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Further studies on the concentration of the antipellagra factor
... Niacin (nicotinic acid or vitamin B3) is a functional group present in the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which are essential for oxidative processes. Niacin was first identified in 1937 as the dietary factor that prevented black tongue disease in dogs, the animal model for pellagra (Koehn & Elvehjem, 1937). Pellagra is a dietary-deficiency disease whose study facilitated the identification of niacin as the pellagra-preventing factor, the discovery of niacin as the essential vitamin required for adequate NAD synthesis in humans, and the identification of multiple roles of coenzyme NAD(P) in metabolism. ...
... In 1937, Koehn and Elvehjem used liver extracts to isolate the dietary PdP factor that prevented black tongue disease in a dog model of pellagra and subsequently identified it as nicotinic acid (Elvehjem, Madden, Strong, & Woolley, 1937;Koehn & Elvehjem, 1937). This discovery laid the foundation for more studies that confirmed lack of nicotinic acid as the underlying cause of pellagra in humans, and the rapid implementation of nicotinic acid and nicotinamide supplementation as the efficient treatment. ...
Nicotinic acid and nicotinamide, collectively referred to as niacin, are nutritional precursors of the bioactive molecules nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). NAD and NADP are important cofactors for most cellular redox reactions, and as such are essential to maintain cellular metabolism and respiration. NAD also serves as a cosubstrate for a large number of ADP-ribosylation enzymes with varied functions. Among the NAD-consuming enzymes identified to date are important genetic and epigenetic regulators, e.g., poly(ADP-ribose)polymerases and sirtuins. There is rapidly growing knowledge of the close connection between dietary niacin intake, NAD(P) availability, and the activity of NAD(P)-dependent epigenetic regulator enzymes. It points to an exciting role of dietary niacin intake as a central regulator of physiological processes, e.g., maintenance of genetic stability, and of epigenetic control mechanisms modulating metabolism and aging. Insight into the role of niacin and various NAD-related diseases ranging from cancer, aging, and metabolic diseases to cardiovascular problems has shifted our view of niacin as a vitamin to current views that explore its potential as a therapeutic.
... The first experimental phenotype closely resembling the symptoms of pellagra in humans was identified using a dog model [112]. In 1937, black tongue disease, the manifestation of pellagra in dogs, was cured using nicotinic acid that was isolated from liver extracts [113,114]. Additional early nutritional studies on laboratory animals reported the requirement of dietary niacin for survival and the adequate growth of rats [115], mice [116], guinea pigs [117], and rabbits [118]. ...
Research into the functions of nicotinamide adenine dinucleotide (NAD) has intensified in recent years due to the insight that abnormally low levels of NAD are involved in many human pathologies including metabolic disorders, neurodegeneration, reproductive dysfunction, cancer, and aging. Consequently, the development and validation of novel NAD-boosting strategies has been of central interest, along with the development of models that accurately represent the complexity of human NAD dynamics and deficiency levels. In this review, we discuss pioneering research and show how modern researchers have long since moved past believing that pellagra is the overt and most dramatic clinical presentation of NAD deficiency. The current research is centered on common human health conditions associated with moderate, but clinically relevant, NAD deficiency. In vitro and in vivo research models that have been developed specifically to study NAD deficiency are reviewed here, along with emerging strategies to increase the intracellular NAD concentrations.
... La "Biological Chemistry Nomenclature Comission" de la IUPAC propuso unificar bajo los nombres NAD y NADP para que hicieran referencia clara a su estructura y pudieran ser comparables con otros cofactores como FAD y FMN(Dixon, 1960).26 Ambos son productos de descomposición de NAD.27 Elvehjem y su equipo detectaron que el ácido nicotínico y la nicotinamida eran agentes efectivos tanto para el tratamiento como para la prevención de la lengua negra en perros, y el equivalente humano, la pelagra(Axelrod, Madden, y Elvehjem, 1939;Elvehjem, Madden, Strong, y Woolley, 1938;Koehn y Elvehjem, 1937). Su trabajo permitió identificar que esta condición era generada por un déficit de nutrientes y no se trataba de una enfermedad infecciosa como se pensaba hasta ese momento, sino que era resultante de una ingesta deficiente de vitamina B3 (niacina), precursora de la Coenzima I (NAD).28 ...
