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From Research on Vitamin B3, NAD+ and ADP-Ribose Metabolism...
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From Research on Vitamin B3, NAD+ and ADP-Ribose Metabolism to Clinical Applications in Human Health

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Metabolism".

Deadline for manuscript submissions: closed (15 October 2023) | Viewed by 24470

Special Issue Editors

Prof. Dr. Michael O. Hottiger

E-Mail Website
Guest Editor
Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland
Interests: inflammatory signaling; NAD; ADP-ribose; ADP-ribosylation; ADP-ribosyltransferase
Dr. Michael S. Cohen

E-Mail Website
Guest Editor
Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, USA
Interests: chemical biology; NAD+; ADP-ribosylation; ADP-ribosyltransferases; PARPs

Special Issue Information

Dear Colleagues,

Science writer David Rains Wallace once said that “fermentation may have been a better invention than fire.” Tongue-and-cheek, yes, but he was quite right: NAD+, a molecule essential for life, was in fact discovered (in 1906) while studying the mechanism of fermentation. Thirty years of research and three Nobel prizes later, the structure of NAD+ (i.e., a dinucleotide containing nicotinamide and adenine) and its function in fermentation (i.e., redox reactions known as hydride transfers) were resolved. The importance of NAD+ in human health was first demonstrated in 1937 when it was reported that the NAD+ biosynthetic precursors nicotinic acid and nicotinamide (also known as vitamin B3) could effectively be used for the treatment of pellagra, a devastating human disease that is due to NAD+ deficiency.

In the 1960s, a paradigm shift in the NAD+ field occurred when it was shown that an enzyme (now known as PARP1) cleaves the glycosidic bond of NAD+, transfers the ADP-ribose group to amino acid side chains, and forms polymers of ADP-ribose. Fast forward to today, we now know that multiple classes of NAD+-consuming enzymes exist, including PARPs (17 in humans) and other ADP-ribosyltransferases, cyclic ADP-ribose synthases, and NAD+-dependent protein deacetylases which are involved in fundamental processes affecting health and disease. While much focus of current research is on protein acceptors, DNA, RNA, and NAD itself have been identified as acceptors.

This Special Issue honors Myron (Mike) and Elaine Jacobson, who made an indelible imprint on the NAD+ field: from our understanding of NAD+ homeostasis and ADP-ribosylation to developing novel NAD+ precursors for the treatment of human diseases. The aim of this Special Issue is to summarize our current knowledge on the synthesis, biological, and functional roles of NAD+ and its metabolites and how they are clinically applied for human health.

We look forward to your contributions.

 

Prof. Dr. Michael Hottiger
Dr. Michael S. Cohen
Guest Editors

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • vitamin B3
  • nicotinic acid
  • nicotinamide
  • nicotine riboside
  • NAD
  • ADP-ribose
  • ADP-ribosylation
  • MARylation
  • PARylation
  • NAD metabolism

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Published Papers (7 papers)

