time-restricted feeding, and fasting potentially manipulate immune cell functions. For instance, intermittent fasting prevents the development of experimental autoimmune encephalomyelitis. Meanwhile, the fasting response diminishes the lymphocyte pool in gut-associated lymphoid tissue to minimize energy expenditure, leading to the attenuation of Immunoglobulin A (IgA) response. The nutritional status also influences the dynamics of several immune cell subsets. Here, we describe the current understanding of the significance of immunometabolism in the differentiation and functionality of lymphocytes and macrophages. The underlying molecular mechanisms also are discussed. These experimental observations could offer new therapeutic strategies for immunological disorders like autoimmunity.

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NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

Cited by 551 publications

References 680 publications

Nicotinamide Mononucleotide Alleviates Hyperosmolarity-Induced IL-17a Secretion and Macrophage Activation in Corneal Epithelial Cells/Macrophage Co-Culture System

Nicotinamide Mononucleotide Alleviates Hyperosmolarity-Induced IL-17a Secretion and Macrophage Activation in Corneal Epithelial Cells/Macrophage Co-Culture System

Mono(ADP-ribosyl)ation Enzymes and NAD+ Metabolism: A Focus on Diseases and Therapeutic Perspectives

Dietary Intervention Impacts Immune Cell Functions and Dynamics by Inducing Metabolic Rewiring

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