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Excess nicotinamide inhibits methylation-mediated degradation of catecholamines in normotensives and hypertensives
Abstract
Nicotinamide and catecholamines are both degraded by S-adenosylmethionine-dependent methylation. Whether excess nicotinamide affects the degradation of catecholamines is unknown. The aim of this study was to investigate the effect of nicotinamide on the methylation status of the body and methylation-mediated catecholamine degradation in both normotensives and hypertensives. The study was conducted in 19 normotensives and 27 hypertensives, using a nicotinamide-loading test (100 mg orally). Plasma nicotinamide, N(1)-methylnicotinamide, homocysteine (Hcy), betaine, norepinephrine, epinephrine, normetanephrine and metanephrine levels before and 5 h after nicotinamide loading were measured. Compared with normotensives, hypertensives had higher baseline (fasting) levels of plasma nicotinamide, Hcy and norepinephrine, but lower levels of plasma normetanephrine, a methylated norepinephrine derivative. Nicotinamide loading induced a significant increase in the levels of plasma N(1)-methylnicotinamide and norepinephrine, and a significant decrease in the levels of O-methylated epinephrine (metanephrine) and betaine, a major methyl donor, in both hypertensives and normotensives. Moreover, nicotinamide-loading significantly increased plasma Hcy levels, but decreased plasma normetanephrine levels in normotensives. The baseline levels of plasma epinephrine in hypertensives were similar to those of normotensives, but the post-nicotinamide-loading levels of plasma epinephrine in hypertensives were higher than those of normotensives. This study demonstrated that excess nicotinamide might deplete the labile methyl pool, increase Hcy generation and inhibit catecholamine degradation. It also revealed that hypertensives had an abnormal methylation pattern, characterized by elevated fasting plasma levels of unmethylated substrates, nicotinamide, Hcy and norepinephrine. Therefore, it seems likely that high nicotinamide intake may be involved in the pathogenesis of Hcy-related cardiovascular disease.
... The catabolites that are known and measured see their abundance and distribution change depending on the precursor applied, the animal model, the clinical condition being investigated, and the biospecimens being measured [68,[71][72][73]. Overall, the nature and the effects of catabolites of NAD + and NADH and their sustained endogenous increase in disease or upon supplementation remain poorly understood, although concerns have been raised [73][74][75][76][77]. This warrants the need for more robust identification and characterization of the catabolites of NAD(P)(H). ...
... Excess nicotinamide (from supplementation or increased NAD + consumption) is often associated with increased plasma, serum, and urinary levels of N-Me-NAM (Table 1) [31,80]. Sun et al., demonstrated that excess nicotinamide led to catecholamine degradation in hypertensive mice resulting from the perturbation of the methylation pool and ultimately leading to enhanced levels of nicotinamide, homocysteine, and norepinephrine [77]. The enzyme responsible for the methylation of nicotinamide is now known as nicotinamide N-methyl transferase (NNMT) [86]. ...
... Alternatively, the progression of chronic kidney diseases is associated with a trend toward an increase in methylated catabolites of nicotinamide, whereby NNMT expression induces NAD + and methionine metabolism perturbation contributing to renal and hepatic fibrosis [90,91]. NNMT hyper-activity not only affects NAD + and SAM levels but can also redirect epigenomics and epi transcriptomics events [77,92]. However, a recent publication reported that NR supplementation (1 g/day) is not associated with altered methylation homeostasis in Parkinson's disease [93]. ...
Dietary vitamin B3 components, such as nicotinamide and nicotinic acid, are precursors to the ubiquitous redox cofactor nicotinamide adenine dinucleotide (NAD+). NAD+ levels are thought to decline with age and disease. While the drivers of this decline remain under intense investigation, strategies have emerged seeking to functionally maintain NAD+ levels through supplementation with NAD+ biosynthetic intermediates. These include marketed products, such as nicotinamide riboside (NR) and its phosphorylated form (NMN). More recent developments have shown that NRH (the reduced form of NR) and its phosphorylated form NMNH also increases NAD+ levels upon administration, although they initially generate NADH (the reduced form of NAD+). Other means to increase the combined levels of NAD+ and NADH, NAD(H), include the inhibition of NAD+-consuming enzymes or activation of biosynthetic pathways. Multiple studies have shown that supplementation with an NAD(H) precursor changes the profile of NAD(H) catabolism. Yet, the pharmacological significance of NAD(H) catabolites is rarely considered although the distribution and abundance of these catabolites differ depending on the NAD(H) precursor used, the species in which the study is conducted, and the tissues used for the quantification. Significantly, some of these metabolites have emerged as biomarkers in physiological disorders and might not be innocuous. Herein, we review the known and emerging catabolites of the NAD(H) metabolome and highlight their biochemical and physiological function as well as key chemical and biochemical reactions leading to their formation. Furthermore, we emphasize the need for analytical methods that inform on the full NAD(H) metabolome since the relative abundance of NAD(H) catabolites informs how NAD(H) precursors are used, recycled, and eliminated.
... Thus, it is expected that niacin may affect the methylation-mediated degradation of monoamine neurotransmitters by competing for labile methyl groups. In our previous study we found that nicotinamide load increases the plasma norepinephrine, but decreases its methylated metabolites [7] . In the present study, we further investigate the effect of excess nicotinamide on the plasma levels of serotonin and histamine in healthy subjects. ...
... Plasma N 1 -methylnicotinamide, urinary N 1 -methyl-2pyridone-5-carboxamide (2-Py), and plasma betaine levels were measured by using high-performance liquid chromatography (HPLC), as described previously [7,8] . ...
... This study demonstrated that excess nicotinamide may play a causal role in increased plasma serotonin and histamine levels. methylated derivatives [7] , suggest that excessive nicotinamide could inhibit the degradation of monoamine neurotransmitters presumably due to methyl-group pool depletion. ...
Methylation, a methyl group-consuming reaction, plays a key role in the degradation (i.e., inactivation) of monoamine neurotransmitters, including catecholamines, serotonin and histamine. Without labile methyl groups, the methylation-mediated degradation cannot take place. Although high niacin (nicotinic acid and nicotinamide) intake, which is very common nowadays, is known to deplete the body's methyl-group pool, its effect on monoamine-neurotransmitter degradation is not well understood. The aim of this article was to investigate the effect of excess nicotinamide on the levels of plasma serotonin and histamine in healthy subjects. Urine and venous blood samples were collected from nine healthy male volunteers before and after oral loading with 100 mg nicotinamide. Plasma N(1)-methylnicotinamide, urinary N(1)-methyl-2-pyridone-5-carboxamide (2-Py), and plasma betaine levels were measured by using high-performance liquid chromatography (HPLC). Plasma concentrations of choline, serotonin and histamine were measured using commercial kits. The results showed that the plasma N(1)-methylnicotinamide level and the urinary excretion of 2-Py significantly increased after oral loading with 100 mg nicotinamide, which was accompanied with a decrease in the methyl-group donor betaine. Compared with those before nicotinamide load, five-hour postload plasma serotonin and histamine levels significantly increased. These results suggest that excess nicotinamide can disturb monoamine-neurotransmitter metabolism. These findings may be of significance in understanding the etiology of monoamine-related mental diseases, such as schizophrenia and autism (a neurodevelopmental disorder).
... Therefore, high xenobiotic exposure may disturb the methylation of endogenous substrates due to competition for labile methyl groups. For example, excess nicotinamide (a form of niacin) can inhibit methylation-mediated degradation/inactivation of catecholamines, resulting in an increase in the levels of circulating norepinephrine [17], a phenomenon commonly seen in MetS [18], which provides the first evidence that methyl-consuming xenobiotics may contribute to increased circulating norepinephrine. In animal studies, arsenic, a common environmental methylconsuming toxin that increases the risk of MetS [19], is found to cause global DNA hypomethylation [20,21]. ...
... Moreover, current research also shows correlations between polymorphisms in xenobiotic/drug-metabolizing enzymes and cancer susceptibility414243. 7) Dysfunctions of the organs that are responsible for the biotransformation and excretion of xenobiotics, such as the liver and kidney [44,45], may increase the risk for MetS. Recently, we hypothesize that MetS may be a consequence of chronic xenobiotic poisoning [2], which may involve a mechanism of xenobiotic-induced systemic tissue damage and subsequent decrease in cellular response to physiological signals (e.g., insensitive to insulin [46,47]), and methyl depletion and subsequent disturbance in numerous methylation-mediated reactions in the body (e.g., inhibition of catecholamine degradation [17]). All of the above evidence suggests that environmental/dietary factors and genetic factors in MetS may be, to some extent, a reflection of xenobiotic exposure and the efficiency of the body's xenobiotic-biotransforming/eliminating system and ROS-scavenging system (Figure 1). ...
