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Nicotinamide in Health and Diseases

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Natural and Bio-derived Molecules".

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 93197

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Prof. Dr. Eun Seong Hwang

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Department of Life Science, University of Seoul, Seoul, Korea
Interests: cellular senescence and aging; mitochondria biology; biochemistry of nicotinamide
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Special Issue Information

Dear Colleagues,

Nicotinamide (NAM), a vitamin B3, has been shown or suggested to be therapeutically effective against many diseases and body conditions when administered at near-gram doses. The effects of NAM that have been found or suggested so far are incredibly diverse, ranging from neuroprotection against ischemia/reperfusion and various neurological diseases, anti-inflammation, anti-diabetes, anti-fibrosis, anti-HIV and AIDS, anti-metastasis and adjuvant in cancer treatment, immune modulation, cosmetic improvement and protection of skin, amelioration of depression and psychological disorders, and alleviation of renal dysfunction. NAM administration mainly alters NAD⁺ and tryptophan metabolisms, but also directly affects certain key enzymes. Based on these, mechanisms have been proposed for many therapeutic effects at the molecular and cellular levels. However, many of these are speculative, and our understanding is limited to those associated with certain key factors and may even be inaccurate in some molecular models. The changes induced in the dermal matrix are examples of such poor understanding. Currently, the utilization of NAM as a therapeutic, pharmaceutical, or dietary or cosmetic supplements has been increasing rapidly. According to the Market Study Report, sales of NAM increased from 55,407 MT in 2013 to 76,862 MT in 2017 urgently demanding a greater understanding of NAM and the associated physiology. Thus, this Special Issue is focused on but not limited to studies on the molecular mechanisms underlying the proposed effects and new possible applications of NAM. The effects of NAM on sirtuin family proteins and other NAD⁺-consuming enzymes are important molecular targets of study. The metabolism of NAM and NAD⁺ need to be better understood to minimize potential side effects. In addition, studies of NAM’s association to autophagy and organelle turnover will provide invaluable information on the cellular process of aging and shed light on its efficacy as an anti-aging regimen.

Prof. Dr. Eun Seong Hwang
Guest Editor

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Keywords

nicotinamide
nicotinamide adenine dinucleotide (NAD⁺)
PARP-1
SIRT1
mitochondrial quality
inflammation
neuroprotection

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Published Papers (9 papers)

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Research

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9 pages, 586 KiB

Open AccessArticle

Systemic Photoprotection in Skin Cancer Prevention: Knowledge among Dermatologists

by Luca Fania, Francesca Sampogna, Francesco Ricci, Mariafrancesca Hyeraci, Andrea Paradisi, Enzo Palese, Giovanni Di Lella, Sabatino Pallotta, Annarita Panebianco, Eleonora Candi, Elena Dellambra and Damiano Abeni

Biomolecules 2021, 11(2), 332; https://doi.org/10.3390/biom11020332 - 23 Feb 2021

Cited by 9 | Viewed by 3493

Abstract

Background: Systemic photoprotection (i.e., administration of substances such as nicotinamide, carotenoids, and vitamin D) may be important to reduce photocarcinogenesis or to support long-term protection against UV irradiation. Clinical trials showed that oral nicotinamide is effective in reducing the onset of new nonmelanoma skin cancers (NMSCs), while other oral photoprotectors failed to achieve the reduction of new melanoma or NMSC formation in humans. The aim of this study was to summarize the current state of knowledge of systemic photoprotection and to evaluate the knowledge and attitude of dermatologists regarding these treatments. Methods: The survey was conducted on a sample of dermatologists recruited according to a snowball sampling procedure. The questionnaire consisted of a first part asking for characteristics of the participant and a second part with 12 specific questions on their knowledge about systemic photoprotection, particularly their knowledge of astaxanthin, β-carotene, nicotinamide, and vitamin D3. Results: One hundred eight dermatologists answered the survey. Most of them (85.2%) stated that oral photoprotectors have a role in the prevention of skin cancer, and responses mainly mentioned nicotinamide. More than half of them (54.6%) had prescribed all the considered oral photoprotectors, but the majority of them had prescribed nicotinamide, mainly for 2 to 3 months during summer, almost invariably (n = 106) associated with topical photoprotectors. Most dermatologists (>80%) were aware of scientific publications demonstrating an effect of systemic photoprotectors on NMSC. Conclusions: Most Italian dermatologists have positive views on oral photoprotection in skin cancer and are aware of the demonstrated potential of nicotinamide in the prevention of NMSCs. Full article

(This article belongs to the Special Issue Nicotinamide in Health and Diseases)