This PhD thesis presents an extensive analysis of the results obtained in a research regarding the teaching as well as the learning concepts of Biological Chemistry implied in the cellular respiration topic, in eukaryotes. To carry out the present study, both quantitative and qualitative research methods were implemented. We worked, mainly, with three populations: one of secondary school level and two of university level, from the Common Basic Cycle (first year of university) and from the Faculty of Exact and Natural Sciences, both from the UBA.
Didactical, historical, and epistemological resources have been used as multidisciplinary theoretical frameworks to encompass visions of communication between experts and novices. Models, arguments, languages, and the evolution of scientific knowledge have been premises for the analysis of explanatory discourses on the analogy between chemical combustion and the global reaction of cellular respiration, and on the chain of electron transport in mitochondria. Likewise, those theoretical frameworks have also been used to support the design of original inquiry devices, which were applied to reveal learning efficiencies either in freshmen and fourth-year university students.
In Part A of the Thesis, the design of an original interdisciplinary proposal for teaching the concept of chemical combustión is presented. Its application on a secondary-level students population shows very satisfactory results, at the same time that reveals implicit underlying obstacles for professors as challenges from innovative teaching methodologies.
In Part B, a historical-epistemological analysis of the analogy between cellular respiration and glucose combustion and its use as a teaching device are carried out. Finally, freshmen students’ learning epistemological obstacles have been detected due to the application of this analogy during teaching processes.
In Part C of the Thesis, a historical-epistemological analysis of redox aspects of cellular respiration in mitochondria from the 18th century to the present is presented, with particular emphasis on the analysis of the Electron Transport Chain model, its structural components, and the participation of cofactors. Likewise, the research about the impact of teaching with the analogy finds new epistemological obstacles, particularly in freshmen’s learnings.
In Part D of the Thesis, a teaching proposal is presented to show the transport of electrons in prokaryotic cellular respiration, through an experimental device known as Sedimentary Microbial Fuel Cell that simulates an aerobic respiration mechanism for anaerobic bacteria (that do not have mitochondria). This PhD Thesis makes original historical-epistemological-didactic contributions in two dimensions, one related to the integrated visions about teaching redox aspects of cellular respiration, and the other to the design of original instruments. However these instruments are used in the present context to the inquiry about learning, they may also be used as teaching devices, due to their possible didactic power to elicit metacongintive reflections and help students to overcome conceptual obstacles during
their respective learning processes.
... Tien jaar later werd duidelijk dat ook leverconsumptie genezend werkt bij pellagra-patiënten (8,9). Elvehjem et al. lieten zien dat een pentanolextract van lever honden met voedergemedieerde black tongue genas (10,Noot 4,5). Het extract bevatte nicotinezuuramide, dat eveneens werkzaam was (11). ...
... At that time, pellagra was endemic in parts of the United States, and so the Red Cross supplemented Brewer's yeast to its food rations in pellagra-endemic areas, and within weeks the disease burden dissipated 2,3 . The health significance of NAD+ was established in 1937 when Conrad Elvehjem and his colleagues made the major discovery that the factor that prevented and cured pellagra was the NAD+ precursor, nicotinic acid 4,5 . ...
Nicotinamide Adenine Dinucleotide (NAD+) is an established cofactor for enzymes serving cellular metabolic reactions. More recent research identified NAD+ as a signaling molecule and substrate for sirtuins and poly-ADP polymerases; enzymes that regulate protein deacetylation and DNA repair, and translate changes in energy status into metabolic adaptations. Deranged NAD+ homeostasis and concurrent alterations in mitochondrial function are intrinsic in metabolic disorders such as type 2 diabetes, non-alcoholic fatty liver and age-related diseases. Contemporary NAD+ precursors show promise as nutraceuticals to restore target tissue NAD+, and have demonstrated the ability to improve mitochondrial function and sirtuin-dependent signaling. This review will precis the accumulating evidence for targeting NAD+ metabolism in metabolic disease, map the different NAD+ boosting strategies and discuss the challenges and open questions in the field. The health potential of targeting NAD+ homeostasis will inform clinical study design to identify nutraceutical approaches for combating metabolic disease and the unwanted effects of aging.