... Catecholamines, which mediate the cardiovascular effects of the adrenergic nervous system, are degraded/ inactivated by monoamine oxidase and catechol-O- methyhransferase [105]. An increase in the degradation of catecholamines generates more end metabolites (i.e., homovanillic acid and vanillylmandelic acid), while a decrease in the degradation might result in an increase in the levels of circulating catecholamines [17]. The skin expresses monoamine oxidase and catechol-O- methyhransferase [48], and thus might play a role in the inactivation of circulating catecholamines. ...
The body's total antioxidant capacity represents a sum of the antioxidant capacity of various tissues/organs. A decrease in the body's antioxidant capacity may induce oxidative stress and subsequent metabolic syndrome, a clustering of risk factors for type 2 diabetes and cardiovascular disease. The skin, the largest organ of the body, is one of the major components of the body's total antioxidant defense system, primarily through its xenobiotic/drug biotransformation system, reactive oxygen species-scavenging system, and sweat glands- and sebaceous glands-mediated excretion system. Notably, unlike other contributors, the skin contribution is variable, depending on lifestyles and ambient temperature or seasonal variations. Emerging evidence suggests that decreased skin's antioxidant and excretory functions (e.g., due to sedentary lifestyles and low ambient temperature) may increase the risk for metabolic syndrome. This review focuses on the relationship between the variability of skin-mediated detoxification and elimination of exogenous and endogenous toxic substances and the development of metabolic syndrome. The potential role of sebum secretion in lipid and cholesterol homeostasis and its impact on metabolic syndrome, and the association between skin disorders (acanthosis nigricans, acne, and burn) and metabolic syndrome are also discussed.
... Niacin appears to have antioxidant and anti-inflammatory properties [8] and consumption may regulate abnormal lipid metabolism and improve endothelial function [9]. Excessive niacin intake may result in insulin resistance (IR) [10,11], abnormal blood pressure and high homocysteine levels [12]. Clinical trials evaluating niacin supplementation in groups at high risk of DM [13][14][15][16]. ...
... Therefore, non-moderate exercise has a higher risk of diabetes. Sun WP et.al reported that an increased nicotinamide load resulted in a significant increase in pulse pressure, and inhibits catecholamine degradation [12]. Thus, niacin intake was linked to hypertension, a high risk factor for DM. ...
Purposes
Previous studies show inconsistent associations between niacin supplementation and diabetes mellitus (DM) in high-risk population, but little is known about the relationship between dietary intake of niacin and DM in the generation population. Our study aimed to explore the associations of dietary niacin intake with the risk of DM in the United States (US) adult population.
Methods
These data were derived from the National Health and Nutrition Examination Survey (NHANES) 2003–2018 of 35,606 individuals aged 20 years or older. Niacin intake and food sources were measured by two 24-h dietary recall interviews. The diagnosis of DM was established according to the American Diabetes Association (ADA) criteria. Binary logistic regression and restricted cubic spline models were applied to evaluate the association of dietary niacin intake and DM.
Results
Among the 35,606 individuals, the prevalence of DM was 11.47%. The full-adjusted odds ratio(aOR) of DM was 1.27(95%CI 1.06–1.52) for quartile (Q) 4 v. Q1 of dietary niacin intake. In the dose–response analysis, the shape of the association of niacin intake with the risk of DM was approximately J-shaped (non-linear, p < 0.05). Energy-adjusted niacin of 26.08 mg/day was the optimal cut-off value for predicting DM.
Conclusions
High dietary niacin intake was positively associated with DM among US adults.
Level of evidence
Level V: Opinions of authorities, based on descriptive studies, narrative reviews, clinical experience, or reports of expert committees.
... 7 Nevertheless, excessive niacin is also engaged in numerous pathologies, including insulin resistance and elevated homocysteine (HCY) levels. 8,9 Several randomized clinical trials have assessed the effect of niacin supplementation on blood pressure (BP), but the results were inconsistent. [10][11][12][13][14][15] Of note, these trials mainly examined the effects of relatively high niacin supplementation in high-risk populations rather than the effects of dietary niacin derived from foods in general populations. ...
... 34,35 It was reported that an increased nicotinamide load resulted in a significant increase in pulse pressure, which might be related to the fact that high niacin intake depletes the methyl pool, increases HCY generation and betaine consumption, and inhibits catecholamine degradation. 9,36 In addition, a previous study found that treatment with niacin was related to increased insulin resistance as well. 14 Of note, Table 1 shows that participants with lower dietary niacin (quartile 1 and 2) were older and had higher SBP and DBP levels, lower percentages of residence in urban and southern regions, and a higher sodium to potassium intake ratio. ...
Importance
The relationship of dietary niacin intake with the risk of hypertension remains unknown.
Objective
To determine the prospective association between dietary niacin intake and new-onset hypertension, and examine factors that may modify the association among Chinese adults.
Design, Setting, and Participants
This nationwide cohort study of 12 243 Chinese adults used dietary intake data from 7 rounds of the China Health and Nutrition Survey. Dietary intake was measured by 3 consecutive 24-hour dietary recalls from participants in combination with a weighing inventory taken over the same 3 days at the household level. Statistical analysis was conducted from May 2020 to August 2020.
Exposures
Dietary intake.
Main Outcomes and Measures
The study outcome was new-onset hypertension, defined as systolic blood pressure 140 mm Hg or greater and/or diastolic blood pressure 90 mm Hg or greater, diagnosis by physician, or current antihypertensive treatment during the follow-up.
Results
The mean (SD) age of the study population was 41.2 (14.2) years, and 5728 (46.8%) of participants were men. The mean (SD) dietary niacin intake level was 14.8 (4.1) mg/d. A total of 4306 participants developed new-onset hypertension during a median (interquartile range) follow-up duration of 6.1 (3.6-11.3) years. When dietary niacin was assessed in quartiles, the lowest risk of new-onset hypertension was found in participants in quartile 3 (14.3 to <16.7 mg/d; adjusted hazard ratio, 0.83; 95% CI, 0.75-0.90) compared with those in quartile 1 (<12.4 mg/d). Consistently in the threshold analysis, for every 1 mg/d increase in dietary niacin, there was a 2% decrease in new-onset hypertension (adjusted HR, 0.98; 95% CI, 0.96-1.00) in those with dietary niacin intake less than 15.6 mg/d, and a 3% increase in new-onset hypertension (adjusted HR, 1.03; 95% CI, 1.02-1.04) in participants with dietary niacin 15.6 mg/d or greater. Based on these results, there was a J-shaped association between dietary niacin intake and new-onset hypertension in the general population of Chinese adults, with an inflection point at 15.6 mg/d and a minimal risk at 14.3 to 16.7 mg/d (quartile 3) of dietary niacin intake.
Conclusions and Relevance
The results of this study provide some evidence for maintaining the optimal dietary niacin intake levels for the primary prevention of hypertension.
... Plasma Hcy and betaine were measured as previously described [17]. To measure plasma Hcy concentrations, 50 ml of plasma added with 25 ml of internal standard (10 mmol/l cystamine) and 25 ml of PBS (pH 7.4), subsequently incubated with 10 ml of 100 g/l tris (2carboxyethyl) phosphine hydrochloride for 30 min at RT, then 90 ml of 100 g/l trichloroacetic acid containing 1 mmol/l EDTA was added for deproteinization. ...
... The methylation of nicotinamide and nicotinic acid increases the consumption of methyl groups. This effect can disturb the methylation of other substrates, such as the methylation of catecholamines and DNA, as found in our present and previous studies [12,13,17]. DNA hypomethylation may occur in the skin as well after long-term nicotinamide treatment, which might be somehow responsible for reducing the rates of new nonmelanoma skin cancers and actinic keratoses in high-risk patients [6]. ...
Aim
The present study was to compare the effects of nicotinic acid and nicotinamide on the plasma methyl donors, choline and betaine.
Methods
Thirty adult subjects were randomly divided into three groups of equal size, and orally received purified water (C group), nicotinic acid (300 mg, NA group) or nicotinamide (300 mg, NM group). Plasma nicotinamide, N¹-methylnicotinamide, homocysteine, betaine and choline levels before and 1.5-h and 3-h post-dosing, plasma normetanephrine and metanephrine concentrations at 3-h post-dosing, and the urinary excretion of N¹-methyl-2-pyridone-5-carboxamide during the test period were examined.