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15 pages, 3382 KiB

Open AccessEditor’s ChoiceArticle

A Novel NAD-RNA Decapping Pathway Discovered by Synthetic Light-Up NAD-RNAs

by Florian Abele, Katharina Höfer, Patrick Bernhard, Julia Grawenhoff, Maximilian Seidel, André Krause, Sara Kopf, Martin Schröter and Andres Jäschke

Biomolecules 2020, 10(4), 513; https://doi.org/10.3390/biom10040513 - 28 Mar 2020

Cited by 14 | Viewed by 7518

Abstract

The complexity of the transcriptome is governed by the intricate interplay of transcription, RNA processing, translocation, and decay. In eukaryotes, the removal of the 5’-RNA cap is essential for the initiation of RNA degradation. In addition to the canonical 5’-N7-methyl guanosine cap in eukaryotes, the ubiquitous redox cofactor nicotinamide adenine dinucleotide (NAD) was identified as a new 5’-RNA cap structure in prokaryotic and eukaryotic organisms. So far, two classes of NAD-RNA decapping enzymes have been identified, namely Nudix enzymes that liberate nicotinamide mononucleotide (NMN) and DXO-enzymes that remove the entire NAD cap. Herein, we introduce 8-(furan-2-yl)-substituted NAD-capped-RNA (^FurNAD-RNA) as a new research tool for the identification and characterization of novel NAD-RNA decapping enzymes. These compounds are found to be suitable for various enzymatic reactions that result in the release of a fluorescence quencher, either nicotinamide (NAM) or nicotinamide mononucleotide (NMN), from the RNA which causes a fluorescence turn-on. ^FurNAD-RNAs allow for real-time quantification of decapping activity, parallelization, high-throughput screening and identification of novel decapping enzymes in vitro. Using ^FurNAD-RNAs, we discovered that the eukaryotic glycohydrolase CD38 processes NAD-capped RNA in vitro into ADP-ribose-modified-RNA and nicotinamide and therefore might act as a decapping enzyme in vivo. The existence of multiple pathways suggests that the decapping of NAD-RNA is an important and regulated process in eukaryotes. Full article

(This article belongs to the Special Issue Nicotinamide in Health and Diseases)

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17 pages, 2312 KiB

Open AccessReview

Effects of NAD⁺ in Caenorhabditis elegans Models of Neuronal Damage

by Yuri Lee, Hyeseon Jeong, Kyung Hwan Park and Kyung Won Kim

Biomolecules 2020, 10(7), 993; https://doi.org/10.3390/biom10070993 - 2 Jul 2020

Cited by 4 | Viewed by 5446

Abstract

Nicotinamide adenine dinucleotide (NAD⁺) is an essential cofactor that mediates numerous biological processes in all living cells. Multiple NAD⁺ biosynthetic enzymes and NAD⁺-consuming enzymes are involved in neuroprotection and axon regeneration. The nematode Caenorhabditis elegans has served as a model to study the neuronal role of NAD⁺ because many molecular components regulating NAD⁺ are highly conserved. This review focuses on recent findings using C. elegans models of neuronal damage pertaining to the neuronal functions of NAD⁺ and its precursors, including a neuroprotective role against excitotoxicity and axon degeneration as well as an inhibitory role in axon regeneration. The regulation of NAD⁺ levels could be a promising therapeutic strategy to counter many neurodegenerative diseases, as well as neurotoxin-induced and traumatic neuronal damage. Full article

(This article belongs to the Special Issue Nicotinamide in Health and Diseases)

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21 pages, 1138 KiB

Open AccessEditor’s ChoiceReview

Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment

by Eun Seong Hwang and Seon Beom Song

Biomolecules 2020, 10(5), 687; https://doi.org/10.3390/biom10050687 - 29 Apr 2020

Cited by 78 | Viewed by 21015

Abstract

Nicotinamide (NAM) at doses far above those recommended for vitamins is suggested to be effective against a wide spectrum of diseases and conditions, including neurological dysfunctions, depression and other psychological disorders, and inflammatory diseases. Recent increases in public awareness on possible pro-longevity effects of nicotinamide adenine dinucleotide (NAD⁺) precursors have caused further growth of NAM consumption not only for clinical treatments, but also as a dietary supplement, raising concerns on the safety of its long-term use. However, possible adverse effects and their mechanisms are poorly understood. High-level NAM administration can exert negative effects through multiple routes. For example, NAM by itself inhibits poly(ADP-ribose) polymerases (PARPs), which protect genome integrity. Elevation of the NAD⁺ pool alters cellular energy metabolism. Meanwhile, high-level NAM alters cellular methyl metabolism and affects methylation of DNA and proteins, leading to changes in cellular transcriptome and proteome. Also, methyl metabolites of NAM, namely methylnicotinamide, are predicted to play roles in certain diseases and conditions. In this review, a collective literature search was performed to provide a comprehensive list of possible adverse effects of NAM and to provide understanding of their underlying mechanisms and assessment of the raised safety concerns. Our review assures safety in current usage level of NAM, but also finds potential risks for epigenetic alterations associated with chronic use of NAM at high doses. It also suggests directions of the future studies to ensure safer application of NAM. Full article