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Research

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22 pages, 4876 KiB  
Article
NAD+ Acts as a Protective Factor in Cellular Stress Response to DNA Alkylating Agents
by Joanna Ruszkiewicz, Ylea Papatheodorou, Nathalie Jäck, Jasmin Melzig, Franziska Eble, Annika Pirker, Marius Thomann, Andreas Haberer, Simone Rothmiller, Alexander Bürkle and Aswin Mangerich
Cells 2023, 12(19), 2396; https://doi.org/10.3390/cells12192396 - 2 Oct 2023
Cited by 1 | Viewed by 2644
Abstract
Sulfur mustard (SM) and its derivatives are potent genotoxic agents, which have been shown to trigger the activation of poly (ADP-ribose) polymerases (PARPs) and the depletion of their substrate, nicotinamide adenine dinucleotide (NAD+). NAD+ is an essential molecule involved in [...] Read more.
Sulfur mustard (SM) and its derivatives are potent genotoxic agents, which have been shown to trigger the activation of poly (ADP-ribose) polymerases (PARPs) and the depletion of their substrate, nicotinamide adenine dinucleotide (NAD+). NAD+ is an essential molecule involved in numerous cellular pathways, including genome integrity and DNA repair, and thus, NAD+ supplementation might be beneficial for mitigating mustard-induced (geno)toxicity. In this study, the role of NAD+ depletion and elevation in the genotoxic stress response to SM derivatives, i.e., the monofunctional agent 2-chloroethyl-ethyl sulfide (CEES) and the crosslinking agent mechlorethamine (HN2), was investigated with the use of NAD+ booster nicotinamide riboside (NR) and NAD+ synthesis inhibitor FK866. The effects were analyzed in immortalized human keratinocytes (HaCaT) or monocyte-like cell line THP-1. In HaCaT cells, NR supplementation, increased NAD+ levels, and elevated PAR response, however, did not affect ATP levels or DNA damage repair, nor did it attenuate long- and short-term cytotoxicities. On the other hand, the depletion of cellular NAD+ via FK866 sensitized HaCaT cells to genotoxic stress, particularly CEES exposure, whereas NR supplementation, by increasing cellular NAD+ levels, rescued the sensitizing FK866 effect. Intriguingly, in THP-1 cells, the NR-induced elevation of cellular NAD+ levels did attenuate toxicity of the mustard compounds, especially upon CEES exposure. Together, our results reveal that NAD+ is an important molecule in the pathomechanism of SM derivatives, exhibiting compound-specificity. Moreover, the cell line-dependent protective effects of NR are indicative of system-specificity of the application of this NAD+ booster. Full article
(This article belongs to the Special Issue From Research on Vitamin B3, NAD+ and ADP-Ribose Metabolism to Clinical Applications in Human Health)
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22 pages, 3415 KiB  
Article
PARP1 Regulates Circular RNA Biogenesis though Control of Transcriptional Dynamics
by Rebekah Eleazer, Kalpani De Silva, Kalina Andreeva, Zoe Jenkins, Nour Osmani, Eric C. Rouchka and Yvonne Fondufe-Mittendorf
Cells 2023, 12(8), 1160; https://doi.org/10.3390/cells12081160 - 14 Apr 2023
Cited by 6 | Viewed by 2879
Abstract
Circular RNAs (circRNAs) are a recently discovered class of RNAs derived from protein-coding genes that have important biological and pathological roles. They are formed through backsplicing during co-transcriptional alternative splicing; however, the unified mechanism that accounts for backsplicing decisions remains unclear. Factors that [...] Read more.
Circular RNAs (circRNAs) are a recently discovered class of RNAs derived from protein-coding genes that have important biological and pathological roles. They are formed through backsplicing during co-transcriptional alternative splicing; however, the unified mechanism that accounts for backsplicing decisions remains unclear. Factors that regulate the transcriptional timing and spatial organization of pre-mRNA, including RNAPII kinetics, the availability of splicing factors, and features of gene architecture, have been shown to influence backsplicing decisions. Poly (ADP-ribose) polymerase I (PARP1) regulates alternative splicing through both its presence on chromatin as well as its PARylation activity. However, no studies have investigated PARP1’s possible role in regulating circRNA biogenesis. Here, we hypothesized that PARP1’s role in splicing extends to circRNA biogenesis. Our results identify many unique circRNAs in PARP1 depletion and PARylation-inhibited conditions compared to the wild type. We found that while all genes producing circRNAs share gene architecture features common to circRNA host genes, genes producing circRNAs in PARP1 knockdown conditions had longer upstream introns than downstream introns, whereas flanking introns in wild type host genes were symmetrical. Interestingly, we found that the behavior of PARP1 in regulating RNAPII pausing is distinct between these two classes of host genes. We conclude that the PARP1 pausing of RNAPII works within the context of gene architecture to regulate transcriptional kinetics, and therefore circRNA biogenesis. Furthermore, this regulation of PARP1 within host genes acts to fine tune their transcriptional output with implications in gene function. Full article
(This article belongs to the Special Issue From Research on Vitamin B3, NAD+ and ADP-Ribose Metabolism to Clinical Applications in Human Health)
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28 pages, 44900 KiB  
Article
Efficacy of Clinically Used PARP Inhibitors in a Murine Model of Acute Lung Injury
by Vanessa Martins, Sidneia S. Santos, Larissa de O. C. P. Rodrigues, Reinaldo Salomao, Lucas Liaudet and Csaba Szabo
Cells 2022, 11(23), 3789; https://doi.org/10.3390/cells11233789 - 26 Nov 2022
Cited by 7 | Viewed by 2312
Abstract
Poly(ADP-ribose) polymerase 1 (PARP1), as a potential target for the experimental therapy of acute lung injury (ALI), was identified over 20 years ago. However, clinical translation of this concept was not possible due to the lack of clinically useful PARP inhibitors. With the [...] Read more.
Poly(ADP-ribose) polymerase 1 (PARP1), as a potential target for the experimental therapy of acute lung injury (ALI), was identified over 20 years ago. However, clinical translation of this concept was not possible due to the lack of clinically useful PARP inhibitors. With the clinical introduction of several novel, ultrapotent PARP inhibitors, the concept of PARP inhibitor repurposing has re-emerged. Here, we evaluated the effect of 5 clinical-stage PARP inhibitors in oxidatively stressed cultured human epithelial cells and monocytes in vitro and demonstrated that all inhibitors (1–30 µM) provide a comparable degree of cytoprotection. Subsequent in vivo studies using a murine model of ALI compared the efficacy of olaparib and rucaparib. Both inhibitors (1–10 mg/kg) provided beneficial effects against lung extravasation and pro-inflammatory mediator production—both in pre- and post-treatment paradigms. The underlying mechanisms include protection against cell dysfunction/necrosis, inhibition of NF-kB and caspase 3 activation, suppression of the NLRP3 inflammasome, and the modulation of pro-inflammatory mediators. Importantly, the efficacy of PARP inhibitors was demonstrated without any potentiation of DNA damage, at least as assessed by the TUNEL method. These results support the concept that clinically approved PARP inhibitors may be repurposable for the experimental therapy of ALI. Full article
(This article belongs to the Special Issue From Research on Vitamin B3, NAD+ and ADP-Ribose Metabolism to Clinical Applications in Human Health)
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Review