Results
The level of 3-h plasma nicotinamide, N¹-methylnicotinamide, homocysteine, the urinary excretion of N¹-methyl-2-pyridone-5-carboxamide and pulse pressure (PP) in the NM group was 221%, 3972%, 61%, 1728% and 21.2% higher than that of the control group (P < 0.01, except homocysteine and PP P < 0.05), while the 3-h plasma betaine, normetanephrine and metanephrine level in the NM group was 24.4%, 9.4% and 11.7% lower (P < 0.05, except betaine P < 0.01), without significant difference in choline levels. Similar but less pronounced changes were observed in the NA group, with a lower level of 3-h plasma N¹-methylnicotinamide (1.90 ± 0.20 μmol/l vs. 3.62 ± 0.27 μmol/l, P < 0.01) and homocysteine (12.85 ± 1.39 μmol/l vs. 18.08 ± 1.02 μmol/l, P < 0.05) but a higher level of betaine (27.44 ± 0.71 μmol/l vs. 23.52 ± 0.61 μmol/l, P < 0.05) than that of the NM group.
Conclusion
The degradation of nicotinamide consumes more betaine than that of nicotinic acid at identical doses. This difference should be taken into consideration in niacin fortification.
... In fact, MNA could mediate many of NicA beneficial effects. On the other hand, it should be also taken into consideration that during prolonged NicA treatment the robust metabolism of NicA to MNA may alter NAD metabolome and induce detrimental effect due to high endogenous NA concentration and enhanced NA methylation resulting in the depletion of methyl group donors Sun et al., 2012;Guyton & Bays, 2007;Li et al., 2013). ...
... Since NA concentration and the NA/MNA ratio was significantly higher in the plasma of Sun et al., 2012;Guyton & Bays, 2007;Li et al., 2013) and may also increase the risk of drug-induced hepatotoxicity (Bhardwaj & Chalasani, 2007;Demyen et al., 2013). ...
Background:
1-methylnicotinamide (MNA) is a major endogenous metabolite of nicotinic acid (NicA). MNA displays anti-thrombotic and anti-inflammatory activity, both of which could partially contribute to the vasoprotective properties of NicA. In the present study we compare the anti-atherosclerotic effects of MNA and NicA in ApoE/LDLR(-/-) mice.
Experimental approach:
four-month-old ApoE/LDLR(-/-) mice were treated with an equimolar dose of MNA or NicA (100 mg kg(-1)). Plaque size and macrophages content in atherosclerotic plaques of the brachiocephalic artery (BCA), endothelial function (6-keto-PGF1α , nitrite/nitrate) in aortic rings, systemic inflammation, platelet activation, 2,3-dinor-6-keto-PGF1α and 2,3-dinor-TXB2 in urine as well as concentration of MNA metabolites were measured.
Results:
MNA and NicA reduced atherosclerotic plaque area and plaque inflammation in BCA. The anti-atherosclerotic actions of MNA and NicA were associated with improved endothelial function as evidenced by a higher concentration of 6-keto-PGF1α and nitrite/nitrate in the aortic effluent. NicA treatment resulted in an approximately 2-fold higher concentration of MNA and its metabolites in urine and an 8-fold higher NA/MNA ratio in plasma, as compared with MNA treatment.
Conclusions:
MNA displays pronounced anti-atherosclerotic action in ApoE/LDLR(-/-) mice, an effect associated with an improvement in PGI2-dependent endothelial function, inhibition of platelet activation, inhibition of inflammatory burden in plaques, and diminished systemic inflammation. Despite substantially higher MNA availability following NicA treatment, as compared with an equimolar dose of MNA, the anti-atherosclerotic effect of NicA was not stronger. We suggest that detrimental effects of NicA may limit beneficial effects of NicA-derived MNA.
... For example, vitamin C has been known to inhibit the sulfation of other chemicals by competing for limited sulfate [111] . Although there are no systematic studies on the effect of vitamin fortification on the degradation of neurotransmitters, evidence has shown that excess vitamin C [115,116] and nicotinamide [117] can inhibit the degradation of catecholamines by depletion of sulfate and methyl groups, respectively. Thus, in theory, the effect of vitamins on the metabolism of monoamine neurotransmitters may affect the function of the nervous system. ...
... Although the mechanism of global DNA hypomethylation is not well understood, a lack of methyl groups may play a role in abnormal DNA methylation, because an adequate supply of methyl groups is a prerequisite for DNA methylation [123] . The biotransformation of some vitamins, especially niacin [117] , may increase the demand for labile methyl groups and therefore, an excess intake of these vitamins may disturb DNA methylation by competing methyl groups. Recently, we tested this possibility by investigating the effect of nicotinamide supplementation on DNA methylation in rats and found that long-term high nicotinamide exposure led to a decrease in the methyl pool and in the levels of hepatic DNA methylation associated with alteration of gene expression [123] . ...
Over the past few decades, food fortification and infant formula supplementation with high levels of vitamins have led to a sharp increase in vitamin intake among infants, children and adults. This is followed by a sharp increase in the prevalence of obesity and related diseases, with significant disparities among countries and different groups within a country. It has long been known that B vitamins at doses below their toxicity threshold strongly promote body fat gain. Studies have demonstrated that formulas, which have very high levels of vitamins, significantly promote infant weight gain, especially fat mass gain, a known risk factor for children developing obesity. Furthermore, ecological studies have shown that increased B vitamin consumption is strongly correlated with the prevalence of obesity and diabetes. We therefore hypothesize that excess vitamins may play a causal role in the increased prevalence of obesity. This review will discuss: (1) the causes of increased vitamin intake; (2) the non-monotonic effect of excess vitamin intake on weight and fat gain; and (3) the role of vitamin fortification in obesity disparities among countries and different groups within a country.
... Therefore, excess vitamins can increase the levels of monoamine neurotransmitters either by competing for the same biotransformation system or by facilitating the synthesis, or by both. Indeed, evidence shows that high doses of vitamin C decrease plasma-conjugated dopamine and norepinephrine levels by competing for sulfation [30], whereas nicotinamide increases the levels of plasma of norepinephrine [31], serotonin, and histamine [32], presumably due to a decrease in methylation-mediated degradation of the monoamines. Vitamin B 6 supplementation can increase the blood serotonin levels of newborn babies [33]. ...
... Baeckert and colleagues [64] showed that very low-birth-weight infants who received the recommended parenteral vitamin supplement as part of their total parenteral nutrition developed elevated plasma riboflavin concentrations during their first postnatal month with peak concentrations 100-fold above baseline umbilical cord plasma vitamin concentrations. Moreover, there are two studies finding high plasma levels and urinary excretion of methylated metabolites of niacin in autistic patients [65,66], which suggests a niacin overload, because excess niacin is rapidly degraded after ingestion, but its methylated metabolites remain longer in the circulation [31,67]. Given that excess vitamins may lead to neurotoxicity and disturbances in monoamine neurotransmitter metabolism, as mentioned earlier, it is possible that high multivitamin exposure may play a role in the increased prevalence of autism. ...
Autism, a neurodevelopmental disorder that affects boys more than girls, is often associated with altered levels of monoamines (serotonin and catecholamines), especially elevated serotonin levels. The monoamines act as both neurotransmitters and signaling molecules in the gastrointestinal and immune systems. The evidence related to monoamine metabolism may be summarized as follows: (i) monoamine neurotransmitters are enzymatically degraded/inactivated by three mechanisms: oxidative deamination, methylation, and sulfation. The latter two are limited by the supply of methyl groups and sulfate, respectively. (ii) A decrease in methylation- and sulfation-mediated monoamine inactivation can be compensated by an increase in the oxidative deamination catalyzed by monoamine oxidase, an X-linked enzyme exhibiting higher activity in females than in males. (iii) Vitamins can, on one hand, facilitate the synthesis of monoamine neurotransmitters and, on the other hand, inhibit their inactivation by competing for methylation and sulfation. Therefore, we postulate that excess multivitamin feeding in early infancy, which has become very popular over the past few decades, may be a potential risk factor for disturbed monoamine metabolism. In this paper, we will focus on the relationship between excess multivitamin exposure and the inactivation/degradation of monoamine neurotransmitters and its possible role in the development of autism.
... For example, NAD+ degradation in the aging process increases the consumption of S-adenosylmethionine (SAM) [4], an essential cellular methyl donor. Excessive supplementation with nicotinamide (NAM), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) can potentially exacerbate the problem of methylation by increasing NAM levels [5][6][7], as NAM can be methylated to N 1 -methylnicotinamide (MNAM), which lowers methyl donor levels and increases the risk of vascular disease, neurodegenerative disease and chronic kidney disease by producing more homocysteine [8,9]. Unexpectedly, in the long-term study of nicotinamide riboside chloride (Niagen) [10], no increase in homocysteine was observed in subjects who consumed up to 1000 mg of Niagen. ...