... Human digestion and the microbiome 10 play roles in the provision of these vitamins in ways that are not fully characterized. In addition, the conventional NAD þ precursor vitamins, NA and Nam, have long been supplemented into human and animal diets to prevent pellagra and promote growth 11,12 . Though NR has been available as a GMP-produced supplement since 2013 and animal safety assessment indicates that it is as nontoxic as Nam 13 , no human testing has been reported. ...
Nicotinamide riboside (NR) is in wide use as an NAD⁺ precursor vitamin. Here we determine the time and dose-dependent effects of NR on blood NAD⁺ metabolism in humans. We report that human blood NAD⁺ can rise as much as 2.7-fold with a single oral dose of NR in a pilot study of one individual, and that oral NR elevates mouse hepatic NAD⁺ with distinct and superior pharmacokinetics to those of nicotinic acid and nicotinamide. We further show that single doses of 100, 300 and 1,000 mg of NR produce dose-dependent increases in the blood NAD⁺ metabolome in the first clinical trial of NR pharmacokinetics in humans. We also report that nicotinic acid adenine dinucleotide (NAAD), which was not thought to be en route for the conversion of NR to NAD⁺, is formed from NR and discover that the rise in NAAD is a highly sensitive biomarker of effective NAD⁺ repletion.
... One of the early treatments for pellagra was consumption of a 1.5-2 pints of cow milk (1). In 1937, nicotinamide and nicotinic acid (NA) 8 were identified as pellagra-preventive (PP) factors (2,3), and tryptophan was subsequently discovered as a molecule with PP activity (4). Nicotinamide and NA, which are collectively termed niacin, contain a pyridine ring that can be salvaged to form NAD + in 2 or 3 enzymatic steps, whereas tryptophan is the de novo precursor of NAD + , requiring 7 enzymatic steps (5). ...
Background:
Nicotinamide riboside (NR) is a recently discovered NAD(+)precursor vitamin with a unique biosynthetic pathway. Although the presence of NR in cow milk has been known for more than a decade, the concentration of NR with respect to the other NAD(+)precursors was unknown.
Objective:
We aimed to determine NAD(+)precursor vitamin concentration in raw samples of milk from individual cows and from commercially available cow milk.
Methods:
LC tandem mass spectrometry and isotope dilution technologies were used to quantify NAD(+)precursor vitamin concentration and to measure NR stability in raw and commercial milk. Nuclear magnetic resonance (NMR) spectroscopy was used to test for NR binding to substances in milk.
Results:
Cow milk typically contained ∼12 μmol NAD(+)precursor vitamins/L, of which 60% was present as nicotinamide and 40% was present as NR. Nicotinic acid and other NAD(+)metabolites were below the limits of detection. Milk from samples testing positive forStaphylococcus aureuscontained lower concentrations of NR (Spearman ρ = -0.58,P= 0.014), and NR was degraded byS. aureus Conventional milk contained more NR than milk sold as organic. Nonetheless, NR was stable in organic milk and exhibited an NMR spectrum consistent with association with a protein fraction in skim milk.
Conclusions:
NR is a major NAD(+)precursor vitamin in cow milk. Control ofS. aureusmay be important to preserve the NAD(+)precursor vitamin concentration of milk.
... In 1926, Goldberger's work implicated vitamin B deficiency as the cause of pellagra [14]. More than a decade later, Koehn and Elvehjem [15] were the first to isolate niacin when they demonstrated it could cure black tongue (the canine model of pellagra) in dogs. As a result of widespread fortification with niacin of grains and cereals in the US food supply, endemic pellagra has nearly been eradicated [16]. ...