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12 pages, 660 KiB  
Review
Enzymology of Ca2+-Mobilizing Second Messengers Derived from NAD: From NAD Glycohydrolases to (Dual) NADPH Oxidases
by Andreas H. Guse
Cells 2023, 12(4), 675; https://doi.org/10.3390/cells12040675 - 20 Feb 2023
Cited by 6 | Viewed by 2847
Abstract
Nicotinamide adenine dinucleotide (NAD) and its 2′-phosphorylated cousin NADP are precursors for the enzymatic formation of the Ca2+-mobilizing second messengers adenosine diphosphoribose (ADPR), 2′-deoxy-ADPR, cyclic ADPR, and nicotinic acid adenine dinucleotide phosphate (NAADP). The enzymes involved are either NAD glycohydrolases CD38 [...] Read more.
Nicotinamide adenine dinucleotide (NAD) and its 2′-phosphorylated cousin NADP are precursors for the enzymatic formation of the Ca2+-mobilizing second messengers adenosine diphosphoribose (ADPR), 2′-deoxy-ADPR, cyclic ADPR, and nicotinic acid adenine dinucleotide phosphate (NAADP). The enzymes involved are either NAD glycohydrolases CD38 or sterile alpha toll/interleukin receptor motif containing-1 (SARM1), or (dual) NADPH oxidases (NOX/DUOX). Enzymatic function(s) are reviewed and physiological role(s) in selected cell systems are discussed. Full article
(This article belongs to the Special Issue From Research on Vitamin B3, NAD+ and ADP-Ribose Metabolism to Clinical Applications in Human Health)
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23 pages, 1254 KiB  
Review
Beyond Pellagra—Research Models and Strategies Addressing the Enduring Clinical Relevance of NAD Deficiency in Aging and Disease
by Morgan B. Feuz, Mirella L. Meyer-Ficca and Ralph G. Meyer
Cells 2023, 12(3), 500; https://doi.org/10.3390/cells12030500 - 3 Feb 2023
Cited by 8 | Viewed by 5158
Abstract
Research into the functions of nicotinamide adenine dinucleotide (NAD) has intensified in recent years due to the insight that abnormally low levels of NAD are involved in many human pathologies including metabolic disorders, neurodegeneration, reproductive dysfunction, cancer, and aging. Consequently, the development and [...] Read more.
Research into the functions of nicotinamide adenine dinucleotide (NAD) has intensified in recent years due to the insight that abnormally low levels of NAD are involved in many human pathologies including metabolic disorders, neurodegeneration, reproductive dysfunction, cancer, and aging. Consequently, the development and validation of novel NAD-boosting strategies has been of central interest, along with the development of models that accurately represent the complexity of human NAD dynamics and deficiency levels. In this review, we discuss pioneering research and show how modern researchers have long since moved past believing that pellagra is the overt and most dramatic clinical presentation of NAD deficiency. The current research is centered on common human health conditions associated with moderate, but clinically relevant, NAD deficiency. In vitro and in vivo research models that have been developed specifically to study NAD deficiency are reviewed here, along with emerging strategies to increase the intracellular NAD concentrations. Full article
(This article belongs to the Special Issue From Research on Vitamin B3, NAD+ and ADP-Ribose Metabolism to Clinical Applications in Human Health)
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17 pages, 1983 KiB  
Review
ARH Family of ADP-Ribose-Acceptor Hydrolases
by Hiroko Ishiwata-Endo, Jiro Kato, Sachiko Yamashita, Chanbora Chea, Kazushige Koike, Duck-Yeon Lee and Joel Moss
Cells 2022, 11(23), 3853; https://doi.org/10.3390/cells11233853 - 30 Nov 2022
Cited by 6 | Viewed by 4177
Abstract
The ARH family of ADP-ribose-acceptor hydrolases consists of three 39-kDa members (ARH1-3), with similarities in amino acid sequence. ARH1 was identified based on its ability to cleave ADP-ribosyl-arginine synthesized by cholera toxin. Mammalian ADP-ribosyltransferases (ARTCs) mimicked the toxin reaction, with ARTC1 catalyzing the [...] Read more.