The molecule NAD+ is a coenzyme for enzymes catalyzing cellular redox reactions in several metabolic pathways, encompassing glycolysis, TCA cycle, and oxidative phosphorylation, and is a substrate for NAD+-dependent enzymes. In addition to a hydride and electron transfer in redox reactions, NAD+ is a substrate for sirtuins and poly(adenosine diphosphate–ribose) polymerases and even moderate decreases in its cellular concentrations modify signaling of NAD+-consuming enzymes. Age-related reduction in cellular NAD+ concentrations results in metabolic and aging-associated disorders, while the consequences of increased NAD+ production or decreased degradation seem beneficial. This article reviews the NAD+ molecule in the development of aging and the prevention of chronic age-related diseases and discusses the strategies of NAD+ modulation for healthy aging and longevity.
... High dose supplementation with NAM, NR, and NMN may increase nicotinamide levels [144][145][146]. Excessive NAM is theoretically methylated to MeNAM, which could (i) lead to a deficiency of methyl donors (e.g., S-adenosyl methionine) for dopamine and creatine synthesis and (ii) increased risk of vascular disease neurodegenerative and chronic kidney disease by producing more homocysteine [147,148]. Interestingly, Conze et al. [117] observed no homcysteine increase in subjects consuming up to 1000 mg of Niagen (nicotinamide riboside chloride) over a 56-day period. Thus, further studies are needed to clarify the issue of methylation as a consequence of NR and NMN supplementation. ...
Precursors of nicotinamide adenine dinucleotide (NAD+), modulators of enzymes of the
NAD+ biosynthesis pathways and inhibitors of NAD+ consuming enzymes, are the main boosters
of NAD+. Increasing public awareness and interest in anti-ageing strategies and health-promoting
lifestyles have grown the interest in the use of NAD+ boosters as dietary supplements, both in
scientific circles and among the general population. Here, we discuss the current trends in NAD+
precursor usage as well as the uncertainties in dosage, timing, safety, and side effects. There are
many unknowns regarding pharmacokinetics and pharmacodynamics, particularly bioavailability,
metabolism, and tissue specificity of NAD+ boosters. Given the lack of long-term safety studies,
there is a need for more clinical trials to determine the proper dose of NAD+ boosters and treatment
duration for aging prevention and as disease therapy. Further research will also need to address the
long-term consequences of increased NAD+ and the best approaches and combinations to increase
NAD+ levels. The answers to the above questions will contribute to the more efficient and safer use
of NAD+ boosters.
... The prevalence of obesity has been recognized as a serious global health problem . Obesity is believed to be a result from an imbalance between energy intake and energy expenditure (Ahn et al., 2008), which is also a serious health problem that is implicated in various diseases including type II diabetes, hypertension, coronary heart diseases, and cancer (Pi-Sunyer, 2002;Sun et al., 2012). Thus, obesity has received considerable attention as a major health hazard (Nguyen and El-Serag, 2010). ...
Background:
Obesity is characterized by increased adipose tissue mass that results from increased fat cell size (hypertrophy) and number (hyperplasia). The molecular mechanisms that govern the regulation and differentiation of adipocytes play a critical role for better understanding of the pathological mechanism of obesity. However, the mechanism of adipocyte differentiation is still unclear.
Objective:
The present study aims to compare the gene expression changes during adipocyte differentiation in the transcriptomic level, which may help to better understand the mechanism of adipocyte differentiation.
Methods:
RNA sequencing (RNA-seq) technology, GO and KEGG analysis, quantitative RT-PCR, and oil red O staining methods were used in this study.
Results:
A lot of genes were up- or down-regulated between each two differentiation stages of 3T3-L1 cells. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that lipid metabolism and oxidation-reduction reaction were mainly involved in the whole process of adipocyte differentiation. Decreased immune response and cell cycle adhesion occurred in the late phase of adipocyte differentiation, which was demonstrated by divergent expression pattern analysis. Moreover, quantitative RT-PCR results showed that the mRNA expression levels of Trpv4, Trpm4, Trpm5, and Trpm7 were significantly decreased in the differentiated adipocytes. On the other hand, the mRNA expression levels of Trpv1, Trpv2, Trpv6, and Trpc1 were significantly increased in the differentiated adipocytes. Besides, the mRNA expressions of TRPV2 and TRPM7 were also significantly increased in subcutaneous white adipose tissue from diet-induced mice. In addition, the activation of TRPM7, TRPV1, and TRPV2 suppressed the differentiation of adipocytes.
Conclusion:
These data present the description of transcription profile changes during adipocyte differentiation and provides an in-depth analysis of the possible mechanisms of adipocyte differentiation. These data offer new insight into the understanding of the mechanisms of adipocyte differentiation.
... The prevalence of obesity has been recognized as a serious global health problem [1]. Obesity is believed to be a result from an imbalance between energy intake and energy expenditure [2] and which is also a serious health problem that is implicated in various diseases including type II diabetes, hypertension, coronary heart diseases, and cancer [3,4]. Thus, obesity has received considerable attention as a major health hazard [5]. ...
Background: Obesity is characterized by increased adipose tissue mass that results from increased fat cell size (hypertrophy) and number (hyperplasia). The molecular mechanisms that govern the regulation and differentiation of adipocytes play a critical role for better understanding of the pathological mechanism of obesity. However, the mechanism of adipocyte differentiation is still unclear.
Objective: The present study aims to compare the gene expression changes during adipocyte differentiation in the transcriptomic level, which may help to better understand the mechanism of adipocyte differentiation.
Methods: RNA sequencing technology, GO and KEGG analysis and quantitative RT-PCR menthod were used in this study.
Results: A lot of genes were up- or down- regulated between each two stages of 3T3-L1 adipocyte. GO and KEGG analysis revealed that lipid metabolism and oxidation-reduction reaction were mainly involved in the whole process of adipocyte differentiation. Moreover, decreased immune response and cell cycle, adhesion were occurred in the late phase of adipocyte differentiation, which were demonstrated by divergent expression pattern analysis. In addition, quantitative RT-PCR results demonstrated that the mRNA expression level of Trpv4 , Trpm4 , Trpm5 and Trpm7 were significantly decreased in the differentiated adipocytes. On the other hand, the mRNA expression level of Trpv1 , Trpv2 , Trpv6 and Trpc1 were significantly increased.
Conclusions: These data presents the description of transcription profile changes in adipocyte differentiation and provides an in-depth analysis of the possible mechanisms of adipocyte differentiation. These data offer new insight into the understanding of the mechanisms of adipocyte differentiation.
... Supplementation with NAM has also reported significantly elevated levels of the uremic toxins, MeNAM and 2-PY (Mehr et al., 2018). Increased levels of NAM can induce a decline in serum levels of thyroxin-binding globulin or one of its derivatives which can further stimulate oxidative stress production, methyl group depletion, impaired monoamine transmitter metabolism (Tian et al., 2013), elevate homocysteine levels which is a major risk factor for several age-related diseases (Sun et al., 2011), and increased risk of developing diabetes (Lenglet et al., 2016). Interesting, supplementation with NR did not increase homocysteine, suggesting that some of the NAM mediated effects are precursor specific (Conze et al., 2019). ...
Nicotinamide adenine dinucleotide (NAD+) is an essential pyridine nucleotide that is present in all living cells. NAD+ acts as an important cofactor and substrate for a multitude of biological processes including energy production, DNA repair, gene expression, calcium-dependent secondary messenger signalling and immunoregulatory roles. The de novo synthesis of NAD+ is primarily dependent on the kynurenine pathway (KP), although NAD+ can also be recycled from nicotinic acid (NA), nicotinamide (NAM) and nicotinamide riboside (NR). NAD+ levels have been reported to decline during ageing and age-related diseases. Recent studies have shown that raising intracellular NAD+ levels represents a promising therapeutic strategy for age-associated degenerative diseases in general and to extend lifespan in small animal models. A systematic review of the literature available on Medline, Embase and Pubmed was undertaken to evaluate the potential health and/or longevity benefits due to increasing NAD+ levels. A total of 1545 articles were identified and 147 articles (113 preclinical and 34 clinical) met criteria for inclusion. Most studies indicated that the NAD+ precursors NAM, NR, nicotinamide mononucleotide (NMN), and to a lesser extent NAD+ and NADH had a favourable outcome on several age-related disorders associated with the accumulation of chronic oxidative stress, inflammation and impaired mitochondrial function. While these compounds presented with a limited acute toxicity profile, evidence is still quite limited and long-term human clinical trials are still nascent in the current literature. Potential risks in raising NAD+ levels in various clinical disorders using NAD+ precursors include the accumulation of putative toxic metabolites, tumorigenesis and promotion of cellular senescence. Therefore, NAD+ metabolism represents a promising target and further studies are needed to recapitulate the preclinical benefits in human clinical trials.
... Studies suggest that high NAM intake, that undergoes methylation-mediated degradation, could affect the methyl group pool balance (Sun et al., 2012(Sun et al., , 2017Li et al., 2013;Tian et al., 2013Tian et al., , 2014. However, the Panel considers that these studies on NAM do not allow firm conclusions on potential adverse effects. ...
Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Allergens (NDA) was asked to deliver an opinion on nicotinamide riboside chloride as a novel food (NF) pursuant to Regulation (EU) 2015/2283, including an evaluation of the safety of its use in food supplements as a source of niacin, and the bioavailability of nicotinamide from this source, in the context of Directive 2002/46/EC. The NF, a synthetic form of nicotinamide riboside, is proposed to be used in food supplements for the healthy adult population at levels up to 300 mg/day. The production process, composition, specifications, batch-to-batch variability and stability of the NF do not raise safety concerns. Animal and human data indicate that the NF contributes to the nicotinamide body pool. There are no concerns regarding genotoxicity. Human studies do not raise safety concerns. The proposed maximum use level corresponds to an amount of nicotinamide, which is sixfold lower than the tolerable upper intake level (UL) set for adults, excluding pregnant and lactating women. The margin of exposure (MoE) of 70 derived from repeated dose toxicity studies with rats and dogs is considered sufficient for the adult population, excluding pregnant and lactating women. Regarding these two population groups, the MoE of 76 derived from a developmental toxicity study in rats is considered insufficient in the absence of data which could justify accepting a MoE lower than 100. The Panel concludes that the NF is safe under the proposed conditions of use for the healthy adult population, excluding pregnant and lactating women, and that an intake of the NF up to 230 mg/day is safe for pregnant and lactating women. The Panel also concludes that the NF is a source from which nicotinamide, a form of niacin, is bioavailable. © 2019 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority.
... NAM treatment indeed increases plasma level of serotonin (McCarty 2000), while inhibiting tryptophan 2,3-dioxygenase (TDO), the first enzyme in the pathway of tryptophan oxidation to NAD + (mechanism of this inhibition is not clear yet) (Badawy and Evans 1976). Meanwhile, monoamines are degraded through methylation-modification (Sun et al. 2012), and high level of NAM was proposed to cause a transient depletion of the methyl pool, thereby preserving monoamine neurotransmitters in the plasma (Tian et al. 2013). Further, NAM may also function through an antioxidative effect. ...
Background
Nicotinamide (NAM) is a form of vitamin B3 that, when administered at near-gram doses, has been shown or suggested to be therapeutically effective against many diseases and conditions. The target conditions are incredibly diverse ranging from skin disorders such as bullous pemphigoid to schizophrenia and depression and even AIDS. Similar diversity is expected for the underlying mechanisms. In a large portion of the conditions, NAM conversion to nicotinamide adenine dinucleotide (NAD⁺) may be a major factor in its efficacy. The augmentation of cellular NAD⁺ level not only modulates mitochondrial production of ATP and superoxide, but also activates many enzymes. Activated sirtuin proteins, a family of NAD⁺-dependent deacetylases, play important roles in many of NAM’s effects such as an increase in mitochondrial quality and cell viability countering neuronal damages and metabolic diseases. Meanwhile, certain observed effects are mediated by NAM itself. However, our understanding on the mechanisms of NAM’s effects is limited to those involving certain key proteins and may even be inaccurate in some proposed cases.
Aim of review
This review details the conditions that NAM has been shown to or is expected to effectively treat in humans and animals and evaluates the proposed underlying molecular mechanisms, with the intention of promoting wider, safe therapeutic application of NAM.
Key scientific concepts of review
NAM, by itself or through altering metabolic balance of NAD⁺ and tryptophan, modulates mitochondrial function and activities of many molecules and thereby positively affects cell viability and metabolic functions. And, NAM administration appears to be quite safe with limited possibility of side effects which are related to NAM’s metabolites.
... Important stress-inducing stimuli, which are known to activate redox-sensitive transcription factors such as NF-κB and Nrf2, are reactive oxygen species (ROS). At least in studies with rats, it was shown that NA supplementation increases hydrogen peroxide levels in plasma (Sun et al., 2012;Li et al., 2013a) and causes a dosage-dependent increase in oxidative DNA damage in the liver (Li et al., 2013b). In addition, a study with Jurkat cells demonstrated that NA stimulates ROS production in vitro (Crowley et al., 2000). ...
In dairy cows, administration of high dosages of niacin (nicotinic acid, NA) was found to cause antilipolytic effects, which are mediated by the NA receptor hydroxyl-carboxylic acid receptor 2 (HCAR2) in white adipose tissue (WAT), and thereby an altered hepatic lipid metabolism. However, almost no attention has been paid to possible direct effects of NA in cattle liver, despite evidence that HCAR2 is also expressed in the liver and is even more abundant than in WAT. Because of this, we hypothesized that feeding a high dosage of rumen-protected NA to dairy cows influences critical metabolic or signaling pathways in the liver by inducing changes in the hepatic transcriptome. To identify these pathways, we applied genome-wide transcript profiling in liver biopsies obtained at d 7 postpartum (p.p.) from dairy cows used in our recent study; cows received either no NA (control group, n = 9) or 79 mg of rumen-protected NA/kg of body weight daily (NA group, n = 9) from 21 d before calving until 3 wk p.p. Hepatic transcript profiling revealed that 487 transcripts were differentially expressed (filter criteria: fold change >1.2 or <−1.2 and P < 0.05) in the liver at d 7 p.p. between cows fed NA and control cows. Substantially more transcripts were downregulated (n = 338), whereas only 149 transcripts were upregulated by NA in the liver of cows. Gene set enrichment analysis for the upregulated transcripts revealed that the most-enriched gene ontology biological process terms were exclusively related to immune processes, such as leukocyte differentiation, immune system process, activation of immune response, and acute inflammatory response. Gene set enrichment analysis of the downregulated transcripts showed that the most-enriched biological process terms were related to metabolic processes, such as cellular metabolic process, small molecule metabolic process, lipid catabolic process, organic cyclic compound metabolic process, small molecule biosynthetic process, and cellular lipid catabolic process. In conclusion, hepatic transcriptome analysis showed that rumen-protected NA induces genes that are involved mainly in immune processes, including acute phase response and stress response, in dairy cows at d 7 p.p. Thus, supplementation of a high dosage of rumen-protected NA to dairy cows in the periparturient period may induce or amplify the systemic inflammation-like condition that is typically observed in the liver of high-yielding dairy cows in the p.p. period.
... Nicotinamide supplementation induces tissue-specific alterations in the mRNA expression of the genes encoding nicotinamide N-methyltransferase (NNMT), DNA methyltransferase 1, catalase and tumour protein p53 in the placenta and fetal liver of rats (27). Our previous study further demonstrated that excess nicotinamide inhibited methylation-mediated degradation of catecholamines due to competition of methyl groups (25). These data provided evidences for the first time that food fortification-induced nicotinamide overload may play a role in the development of T2DM and T2DM-related diseases. ...
It has been reported that nicotinamide-overload induces oxidative stress associated with insulin resistance, the key feature of type 2 diabetes mellitus (T2DM). This study aimed to investigate the effects of B vitamins in T2DM. Glucose tolerance tests were carried out in adult Sprague-Dawley rats treated with or without cumulative doses of B vitamins. More specifically, insulin tolerance tests were also carried out in adult Sprague-Dawley rats treated with or without cumulative doses of Vitamin B3. We found that cumulative Vitamin B1 and Vitamin B3 administration significantly increased the plasma H₂O₂ levels associated with high insulin levels. Only Vitamin B3 reduced muscular and hepatic glycogen contents. Cumulative administration of nicotinic acid, another form of Vitamin B3, also significantly increased plasma insulin level and H₂O₂ generation. Moreover, cumulative administration of nicotinic acid or nicotinamide impaired glucose metabolism. This study suggested that excess Vitamin B1 and Vitamin B3 caused oxidative stress and insulin resistance.
... This may explain the sharp increase in prevalence of obesity in the United States after the levels of vitamin fortification methylation, niacin fortification/supplementation (usually using its nicotinamide form) increases the demand for methyl groups on the one hand, and on the other hand, it can reduce the utilization of choline as a methyl donor by causing hepatic and renal oxidative injury, as demonstrated in a rat model [42] . As a result, excess nicotinamide reduces the size of betaine pool and subsequently inhibits the methylation of endogenous substrates (e.g., catecholamines and DNA), leading to an increase in plasma norepinephrine levels [43] and DNA hypomethylation, an important epigenetic alteration in human diseases [42,44] . ...
