A Second Look at Niacin.

Niacin is the third vitamin to be discovered and, therefore. is known as vitamin B3. It has a long history of medicinal use-nutritionally and as a skin tone brightening agent in skin care. Recent studies have suggested that niacin could be useful as an adjunctive treatment for coronavirus disease 2019 (COVID-19) and mitigating the damaging effect of blue light to the skin. Niacin, also known as nicotinic acid, nicotinamide, and niacinamide, is a physiologically active form of vitamin B3. Medicinal benefits of niacin were observed in 1902, when for the first time, patients with pellagra were treated with yeast that contained vitamin B3. Niacin has a variety of uses, particularly in treating various skin conditions, including topically as an anti-acne treatment, promoting epidermal sphingolipid synthesis, moderating photoimmunosuppression, and reducing hyperpigmentation. Niacinamide could be beneficial as an adjunctive treatment for COVID-19 and for decreasing stress if the skin is excessively exposed to blue light.

Overexpression of nicotinamidase 3 (NIC3) gene and the exogenous application of nicotinic acid (NA) enhance drought tolerance and increase biomass in Arabidopsis.

KEY MESSAGE: Overexpressing Nicotinamidase 3 gene, and the exogenous application of its metabolite nicotinic acid (NA), enhance drought stress tolerance and increase biomass in Arabidopsis thaliana. With progressive global climatic changes, plant productivity is threatened severely by drought stress. Deciphering the molecular mechanisms regarding genes responsible for balancing plant growth and stress amelioration could imply multiple possibilities for future sustainable goals. Nicotinamide adenine dinucleotide (NAD) biosynthesis and recycling/ distribution is a crucial feature for plant growth. The current study focuses on the functional characterization of nicotinamidase 3 (NIC3) gene, which is involved in the biochemical conversion of nicotinamide (NAM) to nicotinic acid (NA) in the salvage pathway of NAD biosynthesis. Our data show that overexpression of NIC3 gene enhances drought stress tolerance and increases plant growth. NIC3-OX plants accumulated more NA as compared to WT plants. Moreover, the upregulation of several genes related to plant growth/stress tolerance indicates that regulating the NAD salvage pathway could significantly enhance plant growth and drought stress tolerance. The exogenous application of nicotinic acid (NA) showed a similar phenotype as the effect of overexpressing NIC3 gene. In short, we contemplated the role of NIC3 gene and NA application in drought stress tolerance and plant growth. Our results would be helpful in engineering plants with enhanced drought stress tolerance and increased growth potential.

[Niacin deficiency and cutaneous immunity].

Niacin, also known as vitamin B3, is required for the synthesis of coenzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Niacin binds with G protein-coupled receptor (GPR) 109A on cutaneous Langerhans cells and causes vasodilation with flushing in head and neck area. Niacin deficiency due to excessive alcohol consumption, certain drugs or inadequate uptake in diet causes pellagra, a photosensitivity dermatitis. Recently several studies have revealed the mechanism of photosensitivity in niacin deficiency, which may pave a way for new therapeutic approaches. The expression level of prostaglandin E synthase (PTGES) is up-regulated in the skin of both pellagra patients and niacin deficient pellagra mouse models. In addition, pellagra is mediated through prostaglandin E2-EP4 (PGE2-EP4) signaling via reactive oxygen species (ROS) production in keratinocytes. In this article, we have reviewed the role of niacin in immunity and the mechanism of niacin deficiency-induced photosensitivity.

The high-fat high-fructose hamster as an animal model for niacin's biological activities in humans.

OBJECTIVE: Niacin has been used for more than 50 years to treat dyslipidemia, yet the mechanisms underlying its lipid-modifying effects remain unknown, a situation stemming at least in part from a lack of validated animal models. The objective of this study was to determine if the dyslipidemic hamster could serve as such a model. MATERIALS/METHODS: Dyslipidemia was induced in Golden Syrian hamsters by feeding them a high-fat, high-cholesterol, and high-fructose (HF/HF) diet. The effect of high-dose niacin treatment for 18 days and 28 days on plasma lipid levels and gene expression was measured. RESULTS: Niacin treatment produced significant decreases in plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and free fatty acids (FFA), but had no measureable effect on high-density lipoprotein cholesterol (HDL-C) in the dyslipidemic hamster. Niacin treatment also produced significant increases in hepatic adenosine ATP-Binding Cassette A1 (ABCA1) mRNA, ABCA1 protein, apolipoprotein A-I (Apo A-I) mRNA, and adipose adiponectin mRNA in these animals. CONCLUSIONS: With the exception of HDL-C, the lipid effects of niacin treatment in the dyslipidemic hamster closely parallel those observed in humans. Moreover, the effects of niacin treatment on gene expression of hepatic proteins related to HDL metabolism are similar to those observed in human cells in culture. The HF/HF-fed hamster could therefore serve as an animal model for niacin's lowering of proatherogenic lipids and mechanisms of action relative to lipid metabolism.

