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      The Vitamin Nicotinamide: Translating Nutrition into Clinical Care

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          Abstract

          Nicotinamide, the amide form of vitamin B 3 (niacin), is changed to its mononucleotide compound with the enzyme nicotinic acide/nicotinamide adenylyl-transferase, and participates in the cellular energy metabolism that directly impacts normal physiology. However, nicotinamide also influences oxidative stress and modulates multiple pathways tied to both cellular survival and death. During disorders that include immune system dysfunction, diabetes, and aging-related diseases, nicotinamide is a robust cytoprotectant that blocks cellular inflammatory cell activation, early apoptotic phosphatidylserine exposure, and late nuclear DNA degradation. Nicotinamide relies upon unique cellular pathways that involve forkhead transcription factors, sirtuins, protein kinase B (Akt), Bad, caspases, and poly (ADP-ribose) polymerase that may offer a fine line with determining cellular longevity, cell survival, and unwanted cancer progression. If one is cognizant of the these considerations, it becomes evident that nicotinamide holds great potential for multiple disease entities, but the development of new therapeutic strategies rests heavily upon the elucidation of the novel cellular pathways that nicotinamide closely governs.

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          Signalling through C-type lectin receptors: shaping immune responses

          Teunis B H Geijtenbeek, Sonja Gringhuis (2009)
          Key Points Crosstalk between pattern recognition receptors (PRRs) expressed by dendritic cells orchestrates T helper (TH) cell differentiation through the induction of specific cytokine expression profiles, tailored to invading pathogens. C-type lectin receptors (CLRs) have an important role in orchestrating the induction of signalling pathways that regulate adaptive immune responses. CLRs can control adaptive immunity at various levels by inducing signalling on their own, through crosstalk with other PRRs or by inducing carbohydrate-specific signalling pathways. DC-specific ICAM3-grabbing non-integrin (DC-SIGN) interacts with mannose-carrying pathogens including Mycobacterium tuberculosis, HIV-1, measles virus and Candida albicans to activate the serine/threonine protein kinase RAF1. RAF1 signalling leads to the acetylation of Toll-like receptor (TLR)-activated nuclear factor-κB (NF-κB) subunit p65 and affects cytokine expression, such as inducing the upregulation of interleukin-10 (IL-10). DC-associated C-type lectin 1 (dectin 1) triggering by a broad range of fungal pathogens, such as C. albicans, Aspergillus fumigatus and Pneumocystis carinii, results in protective antifungal immunity through the crosstalk of two independent signalling pathways — one through spleen tyrosine kinase (SYK) and one through RAF1 — that are essential for the expression of TH1 and TH17 cell polarizing cytokines. Crosstalk between the SYK and RAF1 pathways is both synergistic and antagonizing to fine-tune NF-κB activity: although Ser276 phosphorylation of p65 leads to enhanced transcriptional activity of p65 itself through acetylation, it also inhibits the transcriptional activity of the NF-κB subunit RELB by sequestering it in p65–RELB dimers, which are transcriptionally inactive. The diversity in CLR-mediated signalling provides some major challenges for the researches to elucidate and manipulate the signalling properties of this exciting family of receptors. However, the recent advances strongly support the use of CLR targeting vaccination strategies using dendritic cells to induce or redirect adaptive immune responses as well as improve antigen delivery.
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            Negative control of p53 by Sir2alpha promotes cell survival under stress.

            J. Luo, A Y Nikolaev, S. Imai … (2001)
            The NAD-dependent histone deacetylation of Sir2 connects cellular metabolism with gene silencing as well as aging in yeast. Here, we show that mammalian Sir2alpha physically interacts with p53 and attenuates p53-mediated functions. Nicotinamide (Vitamin B3) inhibits an NAD-dependent p53 deacetylation induced by Sir2alpha, and also enhances the p53 acetylation levels in vivo. Furthermore, Sir2alpha represses p53-dependent apoptosis in response to DNA damage and oxidative stress, whereas expression of a Sir2alpha point mutant increases the sensitivity of cells in the stress response. Thus, our findings implicate a p53 regulatory pathway mediated by mammalian Sir2alpha. These results have significant implications regarding an important role for Sir2alpha in modulating the sensitivity of cells in p53-dependent apoptotic response and the possible effect in cancer therapy.
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              Mammalian SIRT1 represses forkhead transcription factors.

              Maria Carla Motta, Nullin Divecha, Madeleine Lemieux … (2004)
              The NAD-dependent deacetylase SIR2 and the forkhead transcription factor DAF-16 regulate lifespan in model organisms, such as yeast and C. elegans. Here we show that the mammalian SIR2 ortholog SIRT1 deacetylates and represses the activity of the forkhead transcription factor Foxo3a and other mammalian forkhead factors. This regulation appears to be in the opposite direction from the genetic interaction of SIR2 with forkhead in C. elegans. By restraining mammalian forkhead proteins, SIRT1 also reduces forkhead-dependent apoptosis. The inhibition of forkhead activity by SIRT1 parallels the effect of this deacetylase on the tumor suppressor p53. We speculate how down-regulating these two classes of damage-responsive mammalian factors may favor long lifespan under certain environmental conditions, such as calorie restriction.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Molecules
                Journal ID (iso-abbrev): Molecules
                Journal ID (publisher-id): molecules
                Title: Molecules
                Publisher: Molecular Diversity Preservation International
                ISSN (Electronic): 1420-3049
                Publication date (Electronic): 09 September 2009
                Publication date Collection: September 2009
                Volume: 14
                Issue: 9
                Pages: 3446-3485
                Affiliations
                [1 ]Division of Cellular and Molecular Cerebral Ischemia, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
                [2 ]Departments of Neurology and Anatomy & Cell Biology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
                [3 ]Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
                [4 ]Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
                [5 ]Institute of Environmental Health Sciences, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
                Author notes
                [* ]Author to whom correspondence should be addressed; E-mails: kmaiese@ 123456med.wayne.edu or aa2088@ 123456wayne.edu ; Fax: +1-313-966-0486.
                Article
                Publisher ID: molecules-14-03446
                DOI: 10.3390/molecules14093446
                PMC ID: 2756609
                PubMed ID: 19783937
                SO-VID: 963065cd-665a-4273-871b-31b9596f1b6c
                Copyright © © 2009 by the authors;
                License:

                licensee Molecular Diversity Preservation International, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 17 August 2009
                Date revision received : 08 September 2009
                Date accepted : 08 September 2009
                Categories
                Subject: Review

                Keywords: alzheimer’s disease,diabetes,erythropoietin,forkhead transcription factors,wnt
                Data availability:
                Keywords: alzheimer’s disease, diabetes, erythropoietin, forkhead transcription factors, wnt

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