Since synthetic vitamins were used to fortify food and as supplements in the late 1930s, vitamin intake has significantly increased. This has been accompanied by an increased prevalence of obesity, a condition associated with diabetes, hypertension, cardiovascular disease, asthma and cancer. Paradoxically, obesity is often associated with low levels of fasting serum vitamins, such as folate and vitamin D. Recent studies on folic acid fortification have revealed another paradoxical phenomenon: obesity exhibits low fasting serum but high erythrocyte folate concentrations, with high levels of serum folate oxidation products. High erythrocyte folate status is known to reflect long-term excess folic acid intake, while increased folate oxidation products suggest an increased folate degradation because obesity shows an increased activity of cytochrome P450 2E1, a monooxygenase enzyme that can use folic acid as a substrate. There is also evidence that obesity increases niacin degradation, manifested by increased activity/expression of niacin-degrading enzymes and high levels of niacin metabolites. Moreover, obesity most commonly occurs in those with a low excretory reserve capacity (e.g., due to low birth weight/preterm birth) and/or a low sweat gland activity (black race and physical inactivity). These lines of evidence raise the possibility that low fasting serum vitamin status in obesity may be a compensatory response to chronic excess vitamin intake, rather than vitamin deficiency, and that obesity could be one of the manifestations of chronic vitamin poisoning. In this article, we discuss vitamin paradox in obesity from the perspective of vitamin homeostasis.
... In fact, over the past several decades, increased prevalence of obesity and type 2 diabetes is closely correlated with increased nicotinamide intake, due to nicotinamide fortification and a high intake of animal-derived foods [3][4][5]. High fasting nicotinamide levels have been observed in hypertension, a disorder closely related to insulin resistance [6]. Therefore, to explore the cause of increased expression of NNMT and high levels of serum MNA, nicotinamide intake and blood nicotinamide status should also be taken into consideration. ...
... Thus, excessive niacin intake has the potential to deplete the hepatic methyl donor pool (and conceivably that of extrahepatic tissues), increasing plasma homocysteine levels and causing methylation-related abnormalities. Indeed, such adverse effects of excess NA intake have been described (Basu et al., 2002;Florentin et al., 2011;Li et al., 2013;Sun et al., 2012;Tian et al., 2013). In addition, niacin intake can cause mildto-moderate increases in serum aminotransferases and high doses (at above 3 g/d), and certain formulations of niacin, such as the sustained release form, have been linked to acute liver injury that can be severe and even fatal (Clementz and Holmes, 1987;De Marzio and Navarro, 2013;Patterson et al., 1983). ...
Li and colleagues (2014) in this issue report that dietary nicotinic acid (NA) supplementation ameliorates ethanol-induced hepatic steatosis, but a deficiency does not worsen injury induced by alcohol alone. The authors further present some mechanistic insights into the protective role of NA supplementation. Results of this and other previous studies in the context of alcoholic liver injury raise one important question as to what should be an adequate dose of NA that will provide the maximum benefit to hepatic and extrahepatic tissues and with minimum adverse effects.
... Thus, the methylation of excess niacin may affect other methylation reactions by competing for the limited methyl-group pool. A previous study (10) in our laboratory revealed that nicotinamide (100 mg, orally) led to a significant decrease in the level of plasma betaine in healthy subjects. Long-term nicotinamide supplementation (4 g/kg diet) in developing rats induced a significant decrease in the level of plasma betaine and a significant increase in choline level associated with a decrease in hepatic global DNA methylation (an epigenetic change) and uracil content in genomic DNA (11) . ...
Recent evidence shows that excess nicotinamide can cause epigenetic changes in developing rats. The aim of the present study was to investigate the effects of maternal nicotinamide supplementation on the fetus. Female rats were randomised into four groups fed a standard chow diet (control group) or diets supplemented with 1 g/kg of nicotinamide (low-dose group), 4 g/kg of nicotinamide (high-dose group) or 4 g/kg of nicotinamide plus 2 g/kg of betaine (betaine group) for 14-16 d before mating and throughout the study. Fetal tissue samples were collected on the 20th day of pregnancy. Compared with the control group, the high-dose group had a higher fetal death rate, and the average fetal body weight was higher in the low-dose group but lower in the high-dose group. Nicotinamide supplementation led to a decrease in placental and fetal hepatic genomic DNA methylation and genomic uracil contents (a factor modifying DNA for diversity) in the placenta and fetal liver and brain, which could be completely or partially prevented by betaine. Moreover, nicotinamide supplementation induced tissue-specific alterations in the mRNA expression of the genes encoding nicotinamide N-methyltransferase, DNA methyltransferase 1, catalase and tumour protein p53 in the placenta and fetal liver. High-dose nicotinamide supplementation increased fetal hepatic α-fetoprotein mRNA level, which was prevented by betaine supplementation. It is concluded that maternal nicotinamide supplementation can induce changes in fetal epigenetic modification and DNA base composition. The present study raises the concern that maternal nicotinamide supplementation may play a role in the development of epigenetic-related diseases in the offspring.
... The whole process of chromatography was performed at room temperature. Details of the analytical methods have been described previously (15) . ...
Ecological evidence suggests that niacin (nicotinamide and nicotinic acid) fortification may be involved in the increased prevalence of obesity and type 2 diabetes, both of which are associated with insulin resistance and epigenetic changes. The purpose of the present study was to investigate nicotinamide-induced metabolic changes and their relationship with possible epigenetic changes. Male rats (5 weeks old) were fed with a basal diet (control group) or diets supplemented with 1 or 4 g/kg of nicotinamide for 8 weeks. Low-dose nicotinamide exposure increased weight gain, but high-dose one did not. The nicotinamide-treated rats had higher hepatic and renal levels of 8-hydroxy-2′-deoxyguanosine, a marker of DNA damage, and impaired glucose tolerance and insulin sensitivity when compared with the control rats. Nicotinamide supplementation increased the plasma levels of nicotinamide, N
1-methylnicotinamide and choline and decreased the levels of betaine, which is associated with a decrease in global hepatic DNA methylation and uracil content in DNA. Nicotinamide had gene-specific effects on the methylation of CpG sites within the promoters and the expression of hepatic genes tested that are responsible for methyl transfer reactions (nicotinamide N-methyltransferase and DNA methyltransferase 1), for homocysteine metabolism (betaine–homocysteine S-methyltransferase, methionine synthase and cystathionine β-synthase) and for oxidative defence (catalase and tumour protein p53). It is concluded that nicotinamide-induced oxidative tissue injury, insulin resistance and disturbed methyl metabolism can lead to epigenetic changes. The present study suggests that long-term high nicotinamide intake (e.g. induced by niacin fortification) may be a risk factor for methylation- and insulin resistance-related metabolic abnormalities.
La información nos da forma, cambia el conocimiento, modifica el significado de las palabras, nos permite corregir errores, nos permite comprender mejor la realidad y, en
consecuencia, tomar mejores decisiones. En este libro se compila la información dada a conocer en más de cuatrocientas cincuenta publicaciones seleccionadas por su vigencia, pertinencia y relevancia por veinte profesionales estudiosos de la obesidad, de manera que nos ofrece el estado actual del conocimiento sobre este complejo e importante tema.
Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on the safety of an extension of use of the novel food (NF) nicotinamide riboside chloride (NRC) pursuant to Regulation (EU) 2015/2283. The assessment addresses the use of NRC in 'meal replacement products' and 'nutritional drink mixes' at levels up to 300 mg/day for the general population, and in food for special medical purposes (FSMP) and total diet replacement for weight control (TDRWC) (as per Regulation (EU) No 609/2013) at levels up to 500 mg/day in adults. Benchmark dose modelling was carried out on data from the 90-day oral toxicity studies in rats relevant to the safety assessment. Considering the lack of tolerable upper intake level (UL) for nicotinamide in infants and the narrow margin of exposure between the estimated intake in infants and the lower confidence bound of the benchmark doses (BMDL 05) estimated by the models, the Panel concludes that the safety of the NF has not been established for use in 'meal replacement products' and 'nutritional drink mixes' under the proposed conditions of use. For FSMP and TDRWC, the proposed maximum use level corresponds to an intake of 210 mg nicotinamide per day, which is below the current UL for nicotinamide of 900 mg/day for adults. The Panel considers that the NF is as safe as pure nicotinamide for use in FSMP and TDRWC. The Panel, however, notes experimental data which indicate several pathways by which intakes of nicotinamide (or its precursors), at levels that are substantially higher than the physiological requirement, might cause adverse effects. The Panel considers that further investigations are required and that a re-evaluation of the UL for nicotinamide may be warranted.
Catechol-O-methyltransferase (COMT) is an enzyme that catalyses the methylation of catechol substrates, classically in catecholamine metabolism, but also acting upon other substrates such as oestrogen and polyphenols. Although its classical function has been established for more than five decades, an ever expanding COMT role in other pathways and diseases has become a subject of active study in recent years. The most highlighted domains are related with COMT involvement in neuropsychiatric disorders and its role in the neurobiology of cognition, behaviour, emotions, pain processing and perception, sleep regulation, addictive behaviour and neurodegeneration. Nonetheless, great attention is also being devoted to a possible COMT contribution to the development of cardiovascular disorders and hormonally influenced diseases, including cancer. This review aims to update the role of COMT function and its involvement in cardiovascular and neurological disorders.