The ARH family of ADP-ribose-acceptor hydrolases consists of three 39-kDa members (ARH1-3), with similarities in amino acid sequence. ARH1 was identified based on its ability to cleave ADP-ribosyl-arginine synthesized by cholera toxin. Mammalian ADP-ribosyltransferases (ARTCs) mimicked the toxin reaction, with ARTC1 catalyzing the synthesis of ADP-ribosyl-arginine. ADP-ribosylation of arginine was stereospecific, with β-NAD+ as substrate and, α-anomeric ADP-ribose-arginine the reaction product. ARH1 hydrolyzed α-ADP-ribose-arginine, in addition to α-NAD+ and O-acetyl-ADP-ribose. Thus, ADP-ribose attached to oxygen-containing or nitrogen-containing functional groups was a substrate. Arh1 heterozygous and knockout (KO) mice developed tumors. Arh1-KO mice showed decreased cardiac contractility and developed myocardial fibrosis. In addition to Arh1-KO mice showed increased ADP-ribosylation of tripartite motif-containing protein 72 (TRIM72), a membrane-repair protein. ARH3 cleaved ADP-ribose from ends of the poly(ADP-ribose) (PAR) chain and released the terminal ADP-ribose attached to (serine)protein. ARH3 also hydrolyzed α-NAD+ and O-acetyl-ADP-ribose. Incubation of Arh3-KO cells with H2O2 resulted in activation of poly-ADP-ribose polymerase (PARP)-1, followed by increased nuclear PAR, increased cytoplasmic PAR, leading to release of Apoptosis Inducing Factor (AIF) from mitochondria. AIF, following nuclear translocation, stimulated endonucleases, resulting in cell death by Parthanatos. Human ARH3-deficiency is autosomal recessive, rare, and characterized by neurodegeneration and early death. Arh3-KO mice developed increased brain infarction following ischemia-reperfusion injury, which was reduced by PARP inhibitors. Similarly, PARP inhibitors improved survival of Arh3-KO cells treated with H2O2. ARH2 protein did not show activity in the in vitro assays described above for ARH1 and ARH3. ARH2 has a restricted tissue distribution, with primary involvement of cardiac and skeletal muscle. Overall, the ARH family has unique functions in biological processes and different enzymatic activities. Full article
(This article belongs to the Special Issue From Research on Vitamin B3, NAD+ and ADP-Ribose Metabolism to Clinical Applications in Human Health)
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21 pages, 2605 KiB  
Review
Paracrine ADP Ribosyl Cyclase-Mediated Regulation of Biological Processes
by Cecilia Astigiano, Andrea Benzi, Maria Elena Laugieri, Francesco Piacente, Laura Sturla, Lucrezia Guida, Santina Bruzzone and Antonio De Flora
Cells 2022, 11(17), 2637; https://doi.org/10.3390/cells11172637 - 24 Aug 2022
Cited by 6 | Viewed by 2716
Abstract
ADP-ribosyl cyclases (ADPRCs) catalyze the synthesis of the Ca2+-active second messengers Cyclic ADP-ribose (cADPR) and ADP-ribose (ADPR) from NAD+ as well as nicotinic acid adenine dinucleotide phosphate (NAADP+) from NADP+. The best characterized ADPRC in mammals [...] Read more.
ADP-ribosyl cyclases (ADPRCs) catalyze the synthesis of the Ca2+-active second messengers Cyclic ADP-ribose (cADPR) and ADP-ribose (ADPR) from NAD+ as well as nicotinic acid adenine dinucleotide phosphate (NAADP+) from NADP+. The best characterized ADPRC in mammals is CD38, a single-pass transmembrane protein with two opposite membrane orientations. The first identified form, type II CD38, is a glycosylated ectoenzyme, while type III CD38 has its active site in the cytosol. The ectoenzymatic nature of type II CD38 raised long ago the question of a topological paradox concerning the access of the intracellular NAD+ substrate to the extracellular active site and of extracellular cADPR product to its intracellular receptors, ryanodine (RyR) channels. Two different transporters, equilibrative connexin 43 (Cx43) hemichannels for NAD+ and concentrative nucleoside transporters (CNTs) for cADPR, proved to mediate cell-autonomous trafficking of both nucleotides. Here, we discussed how type II CD38, Cx43 and CNTs also play a role in mediating several paracrine processes where an ADPRC+ cell supplies a neighboring CNT-and RyR-expressing cell with cADPR. Recently, type II CD38 was shown to start an ectoenzymatic sequence of reactions from NAD+/ADPR to the strong immunosuppressant adenosine; this paracrine effect represents a major mechanism of acquired resistance of several tumors to immune checkpoint therapy. Full article
(This article belongs to the Special Issue From Research on Vitamin B3, NAD+ and ADP-Ribose Metabolism to Clinical Applications in Human Health)
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