Niacin promotes adipogenesis by reducing production of anti-adipogenic PGF2α through suppression of C/EBPß-activated COX-2 expression.

Niacin is converted to NAD and NADP in tissues, whose products are involved in a number of cellular processes; and it is associated with the regulation of adipogenesis. In this study, we identified the molecular mechanism by which niacin promotes the adipogenesis in mouse 3T3-L1 cells. When the cells were cultured with niacin, the expression of adipogenic peroxisome proliferator-activated receptor γ, CCAAT enhancer binding protein (C/EBP)α, and their target genes was enhanced concomitant with an increase in triglyceride storage. Moreover, niacin suppressed the expression of cyclooxygenase-2 and decreased the production of prostaglandin (PG) F(2α) in the early phase of adipogenesis, which PG suppresses the progression of adipogenesis via the PGF(2α) receptor. Furthermore, niacin decreased the C/EBPß level in the early phase of adipogenesis. These results indicate that niacin promoted adipogenesis by suppressing the production of the anti-adipogenic PGF(2α) through down-regulation of C/EBPß-activated cyclooxygenase-2 expression in adipocytes.

Niacin skin flush test: a research tool for studying schizophrenia.

BACKGROUND: A body of biochemical evidence suggests that abnormal phospholipid metabolism may play a role in the etiology of schizophrenia, and possibly, other psychiatric and neurological diseases. Niacin, a B-complex vitamin, induces prostaglandin synthesis, vasodilatation, and skin flushing when applied as a solution on the skin or taken orally. In schizophrenia, diminished or absent skin response to niacin represents a robust finding. RESULTS: Attenuated niacin skin-flush response has been analysed as a potential biochemical marker of impaired prostaglandin signaling in schizophrenia. Diminished skin redness after topical application of niacin might be caused by a reduced level of the precursor arachidonic acid in the peripheral membranes, increased activity of the enzyme phospholipase A2, abnormal expression of niacin or prostaglandin receptors, or poor vasomotor activity of cutaneous capillary walls. Heritability estimates established in several studies support niacin skin flush response as a vulnerability trait for the development of psychosis. However, the exact mechanism of a reduced skin flush, the possible influence of the long-term use of antipsychotics, and the usefulness of the test for diagnostic purpose are not clear yet. CONCLUSIONS: Niacin skin flush test is a simple, non-invasive and easily replicable method in the research of schizophrenia. The studies investigating niacin flushing in schizophrenia are numerous but incoherent regarding methods of niacin application and evaluation of the results. New studies, controlling adequately for age, sex, drug abuse, diet, as well as genetic factors that may influence the intensity and reaction time, are necessary to clarify the usefulness of niacin testing in psychiatry.

Niacin status and treatment-related leukemogenesis.

Chemotherapy often causes damage to hematopoietic tissues, leading to acute bone marrow suppression and the long term development of leukemias. Niacin deficiency, which is common in cancer patients, causes dramatic genomic instability in bone marrow cells in an in vivo rat model. From a mechanistic perspective, niacin deficiency delays excision repair and causes double strand break accumulation, which in turn favors chromosome breaks and translocations. Niacin deficiency also impairs cell cycle arrest and apoptosis in response to DNA damage, which combine to encourage the survival of cells with leukemogenic potential. Conversely, pharmacological supplementation of rats with niacin increases bone marrow poly(ADP-ribose) formation and apoptosis. Improvement of niacin status in rats significantly decreased nitrosourea-induced leukemia incidence. The data from our rat model suggest that niacin supplementation of cancer patients may decrease the severity of short- and long-term side effects of chemotherapy, and could improve tumor cell killing through activation of poly(ADP-ribose)-dependent apoptosis pathways.

The role of dietary niacin intake and the adenosine-5'-diphosphate-ribosyl cyclase enzyme CD38 in spatial learning ability: is cyclic adenosine diphosphate ribose the link between diet and behaviour?

The pyridine nucleotide NAD+ is derived from dietary niacin and serves as the substrate for the synthesis of cyclic ADP-ribose (cADPR), an intracellular Ca signalling molecule that plays an important role in synaptic plasticity in the hippocampus, a region of the brain involved in spatial learning. cADPR is formed in part via the activity of the ADP-ribosyl cyclase enzyme CD38, which is widespread throughout the brain. In the present review, current evidence of the relationship between dietary niacin and behaviour is presented following investigations of the effect of niacin deficiency, pharmacological nicotinamide supplementation and CD38 gene deletion on brain nucleotides and spatial learning ability in mice and rats. In young male rats, both niacin deficiency and nicotinamide supplementation significantly altered brain NAD+ and cADPR, both of which were inversely correlated with spatial learning ability. These results were consistent across three different models of niacin deficiency (pair feeding, partially restricted feeding and niacin recovery). Similar changes in spatial learning ability were observed in Cd38- / - mice, which also showed decreases in brain cADPR. These findings suggest an inverse relationship between spatial learning ability, dietary niacin intake and cADPR, although a direct link between cADPR and spatial learning ability is still missing. Dietary niacin may therefore play a role in the molecular events regulating learning performance, and further investigations of niacin intake, CD38 and cADPR may help identify potential molecular targets for clinical intervention to enhance learning and prevent or reverse cognitive decline.