Nicotinamide (NAM), or vitamin B3, is an essential coenzyme for ATP synthesis and an inhibitor of sirtuin 1. Recently, conflicting results were reported regarding the treatment of NAM in type 2 diabetes and obesity. The aim of this study was to determine whether and how long-term treatment with NAM at lower dose would affect insulin sensitivity in mice fed chow diet. We treated mice with NAM (100 mg/kg/day) and normal chow for 8 weeks. Strikingly, NAM induced glucose intolerance and skeletal muscle lipid accumulation in nonobese mice. NAM impaired mitochondrial respiration capacity and energy production in skeletal muscle, in combination with increased expression of the mediators for mitophagy (p62, PINK1, PARK2 and NIX) and autophagy (FOXO3, Bnip3, CTSL, Beclin1 and LC-3b). Next, we treated mice with high-fat diet (HFD) and resveratrol (RSV; 100 mg/kg/day) for 8 weeks. RSV protected against HFD-induced insulin resistance and obesity. HFD increased skeletal muscle lipid content as well as NAM, but this increase was attenuated by RSV. In contrast to NAM, HFD enhanced fatty acid oxidative capacity. Muscle transcript levels of genes for mitophagy and autophagy were largely suppressed by HFD, whereas RSV did not rescue these effects. These differences suggest that skeletal muscle autophagy may represent adaptive response to NAM-induced lipotoxicity, whereas reduced autophagy in skeletal muscle may promote HFD-induced lipotoxicity. Our results demonstrate that chronic NAM supplementation in healthy individuals, although at lower dose than previously reported, is still detrimental to glucose homeostasis and skeletal muscle lipid metabolism.
Objective:
To summarize the reported evidence on the relationship between vasoactive amines and preeclampsia.
Methods:
A literature search was conducted in MEDLINE/PubMed and EMBASE.
Results:
The summarized results are as follows: (1) Menstruation can effectively eliminate vasoactive amines norepinephrine, serotonin and histamine. (2) Pregnancy increases norepinephrine production due to fetal brain development and decreases vasoactive-amine elimination due to amenorrhea. (3) Preeclampsia is associated with a low renal and/or sweating capacity, or in rare cases, with increased norepinephrine production due to maternal pheochromocytoma and fetal neuroblastoma.
Conclusion:
Preeclampsia is mainly due to decreased excretion of norepinephrine and other vasoactive amines.
Context:
Recent ecological evidence has showed a lag-correlation between the prevalence of diabetes and consumption of niacin (nicotinamide and nicotinic acid) in the US. Nicotinamide has been demonstrated to induce insulin resistance due to excess reactive oxygen species and methyl depletion, whereas the effect of nicotinic acid is poorly understood.
Objective:
To examine the mechanism of the effect of nicotinic acid on glucose metabolism.
Materials and methods:
Rats were injected with different cumulative doses of nicotinic acid (0.5, 2, 4 g/kg) and nicotinamide (2 g/kg). A glucose tolerance test was given 2 h after the final injection. The role of methyl consumption and reactive oxygen species generation were evaluated by measuring N(1)-methylnicotinamide and hydrogen peroxide.
Results:
Cumulative doses of nicotinic acid produced a dose-dependent increase in the plasma levels of N(1)-methylnicotinamide and hydrogen peroxide, which was associated with a decrease in liver and skeletal muscle glycogen levels. At the same dosage (2 g/kg), in comparison with nicotinamide, nicotinic acid was weaker in raising plasma N(1)-methylnicotinamide levels (0.7 ± 0.11 µg/mL vs. 4.69 ± 0.24 µg/mL, P < 0.001), but stronger in increasing plasma hydrogen peroxide levels (1.88 ± 0.07 µmol/L vs. 1.55 ± 0.05 µmol/L, P < 0.001). Moreover, nicotinamide, unlike nicotinic acid, did not reduce liver glycogen levels.
Discussion and conclusion:
This study suggested that excessive nicotinic acid, like nicotinamide, might induce methyl consumption, oxidative stress and insulin resistance. Long-term consumption high niacin may increase the risk of type 2 diabetes.
The metabolic syndrome, a cluster of risk factors for cardiovascular disease, is closely related to environmental and lifestyle risk factors. Increasing evidence suggests that environmental risk factors may involve an increase in xenobiotic exposure, for example due to environmental toxins, medications, high meat intake, food additives and supplements; while lifestyle risk factors, such as sedentary lifestyles, may involve a decrease in the detoxification and elimination of xenobiotics. The skin, the body's largest organ, plays a distinct role in the detoxification and elimination of xenobiotics and the body lipid homeostasis, which is affected by sedentary lifestyle and physical activity, as well as by ambient temperature. Thus, it seems that decreased skin biotransformation and excretion, for example due to low ambient temperature and sedentary lifestyle, may be an important risk factor for metabolic syndrome. This review aims to provide insight into the role of the skin in the development of metabolic syndrome.
The progression of chronic kidney diseases toward end-stage renal failure is a prominent issue in clinical nephrology.¹ Tubulointerstitial fibrosis, a pathological scarring process involving the kidney parenchyma, is the common mechanism underlying the progression of chronic nephropathies.¹ In the absence of specific antifibrotic therapies, the current clinical management of patients with chronic kidney disease requires a multimodal strategy, including intensified blood pressure control, the correction of dyslipidemia, discontinuation of potential nephrotoxic drugs or smoking and, most importantly, administration of inhibitors of the renin–angiotensin–aldosterone system (RAAS) at high doses.² There are anecdotal reports of the complete prevention or even regression of fibrosis by angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor (ARB blockers, but the prevalence of patients with end-stage renal failure is still on the rise, irrespective of the wide use of ACE inhibitors and AT blockers. The need for therapies to slow, or even halt, the progression of chronic kidney disease is as pressing as ever. In this regard, aliskiren is a specific competitive inhibitor of renin catalytic activity and the first direct renin inhibitor (DRI) approved for the treatment of hypertension. When compared with current standard antihypertensive treatments (that is, atenolol, hydrochlorothiazide, irbesartan, losartan, ramipril or valsartan), aliskiren is as effective in lowering blood pressure in short-term studies but does not fare substantially better. However, it has been suggested that aliskiren is superior in preventing end-organ damage, progression of kidney fibrosis and mortality. The study by Sun et al.⁵ on this topic provides novel insights into the mechanisms that may underlie the antifibrotic action of aliskiren in the kidney: Using a model of chronic ischemia, they demonstrate that the administration of aliskiren ameliorates kidney fibrosis in mice.
The first methods for the measurement of creatinine in serum and plasma were published over a century ago. Today, the Jaffe reaction using alkaline picrate remains the cornerstone of most current routine methods, after continuous refinements attempting to overcome inherent analytical interferences and limitations. With the recent introduction of the reporting of estimated glomerular filtration rate (eGFR), inter-laboratory agreement of serum creatinine results has become an important international priority. Expert professional bodies have recommended that all creatinine methods should become traceable to a reference method based on isotope dilution-mass spectrometry (IDMS). It is important that clinical biochemists have a good understanding of the relative performance of routine creatinine methods. Using a new commutable IDMS-traceable reference material (SRM 967), and a validated tandem IDMS assay developed in our laboratory, we assessed the accuracy of nine routine creatinine methods with assistance from other laboratories in our region. Three methods appeared to have patient sample bias that exceeded 5% in the range of creatinine concentrations where eGFR estimations are most important. Companies are currently recalibrating their creatinine assays. This task should be complete in 2007, and then creatinine results for eGFR calculations will require the use of a modified eGFR equation. Laboratories considering calibration changes before this time can seek advice from the Australasian Creatinine Working Group.
A simple and convenient method using commercially available derivatization reagents is described for the measurement of betaine and N,N-dimethylglycine (DMG) in blood and urine. Precolumn derivatization of plasma or urine is performed directly in acetonitrile without extraction with p-bromophenacyl bromide and crown ether as catalyst. The p-bromophenacyl ester derivatives are then separated by high-performance liquid chromatography, using an isocratic system of acetonitrile and water containing choline. Effluent was monitored at 254 nm. The limit of detection was 5 μmol/L for betaine and 2 μmol/L for DMG. Analytical recovery was >97% for both analytes. Total and within-day CVs were 2.0–4.4% and 0.9–2.2% for DMG. For betaine, the total and within-day CVs were 1.3–5.3% and 0.4–3.8%, respectively. The method is precise and cost-effective and has been used successfully to determine the concentrations of DMG and betaine in human plasma and urine.
AIM: To investigate nicotinamide’s action on glucose metabolism, and the association between niacin consumption and obesity prevalence.
