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.

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 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.

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.

The effect of niacin deficiency on diethylnitrosamine-induced hepatic poly(ADP-ribose) levels and altered hepatic foci in the Fischer-344 rat.

Poly(ADP-ribose) is synthesized on nuclear proteins in response to DNA damage and plays an important role in DNA repair. Niacin and tryptophan are dietary precursors to NAD+, which is the substrate for poly(ADP-ribose) synthesis. This study examined the influence of niacin status on poly(ADP-ribose) metabolism and carcinogenesis. Diets devoid of added niacin, with different levels of tryptophan, were used to produce moderate and severe niacin deficiencies in male Fischer-344 rats. Control rats were pair fed niacin-replete diets. After a 21-day feeding period, rats were injected with diethylnitrosamine (DEN) (Expt 1, 200 mg/kg ip; Expt 2, 100 mg/kg ip). In Experiment 1, blood and liver NAD+ and liver poly(ADP-ribose) were measured over the next 15 hours. Whereas blood and liver NAD+ were decreased by niacin deficiency, blood NAD+ was not affected by DEN. Liver NAD+ decreased significantly in response to DEN treatment in the pair-fed groups, but it did not change in the niacin-deficient groups. Unexpectedly, at 10 hours postinjection, liver poly(ADP-ribose) accumulation was greater (p < 0.05) in the niacin-deficient than in the pair-fed rats (n = 9), despite lower initial NAD+ levels and a lack of NAD+ disappearance in niacin-deficient livers. In Experiment 2, livers were examined for the presence of altered hepatic foci three months after DEN exposure. There were no significant differences in the percentage of liver occupied by foci between the niacin-deficient and pair-fed groups (n = 8). These results indicate that niacin-deficient rats were able to accumulate higher concentrations of hepatic poly(ADP-ribose) in response to DEN and did not show elevated susceptibility to initiation of altered hepatic foci.