(This article belongs to the Special Issue Nicotinamide in Health and Diseases)

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14 pages, 1830 KiB

Open AccessReview

Nicotinamide, Nicotinamide Riboside and Nicotinic Acid—Emerging Roles in Replicative and Chronological Aging in Yeast

by Ivan Orlandi, Lilia Alberghina and Marina Vai

Biomolecules 2020, 10(4), 604; https://doi.org/10.3390/biom10040604 - 15 Apr 2020

Cited by 21 | Viewed by 11273

Abstract

Nicotinamide, nicotinic acid and nicotinamide riboside are vitamin B3 precursors of NAD⁺ in the human diet. NAD⁺ has a fundamental importance for cellular biology, that derives from its essential role as a cofactor of various metabolic redox reactions, as well as an obligate co-substrate for NAD⁺-consuming enzymes which are involved in many fundamental cellular processes including aging/longevity. During aging, a systemic decrease in NAD⁺ levels takes place, exposing the organism to the risk of a progressive inefficiency of those processes in which NAD⁺ is required and, consequently, contributing to the age-associated physiological/functional decline. In this context, dietary supplementation with NAD⁺ precursors is considered a promising strategy to prevent NAD⁺ decrease and attenuate in such a way several metabolic defects common to the aging process. The metabolism of NAD⁺ precursors and its impact on cell longevity have benefited greatly from studies performed in the yeast Saccharomyces cerevisiae, which is one of the most established model systems used to study the aging processes of both proliferating (replicative aging) and non-proliferating cells (chronological aging). In this review we summarize important aspects of the role played by nicotinamide, nicotinic acid and nicotinamide riboside in NAD⁺ metabolism and how each of these NAD⁺ precursors contribute to the different aspects that influence both replicative and chronological aging. Taken as a whole, the findings provided by the studies carried out in S. cerevisiae are informative for the understanding of the complex dynamic flexibility of NAD⁺ metabolism, which is essential for the maintenance of cellular fitness and for the development of dietary supplements based on NAD⁺ precursors. Full article

(This article belongs to the Special Issue Nicotinamide in Health and Diseases)

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20 pages, 1137 KiB

Open AccessReview

The Role of Nicotinamide in Cancer Chemoprevention and Therapy

by Ilias P. Nikas, Stavroula A. Paschou and Han Suk Ryu

Biomolecules 2020, 10(3), 477; https://doi.org/10.3390/biom10030477 - 20 Mar 2020

Cited by 81 | Viewed by 15427

Abstract

Nicotinamide (NAM) is a water-soluble form of Vitamin B3 (niacin) and a precursor of nicotinamide-adenine dinucleotide (NAD⁺) which regulates cellular energy metabolism. Except for its role in the production of adenosine triphosphate (ATP), NAD⁺ acts as a substrate for several enzymes including sirtuin 1 (SIRT1) and poly ADP-ribose polymerase 1 (PARP1). Notably, NAM is an inhibitor of both SIRT1 and PARP1. Accumulating evidence suggests that NAM plays a role in cancer prevention and therapy. Phase III clinical trials have confirmed its clinical efficacy for non-melanoma skin cancer chemoprevention or as an adjunct to radiotherapy against head and neck, laryngeal, and urinary bladder cancers. Evidence for other cancers has mostly been collected through preclinical research and, in its majority, is not yet evidence-based. NAM has potential as a safe, well-tolerated, and cost-effective agent to be used in cancer chemoprevention and therapy. However, more preclinical studies and clinical trials are needed to fully unravel its value. Full article

(This article belongs to the Special Issue Nicotinamide in Health and Diseases)