BACKGROUND: Alcohol withdrawal delirium (AWD) is associated with significant morbidity and mortality. Pellagra (niacin deficiency) can be a cause of delirium during alcohol withdrawal that may often be overlooked.Objectives
We present a three-patient case series of pellagrous encephalopathy (delirium due to pellagra) presenting as AWD. METHODS: We provide a brief review of pellagra's history, data on pellagra's epidemiology, and discuss pellagra's various manifestations, particularly as related to alcohol withdrawal. We conclude by providing a review of existing guidelines on the management of alcohol withdrawal, highlighting that they do not include pellagrous encephalopathy in the differential diagnosis for AWD. RESULTS: Though pellagra has been historically described as the triad of dementia, dermatitis, and diarrhea, it seldom presents with all three findings. The neurocognitive disturbance associated with pellagra is better characterized by delirium rather than dementia, and pellagra may present as an isolated delirium without any other aspects of the triad. DISCUSSION: Although endemic pellagra is virtually eradicated in Western countries, it continues to present and to be attributed to AWD, particularly in patients with risk factors for malnutrition such as chronic alcohol intake, homelessness, and AIDS. Whenever pellagra is suspected, treatment with oral nicotinamide (100 mg three times daily for 3-4 weeks) prior to laboratory confirmation is recommended as an inexpensive, safe, and potentially life-saving intervention.
... It was shown that nicotinic acid could cure black tongue in dogs, which was an early animal model for pellagra. 26 It was a further two decades later, in the early 1950s that the lipid-lowering effects of niacin were described by the pathologist Rudolf Altschul. 27 He reported his initial findings following experiments in rabbits and then in a landmark study of its effects in humans. ...
Statins form the cornerstone of pharmaceutical cardiovascular disease prevention. However, despite very effective statin intervention, the majority of events remain unpreventable. In some cases statin therapy alone is insufficient to achieve adequate lipid levels whereas other patients are unable to tolerate statins. This calls for additional treatment options. Niacin has a long history of success in reducing low-density lipoprotein cholesterol and triglycerides, and increasing high-density lipoprotein cholesterol. It was the first lipid-lowering drug to demonstrate a reduction in cardiovascular events, and remains the only one that has consistently shown benefits on surrogate outcomes when added to background therapies of other lipid-lowering drugs, including statins. Niacin's uptake in clinical practice has been less successful due to its side-effect profile, most notable being flushing. The uncovering of the mechanism by which flushing is induced, together with the development of a prostaglandin D(2) receptor inhibitor (laropiprant) which reduces this downstream flushing effect of niacin, has sparked new promise in therapeutic lipid management. It provides an additional treatment option into managing lipid abnormalities. The uptake in clinical practice of the niacin-laropiprant combination will depend on the relative improvements experienced by the patient in the side-effect profile compared to other treatment options, as well as on the the keenly-awaited outcome studies currently underway. Until these data become available guidelines and recommendations are unlikely to change and niacin's position in therapeutic cardiovascular risk prevention will be determined by clinician opinion and experience, and patient preferences.
... Although it was not yet known that NAD ϩ deficiency was the underlying cause of the disease, pellagra was known as a deficiency of niacin (4). Dogs suffering from "canine black tongue" regained appetite only 2 h after niacin administration, reverted their retarded growth, and appeared completely normal after 3 d of treatment (4,162). The current incidence of pellagra is low due to improved nutritional status, with a notable exception of incidental cases of pellagra in patients with alcoholism or malnutrition disorders (163). ...
A century after the identification of a coenzymatic activity for NAD(+), NAD(+) metabolism has come into the spotlight again due to the potential therapeutic relevance of a set of enzymes whose activity is tightly regulated by the balance between the oxidized and reduced forms of this metabolite. In fact, the actions of NAD(+) have been extended from being an oxidoreductase cofactor for single enzymatic activities to acting as substrate for a wide range of proteins. These include NAD(+)-dependent protein deacetylases, poly(ADP-ribose) polymerases, and transcription factors that affect a large array of cellular functions. Through these effects, NAD(+) provides a direct link between the cellular redox status and the control of signaling and transcriptional events. Of particular interest within the metabolic/endocrine arena are the recent results, which indicate that the regulation of these NAD(+)-dependent pathways may have a major contribution to oxidative metabolism and life span extension. In this review, we will provide an integrated view on: 1) the pathways that control NAD(+) production and cycling, as well as its cellular compartmentalization; 2) the signaling and transcriptional pathways controlled by NAD(+); and 3) novel data that show how modulation of NAD(+)-producing and -consuming pathways have a major physiological impact and hold promise for the prevention and treatment of metabolic disease.
