Nicotinamide

The herbs of Nicotiana tabacum L.

Nicotinamide is a water-soluble vitamin, an active component of coenzymes NAD and NADP, and acts as poly (ADP-ribose) polymerase (PARP) inhibitor.

In Vitro:Pretreatment with the poly (ADP-ribose) polymerase (PARP) inhibitor nicotinamide is able to prevent HCN2 cell death. When nicotinamide is added prior to t-BuOOH, it is able to prevent neuronal cell death and inhibit apoptosis. Nicotinamide-pretreated neurons have higher expression levels of inhibitors of apoptosis (IAP) genes[1]. Nicotinamide inhibits vasoconstriction by ET. Nicotinamide also alleviates oxidative stress, which exacerbates PE and FGR[3].

In Vivo:Normal and streptozotocin-nicotinamide induced adult male diabetic rats receive quercetin (10, 25 and 50 mg/kg/bw) orally, and cause significant decrease in FBG and cardiac injury marker levels with increased in insulin levels[2]. Nicotinamide improves maternal hypertension, proteinuria, and glomerular endotheliosis in RUPP mice. Moreover, nicotinamide prolongs pregnancies, and improves survival and growth of the embryos in RUPP PE mice[3].

References:
[1]. Bhansali SG, et al. Nicotinamide prevents apoptosis in human cortical neuronal cells. Toxicol Mech Methods. 2006;16(4):173-80. [2]. Roslan J, et al. Quercetin ameliorates oxidative stress, inflammation and apoptosis in the heart of streptozotocin-nicotinamide-induced adult male diabetic rats. Biomed Pharmacother. 2016 Dec 24;86:570-582 [3]. Fushima T, et al. Nicotinamide ameliorates a preeclampsia-like condition in mice with reduced uterine perfusion pressure. Am J Physiol Renal Physiol. 2016 Dec 7:ajprenal.00501.2016 [4]. Suzuki E, et al. Protective effect of nicotinamide against poly(ADP-ribose) polymerase-1-mediated astrocyte death depends on its transporter-mediated uptake. Life Sci. 2010 Apr 24;86(17-18):676-82.

Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae.[Pubmed:12736687]

Nature. 2003 May 8;423(6936):181-5.

Calorie restriction extends lifespan in a broad range of organisms, from yeasts to mammals. Numerous hypotheses have been proposed to explain this phenomenon, including decreased oxidative damage and altered energy metabolism. In Saccharomyces cerevisiae, lifespan extension by calorie restriction requires the NAD+-dependent histone deacetylase, Sir2 (ref. 1). We have recently shown that Sir2 and its closest human homologue SIRT1, a p53 deacetylase, are strongly inhibited by the vitamin B3 precursor Nicotinamide. Here we show that increased expression of PNC1 (pyrazinamidase/nicotinamidase 1), which encodes an enzyme that deaminates Nicotinamide, is both necessary and sufficient for lifespan extension by calorie restriction and low-intensity stress. We also identify PNC1 as a longevity gene that is responsive to all stimuli that extend lifespan. We provide evidence that Nicotinamide depletion is sufficient to activate Sir2 and that this is the mechanism by which PNC1 regulates longevity. We conclude that yeast lifespan extension by calorie restriction is the consequence of an active cellular response to a low-intensity stress and speculate that Nicotinamide might regulate critical cellular processes in higher organisms.

Nicotinamide is a potent inducer of endocrine differentiation in cultured human fetal pancreatic cells.[Pubmed:8104197]

J Clin Invest. 1993 Sep;92(3):1459-66.

The effects of Nicotinamide (NIC) on human fetal and adult endocrine pancreatic cells were studied in tissue culture. Treatment of the fetal cells with 10 mM NIC resulted in a twofold increase in DNA content and a threefold increase in insulin content. This was associated with the development of beta cell outgrowths from undifferentiated epithelial cell clusters and an increase in the expression of the insulin, glucagon, and somatostatin genes. DNA synthesis was stimulated only in the undifferentiated cells. Half-maximal doses for the insulinotropic and mitogenic effects of NIC were 5-10 and 1-2 mM, respectively. Islet-like cell clusters cultured with NIC responded to glucose stimulation with a biphasic increase in insulin release (fourfold peak), whereas control cells were unresponsive to glucose. Both control and NIC-treated cells developed into functional islet tissue after transplantation into athymic nude mice. As compared with adult islets, the insulinotropic action of NIC could only be demonstrated in the fetal cells. Our results indicate that NIC induces differentiation and maturation of human fetal pancreatic islet cells. This model should be useful for the study of molecular mechanisms involved in beta cell development.

A modified method of insulin producing cells' generation from bone marrow-derived mesenchymal stem cells.[Pubmed:25405207]

J Diabetes Res. 2014;2014:628591.