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17 pages, 939 KiB

Open AccessReview

Hypothalamic NAD⁺-Sirtuin Axis: Function and Regulation

by Eun Roh and Min-Seon Kim

Biomolecules 2020, 10(3), 396; https://doi.org/10.3390/biom10030396 - 4 Mar 2020

Cited by 16 | Viewed by 5613

Abstract

The rapidly expanding elderly population and obesity endemic have become part of continuing global health care problems. The hypothalamus is a critical center for the homeostatic regulation of energy and glucose metabolism, circadian rhythm, and aging-related physiology. Nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase sirtuins are referred to as master metabolic regulators that link the cellular energy status to adaptive transcriptional responses. Mounting evidence now indicates that hypothalamic sirtuins are essential for adequate hypothalamic neuronal functions. Owing to the NAD⁺-dependence of sirtuin activity, adequate hypothalamic NAD⁺ contents are pivotal for maintaining energy homeostasis and circadian physiology. Here, we comprehensively review the regulatory roles of the hypothalamic neuronal NAD⁺-sirtuin axis in a normal physiological context and their changes in obesity and the aging process. We also discuss the therapeutic potential of NAD⁺ biology-targeting drugs in aging/obesity-related metabolic and circadian disorders. Full article

(This article belongs to the Special Issue Nicotinamide in Health and Diseases)

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18 pages, 822 KiB

Open AccessReview

NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview

by Alvinsyah Adhityo Pramono, Gulam M. Rather, Herry Herman, Keri Lestari and Joseph R. Bertino

Biomolecules 2020, 10(3), 358; https://doi.org/10.3390/biom10030358 - 26 Feb 2020

Cited by 57 | Viewed by 10193

Abstract

Actively proliferating cancer cells require sufficient amount of NADH and NADPH for biogenesis and to protect cells from the detrimental effect of reactive oxygen species. As both normal and cancer cells share the same NAD biosynthetic and metabolic pathways, selectively lowering levels of NAD(H) and NADPH would be a promising strategy for cancer treatment. Targeting nicotinamide phosphoribosyltransferase (NAMPT), a rate limiting enzyme of the NAD salvage pathway, affects the NAD and NADPH pool. Similarly, lowering NADPH by mutant isocitrate dehydrogenase 1/2 (IDH1/2) which produces D-2-hydroxyglutarate (D-2HG), an oncometabolite that downregulates nicotinate phosphoribosyltransferase (NAPRT) via hypermethylation on the promoter region, results in epigenetic regulation. NADPH is used to generate D-2HG, and is also needed to protect dihydrofolate reductase, the target for methotrexate, from degradation. NAD and NADPH pools in various cancer types are regulated by several metabolic enzymes, including methylenetetrahydrofolate dehydrogenase, serine hydroxymethyltransferase, and aldehyde dehydrogenase. Thus, targeting NAD and NADPH synthesis under special circumstances is a novel approach to treat some cancers. This article provides the rationale for targeting the key enzymes that maintain the NAD/NADPH pool, and reviews preclinical studies of targeting these enzymes in cancers. Full article

(This article belongs to the Special Issue Nicotinamide in Health and Diseases)

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19 pages, 1609 KiB

Open AccessReview

NAD⁺ Metabolism and Regulation: Lessons From Yeast

by Trevor Croft, Padmaja Venkatakrishnan and Su-Ju Lin

Biomolecules 2020, 10(2), 330; https://doi.org/10.3390/biom10020330 - 19 Feb 2020

Cited by 35 | Viewed by 11550

Abstract

Nicotinamide adenine dinucleotide (NAD⁺) is an essential metabolite involved in various cellular processes. The cellular NAD⁺ pool is maintained by three biosynthesis pathways, which are largely conserved from bacteria to human. NAD⁺ metabolism is an emerging therapeutic target for several human disorders including diabetes, cancer, and neuron degeneration. Factors regulating NAD⁺ homeostasis have remained incompletely understood due to the dynamic nature and complexity of NAD⁺ metabolism. Recent studies using the genetically tractable budding yeast Saccharomyces cerevisiae have identified novel NAD⁺ homeostasis factors. These findings help provide a molecular basis for how may NAD⁺ and NAD⁺ homeostasis factors contribute to the maintenance and regulation of cellular function. Here we summarize major NAD⁺ biosynthesis pathways, selected cellular processes that closely connect with and contribute to NAD⁺ homeostasis, and regulation of NAD⁺ metabolism by nutrient-sensing signaling pathways. We also extend the discussions to include possible implications of NAD⁺ homeostasis factors in human disorders. Understanding the cross-regulation and interconnections of NAD⁺ precursors and associated cellular pathways will help elucidate the mechanisms of the complex regulation of NAD⁺ homeostasis. These studies may also contribute to the development of effective NAD⁺-based therapeutic strategies specific for different types of NAD⁺ deficiency related disorders. Full article

(This article belongs to the Special Issue Nicotinamide in Health and Diseases)

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