Tuberculosis (TB) is a highly contagious airborne disease with nearly 25% of the world's population infected with it. Challenges such as multi drug resistant TB (MDR-TB), extensive drug resistant TB (XDR-TB) and in rare cases totally drug resistant TB (TDR-TB) emphasizes the critical and urgent need in developing novel TB drugs. Moreover, the prolonged and multi drug treatment regime suffers a major drawback due to high toxicity and vulnerability in TB patients. This calls for intensified research efforts in identifying novel molecular scaffolds which can combat these issues with minimal side effects. In this pursuit, researchers have screened many bio-active molecules among which coumarin have been identified as promising candidates for TB drug discovery and development. Coumarins are naturally occurring compounds known for their low toxicity and varied biological activity. The biological spectrum of coumarin has intrigued medicinal researchers to investigate coumarin scaffolds for their relevance as anti-TB drugs. In this review we focus on the recent developments of coumarin and its critical aspects of structural design required to exhibit anti-tubercular (anti-TB) activity. The information provided will help medicinal chemists to design and identify newer molecular analogs for TB treatment and also broadens the scope of exploring future generation potent yet safer coumarin based anti-TB agents.
Microbiological assays in a 96-well microtiter format for folates, vitamin B12, pantothenic acid, and riboflavin are presented. The methods are suitable for the determination of total vitamin contents. They do not require a classical microbiological laboratory setup and are easy to handle. For the folate assay, the response to various vitamers is presented and the resulting conclusions for analysis of food folates are shown in detail on the examples of a cereal product and of broccoli. For all other assays, extensive validation was performed and the resulting data are presented. Due to their ruggedness and excellent precision and accuracy compared with classical microbiological assays, the VitaFast® assay is suitable for use in routine vitamin analysis.
We reported previously that the pellagragenic property of corn protein is not only low l-tryptophan concentration but also the lower conversion percentage of l-tryptophan to nicotinamide; the amino acid composition greatly affected the conversion percentage. The amino acid value of wheat protein is lower than that of rice protein. In the present study, we compare the conversion percentages of l-tryptophan to nicotinamide between wheat protein and rice protein diets in growing rats. The body weight gain for 28 days in rats fed with a 10% amino acid mixture diet with wheat protein was lower than that of rats fed with a 10% amino acid diet with rice protein (68.1 ± 1.6 g vs 108.4 ± 1.9 g; P < 0.05). The conversion percentage of l-tryptophan to nicotinamide was also lower for the wheat protein diet compared with the rice protein diet (1.44 ± 0.036% vs 2.84 ± 0.19%; P < 0.05). The addition of limiting amino acids (l-isoleucine, l-lysine, l-tryptophan, l-methionine, l-threonine) to the wheat protein diet improved growth and the conversion percentage. In conclusion, our result supports the thinking that the composition of amino acids affects the conversion ratio of l-tryptophan to nicotinamide.
• In adult bitches the excretion of N¹-methylnicotinamide decreases markedly during periods of anabolism induced by anterior pituitary growth preparations or testosterone propionate.
• Coenzymes I and II in the red blood cells do not increase during this apparent storage of niacin.
• Riboflavin output also decreases following administration of testosterone propionate.
• Decreases in the excretion of ascorbic acid during similar experiments were significant but less striking; blood ascorbic acid was unchanged.
• In a single experiment, the concentration of vitamin A in blood fell during the period when testosterone propionate produced its effect.
• Allantoin excretion remained unchanged in these experiments.
• The increase in vitamin requirements during normal growth may also be demonstrable during induced growth.
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