Type 1 diabetes mellitus is a result of autoimmune destruction of pancreatic insulin producing beta-cells and so far it can be cured only by insulin injection, by pancreas transplantation, or by pancreatic islet cells' transplantation. The methods are, however, imperfect and have a lot of disadvantages. Therefore new solutions are needed. The best one would be the use of differentiated mesenchymal stem cells (MSCs). In the present study, we investigated the potential of the bone marrow-derived MSCs line for in vitro differentiation into insulin producing cells (IPSs). We applied an 18-day protocol to differentiate MSCs. Differentiating cells formed cell clusters some of which resembled pancreatic islet-like cells. Using dithizone we confirmed the presence of insulin in the cells. What is more, the expression of proinsulin C-peptide in differentiated IPCs was analyzed by flow cytometry. For the first time, we investigated the influence of growth factors' concentration on IPCs differentiation efficiency. We have found that an increase in the concentration of growth factors up to 60 ng/mL of beta-FGF/EGF and 30 ng/mL of activin A/beta-cellulin increases the percentage of IPCs. Further increase of growth factors does not show any increase of the percentage of differentiated cells. Our findings suggest that the presented protocol can be adapted for differentiation of insulin producing cells from stem cells.

Protective effect of nicotinamide against poly(ADP-ribose) polymerase-1-mediated astrocyte death depends on its transporter-mediated uptake.[Pubmed:20188745]

Life Sci. 2010 Apr 24;86(17-18):676-82.

AIM: Poly(ADP-ribose) polymerase-1 (PARP-1) is a DNA repair enzyme, and its excessive activation, following ischemia, trauma, etc., depletes cellular Nicotinamide adenine dinucleotide (NAD(+)) as a substrate and eventually leads to brain cell death. Nicotinamide, an NAD(+) precursor and a PARP-1 inhibitor, is known to prevent PARP-1-triggered cell death, but there is no available information on the mechanisms involved in its transport. Here we clarified the transport characteristics of Nicotinamide in primary cultured mouse astrocytes. MAIN METHODS: Uptake characteristics of [(14)C]Nicotinamide were assessed by a conventional method with primary cultured mouse astrocytes. Cell viability and PARP-1 activity were determined with intracellular LDH activity and immunocytochemical detection of PAR accumulation, respectively. KEY FINDINGS: PARP-1 activation was induced by treatment of astrocytes with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), an alkylating agent. MNNG-triggered astrocyte death and PAR accumulation were completely inhibited by treatment with Nicotinamide as with DPQ (3,4-dihydro-5-(4-(1-piperidinyl)butoxy)-1(2H)-isoquinolinone), a second generation PARP inhibitor. The uptake of [(14)C]Nicotinamide was time-, temperature-, concentration- and pH-dependent, and was inhibited and stimulated by co- and pre-treatment with N-methylNicotinamide, a representative substrate of an organic cation transport system, respectively. Co-treatment of astrocytes with Nicotinamide and N-methylNicotinamide resulted in a decrease in PAR accumulation and absolute prevention of cell death. SIGNIFICANCE: These findings suggest that Nicotinamide has a protective effect against PARP-1-induced astrocyte death and that its transporter-mediated uptake, which is extracellular pH-sensitive and common to N-methylNicotinamide, is critical for prevention of PARP-1-triggered cell death.

Nicotinamide rescues human embryonic stem cell-derived neuroectoderm from parthanatic cell death.[Pubmed:19544437]

Stem Cells. 2009 Aug;27(8):1772-81.

Abundant cell death is observed when human embryonic stem cells (hESCs) undergo neuralization, a critical first step for future cell-based therapies addressing neurodegeneration. Using hESC neuralization as an in vitro model of human development, we demonstrated that the developing neuroepithelium acquires increased susceptibility to spontaneous cell death. We found that poly(ADP-ribose) polymerase-1 (PARP1)/apoptosis-inducing factor (AIF)-mediated cell death (parthanatos) is a dominant mechanism responsible for cell loss during hESC neuralization. The demise of neural progenitor cells, at least in part, is due to decreased endogenous antioxidant defenses and enhanced reactive oxygen species leakage from mitochondria fuelled by nonphysiological culture conditions. Under such conditions, PARP1 overactivation triggered cell death through the mitochondrial-nuclear translocation of AIF. Blocking PARP1 activity with small hairpin RNA interference or Nicotinamide dramatically enhanced hESC neuralization, providing optimal survival of the developing neuroepithelium. Because Nicotinamide is a physiological metabolite, our results raise the possibility that neural stem/progenitor cell survival in vivo requires a metabolic niche. We argue that small natural metabolites provide a powerful physiological tool to optimize hESC differentiation compatible with the requirements of regenerative medicine.

Nicotinamide is a form of vitamin B3 that plays essential roles in cell physiology through facilitating NAD+ redox homeostasis and providing NAD+ as a substrate to a class of enzymes that catalyze non-redox reactions. Nicotinamide is an inhibitor of SIRT1.

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