Niacin restriction upregulates NADPH oxidase and reactive oxygen species (ROS) in human keratinocytes.

NAD(+) is a substrate for many enzymes, including poly(ADP-ribose) polymerases and sirtuins, which are involved in fundamental cellular processes including DNA repair, stress responses, signaling, transcription, apoptosis, metabolism, differentiation, chromatin structure, and life span. Because these molecular processes are important early in cancer development, we developed a model to identify critical NAD-dependent pathways potentially important in early skin carcinogenesis. Removal of niacin from the cell culture medium allowed control of intracellular NAD. Unlike many nonimmortalized human cells, HaCaT keratinocytes, which are immortalized and have a mutant p53 and aberrant NF-kB activity, become severely NAD depleted but divide indefinitely under these conditions. Niacin-deficient HaCaTs develop a decreased growth rate due to an increase in apoptotic cells and an arrest in the G(2)/M phase of the cell cycle. Long-term survival mechanisms in niacin-deficient HaCats involve accumulation of reactive oxygen species and increased DNA damage. These alterations result, at least in part, from increased expression and activity of NADPH oxidase, whose downstream effects can be reversed by nicotinamide or NADPH oxidase inhibitors. Our data support the hypothesis that glutamine is a likely alternative energy source during niacin deficiency and we suggest a model for NADPH generation important in ROS production.

HDL: the 'new' target of cardiovascular medicine.

Clinical, experimental and epidemiological research has shown the undeniable causal relationship between low HDL plasma concentrations and cardiovascular disease. Low HDL levels are present in about 10% of the general population and represent the most frequent form of dyslipidemia in patients with coronary disease. Reduced HDL concentrations seem to be unable to eliminate efficiently the cholesterol excess at vascular wall level, contributing to the onset of the inflammatory response that typically occurs in the pathogenesis of atherosclerosis right from its earliest stages. The results of numerous studies quite convincingly suggest that HDL is capable of exerting anti-inflammatory activity either directly or by modulating the expression of a number of acute phase proteins. Although the therapeutic options currently available for raising HDL levels still show modest efficacy, both in experimental and pre-clinical fields, genetic investigation and specifically aimed pharmacological treatment have produced more encouraging results, shedding some light on the concrete possibility of being able to treat this disease in the very near future.

[Endogenous factors regulating neuronal apoptosis].

Apoptosis and necrosis of neurons induced by glutamate and nitric oxide (NO) are associated with various disorders including hypoxic-ischemic brain injury, Alzheimer's disease and Parkinson's disease. In search of endogenous protective factors that inhibit NO-mediated glutamate neurotoxicity, we found that excitotoxicity is suppressed by certain neurotransmitters such as nicotinic acetylcholine and dopamine and growth factors such as NGF and BDNF. We recently purified and isolated a novel neuroprotective substance, which has been named 'serofendic acid', from a lipophilic fraction of fetal calf serum. Mass spectrometry and NMR spectroscopy revealed the chemical structure of serofendic acid (15-hydroxy-17-methylsulfinylatisan-19-oic acid) as a sulfur-containing atisane-type diterpenoid. Serofendic acid exhibited potent protective actions on cortical neurons against neurotoxicity of a NO donor as well as of glutamate, although it did not show appreciable influences on glutamate receptor-mediated responses in these neurons. Electron spin resonance analysis demonstrated that serofendic acid had no direct scavenging activity on NO radicals but was capable of inhibiting the generation of hydroxyl radicals. These findings suggest that serofendic acid is a low-molecular-weight bioactive factor that promotes survival of CNS neurons, probably through the attenuation of free radical-mediated insults.

Vitamins, minerals and supplements: part two.

Vitamins and minerals are organic food substances found only in plants and animals and are essential to the normal functioning of the body. Although only required in small amounts, as previously discussed in the past decade there has been an increased use of vitamin, mineral, herbal and nutritional supplements in the general population. While deficiencies in such nutrients can be harmful to health, conflicting claims have been made about the health benefits of such supplementation. In the second of an occasional series on vitamins, minerals, and supplements, JUNE THOMPSON gives an overview of the role that water-soluble vitamins play in the health of the individual, including their functions, and the potential impact of any deficiency of these.

The necessity of niacin in rats fed on a high protein diet.

It is known that niacin itself is not necessary in rats when tryptophan is given in adequate amounts, because rats can biosynthesize niacin from tryptophan. In our experiment, young rats were fed on a 20%, 40%, 60%, or 70% casein diet with or without niacin. The rats fed on the 20%, 40%, and 60% casein diets did not require niacin for growth, but the rats fed on the 70% casein diet needed it. This phenomenon was attributed to the supposition that liver aminocarboxymuconate-semialdehyde decarboxylase activities increased according with the dietary casein levels. The conversion ratio of tryptophan-niacin in rats fed on the 70% casein diet became extremely low, and then the rats needed niacin.

Niacin and carcinogenesis.

The dietary status of niacin (vitamin B3) has the potential to influence DNA repair, genomic stability, and the immune system, eventually having an impact on cancer risk, as well as the side effects of chemotherapy in the cancer patient. In addition to its well-known redox functions in energy metabolism, niacin, in the form of NAD, participates in a wide variety of ADP-ribosylation reactions. Poly(ADP-ribose) is a negatively charged polymer synthesized, predominantly on nuclear proteins, by at least seven different enzymes. Poly(ADP-ribose) polymerase-1 (PARP-1) is responsible for the majority of polymer synthesis and plays important roles in DNA damage responses, including repair, maintenance of genomic stability, and signaling events for stress responses such as apoptosis. NAD is also used in the synthesis of mono(ADP-ribose), often on G proteins, with poorly understood roles in signal transduction. Last, NAD and NADP are required for the synthesis of cyclic ADP-ribose and nicotinic acid adenine dinucleotide (NAADP), two mediators of intracellular calcium signaling pathways. Disruption of any of these processes has the potential to impair genomic stability and deregulate cell division, leading to enhanced cancer risk. There are various sources of evidence that niacin status does have an impact on cancer risk, including animal models of leukemogenesis and skin cancer, as well as epidemiological data from human populations.

Niacin and cholesterol: role in cardiovascular disease (review).

Niacin has been widely used as a pharmacologic agent to regulate abnormalities in plasma lipid and lipoprotein metabolism and in the treatment of atherosclerotic cardiovascular disease. Although the use of niacin in the treatment of dyslipidemia has been reported as early as 1955, only recent studies have yielded an understanding about the cellular and molecular mechanism of action of niacin on lipid and lipoprotein metabolism. In brief, the beneficial effect of niacin to reduce triglycerides and apolipoprotein-B containing lipoproteins (e.g., VLDL and LDL) are mainly through: a) decreasing fatty acid mobilization from adipose tissue triglyceride stores, and b) inhibiting hepatocyte diacylglycerol acyltransferase and triglyceride synthesis leading to increased intracellular apo B degradation and subsequent decreased secretion of VLDL and LDL particles. The mechanism of action of niacin to raise HDL is by decreasing the fractional catabolic rate of HDL-apo AI without affecting the synthetic rates. Additionally, niacin selectively increases the plasma levels of Lp-AI (HDL subfraction without apo AII), a cardioprotective subfraction of HDL in patients with low HDL. Using human hepatocytes (Hep G2 cells) as an in vitro model system, recent studies indicate that niacin selectively inhibits the uptake/removal of HDL-apo AI (but not HDL-cholesterol ester) by hepatocytes, thereby increasing the capacity of retained HDL-apo AI to augment cholesterol efflux through reverse cholesterol transport pathway. The studies discussed in this review provide evidence to extend the role of niacin as a lipid-lowering drug beyond its role as a vitamin.

[Nicotinic acid and nicotinamide].

Nicotinic acid and nicotinamide are called niacin. They are the antipellagra vitamin essential to many animals for growth and health. In human being, niacin is believed necessary together with other vitamins for the prevention and cure of pellagra. Niacin is widely distributed in nature; appreciable amounts are found in liver, fish, yeast and cereal grains. Nicotinamide is a precursor of the coenzyme NAD and NADP. Some of the most understood metabolic processes that involve niacin are glycolysis, fatty acid synthesis and respiration. Niacin is also related to the following diseases: Hartnup disease; blue diaper syndrome; tryptophanuria; hydroxykynureninuria; xanthurenic aciduria; Huntington's disease.

Current knowledge concerning optimum nutritional status of riboflavin, niacin and pyridoxine.

The term 'optimum nutrition' has evolved from a perceived need to base recommendations for nutrient intakes firmly in the context of function. It follows that 'optimum nutritional status' for individual nutrients should be defined in terms of biochemical or physiological markers having some functional value but also showing an appropriate relationship to nutrient intake. The present short review considers the current position regarding such markers for riboflavin, pyridoxine and niacin. It is concluded that whilst there are several biochemical measures which respond to changes in intake of each of these vitamins, no single measure is wholly satisfactory as a marker of optimum status.