METHODS: Dynamic nicotinamide’s effect on plasma hydrogen peroxide and glucose metabolism was investigated using oral glucose tolerance tests with or without nicotinamide in the same five healthy subjects. Lag-regression analysis was used to examine the association between the niacin consumption and the obesity prevalence among US children using the data from the Economic Research Service of the US Department of Agriculture and from US Centers for Disease Control and Prevention, respectively.
RESULTS: Compared with the control oral glucose tolerance test, the 1-h plasma hydrogen peroxide (1.4 ± 0.1 μmol/L vs 1.6 ± 0.1 μmol/L, P = 0.016) and insulin levels (247.1 ± 129.0 pmol/L vs 452.6 ± 181.8 pmol/L, P = 0.028) were significantly higher, and the 3-h blood glucose was significantly lower (5.8 ± 1.2 mmol/L vs 4.5 ± 1.1 mmol/L, P = 0.002) after co-administration of glucose and 300 mg nicotinamide. The obesity prevalence among American children increased with the increasing per capita niacin consumption, the increasing grain contribution to niacin due to niacin-fortification, and the increasing niacin-fortified ready-to-eat cereal consumption, with a 10-year lag. The regression analyses showed that the obesity prevalence in the US children of all age groups was determined by niacin consumption (R2 = 0.814, 0.961 and 0.94 for 2-5 years, 6-11 years and 12-19 years age groups, respectively).
CONCLUSION: The appetite-stimulating effect of nicotinamide appears to involve oxidative stress. Excess niacin consumption may be a major factor in the increased obesity prevalence in US children.
The global increased prevalence of obesity and diabetes occurred after the worldwide spread of B-vitamins fortification, in which whether long-term exposure to high level of B vitamins plays a role is unknown. Our aim was to examine the relationships between B-vitamins consumption and the obesity and diabetes prevalence.
This population based ecological study was conducted to examine possible associations between the consumption of the B vitamins and macronutrients and the obesity and diabetes prevalence in the US population using the per capita consumption data from the US Economic Research Service and the prevalence data from the US Centers for Disease Control and Prevention.
The prevalences of diabetes and adult obesity were highly correlated with per capita consumption of niacin, thiamin and riboflavin with a 26-and 10-year lag, respectively (R2 = 0.952, 0.917 and 0.83 for diabetes, respectively, and R2 = 0.964, 0.975 and 0.935 for obesity, respectively). The diabetes prevalence increased with the obesity prevalence with a 16-year lag (R2 = 0.975). The relationships between the diabetes or obesity prevalence and per capita niacin consumption were similar both in different age groups and in male and female populations. The prevalence of adult obesity and diabetes was highly correlated with the grain contribution to niacin (R2 = 0.925 and 0.901, respectively), with a 10-and 26-year lag, respectively. The prevalence of obesity in US adults during 1971-2004 increased in parallel with the increase in carbohydrate consumption with a 10-year lag. The per capita energy and protein consumptions positively correlated with the obesity prevalence with a one-year lag. Moreover, there was an 11-year lag relationship between per capita energy and protein consumption and the consumption of niacin, thiamin and riboflavin (R2 = 0.932, 0.923 and 0.849 for energy, respectively, and R2 = 0.922, 0.878 and 0.787 for protein, respectively).
Long-term exposure to high level of the B vitamins may be involved in the increased prevalence of obesity and diabetes in the US in the past 50 years. The possible roles of B-vitamins fortification and excess niacin consumption in the increased prevalence of obesity and diabetes were discussed.
The hope that a simple, affordable, and safe homocysteine-lowering intervention with folic acid and vitamin B12 would improve outcomes for patients with established cardiovascular or renal disease has been crushed by the null results from large B-vitamin treatment trials completed to date.
To investigate nicotinamide's action on glucose metabolism, and the association between niacin consumption and obesity prevalence.
Dynamic nicotinamide's effect on plasma hydrogen peroxide and glucose metabolism was investigated using oral glucose tolerance tests with or without nicotinamide in the same five healthy subjects. Lag-regression analysis was used to examine the association between the niacin consumption and the obesity prevalence among US children using the data from the Economic Research Service of the US Department of Agriculture and from US Centers for Disease Control and Prevention, respectively.
Compared with the control oral glucose tolerance test, the 1-h plasma hydrogen peroxide (1.4 +/- 0.1 micromol/L vs 1.6 +/- 0.1 micromol/L, P = 0.016) and insulin levels (247.1 +/- 129.0 pmol/L vs 452.6 +/- 181.8 pmol/L, P = 0.028) were significantly higher, and the 3-h blood glucose was significantly lower (5.8 +/- 1.2 mmol/L vs 4.5 +/- 1.1 mmol/L, P = 0.002) after co-administration of glucose and 300 mg nicotinamide. The obesity prevalence among American children increased with the increasing per capita niacin consumption, the increasing grain contribution to niacin due to niacin-fortification, and the increasing niacin-fortified ready-to-eat cereal consumption, with a 10-year lag. The regression analyses showed that the obesity prevalence in the US children of all age groups was determined by niacin consumption (R(2) = 0.814, 0.961 and 0.94 for 2-5 years, 6-11 years and 12-19 years age groups, respectively).
The appetite-stimulating effect of nicotinamide appears to involve oxidative stress. Excess niacin consumption may be a major factor in the increased obesity prevalence in US children.
Nicotinamide N-methyl transferase (NNMT) is highly expressed in quadriceps muscles of patients with chronic obstructive pulmonary disease (COPD). However, its expression in the diaphragm of these patients has not been assessed. The functional significance of NNMT induction in skeletal muscles of patients with COPD is also unknown.
(1) To compare NNMT expressions in the diaphragm and quadriceps muscles of patients with COPD. (2) To identify the influence of proinflammatory cytokines on NNMT expression. (3) To assess the influence of NNMT on indices of myogenesis (satellite cell migration and proliferation) and the defense against oxidative stress.
Costal diaphragm muscle biopsies were acquired from 13 patients with moderate and severe COPD and 8 control subjects. Quadriceps muscle biopsies were obtained from 12 patients with COPD and 14 control subjects.
NNMT expressions were significantly elevated in the diaphragm and quadriceps muscles of patients with COPD; however, the relative induction of NNMT expression was greater in the quadriceps muscle (10-fold) than it was in the diaphragm (2-fold). NNMT expressions correlated negatively with the severity of COPD and limb muscle wasting. In skeletal myoblasts, NNMT expression was significantly induced by IL-6, transforming growth factor beta, and tumor necrosis factor-alpha. Overexpression of NNMT in myoblasts triggered a significant increase in proliferation and migration, but had no influence on cell death. Carbonyl formation, induced by exposing myoblasts to H(2)O(2), was significantly attenuated when NNMT was overexpressed.
Up-regulation of NNMT expression in the skeletal muscles of patients with COPD may represent an adaptive response designed to improve myogenesis and defend against oxidative stress.
To investigate whether nicotinamide overload plays a role in type 2 diabetes.
Nicotinamide metabolic patterns of 14 diabetic and 14 non-diabetic subjects were compared using HPLC. Cumulative effects of nicotinamide and N(1)-methylnicotinamide on glucose metabolism, plasma H(2)O(2) levels and tissue nicotinamide adenine dinucleotide (NAD) contents of adult Sprague-Dawley rats were observed. The role of human sweat glands and rat skin in nicotinamide metabolism was investigated using sauna and burn injury, respectively.
Diabetic subjects had significantly higher plasma N(1)-methylnicotinamide levels 5 h after a 100-mg nicotinamide load than the non-diabetic subjects (0.89 +/- 0.13 micromol/L vs 0.6 +/- 0.13 micromol/L, P < 0.001). Cumulative doses of nicotinamide (2 g/kg) significantly increased rat plasma N(1)-methylnicotinamide concentrations associated with severe insulin resistance, which was mimicked by N(1)-methylnicotinamide. Moreover, cumulative exposure to N(1)-methylnicotinamide (2 g/kg) markedly reduced rat muscle and liver NAD contents and erythrocyte NAD/NADH ratio, and increased plasma H(2)O(2) levels. Decrease in NAD/NADH ratio and increase in H(2)O(2) generation were also observed in human erythrocytes after exposure to N(1)-methylnicotinamide in vitro. Sweating eliminated excessive nicotinamide (5.3-fold increase in sweat nicotinamide concentration 1 h after a 100-mg nicotinamide load). Skin damage or aldehyde oxidase inhibition with tamoxifen or olanzapine, both being notorious for impairing glucose tolerance, delayed N(1)-methylnicotinamide clearance.
These findings suggest that nicotinamide overload, which induced an increase in plasma N(1)-methylnicotinamide, associated with oxidative stress and insulin resistance, plays a role in type 2 diabetes.
Almost 40 years ago, in 1970, Kakimoto and Akazawa were the first to isolate and describe N-N, N-G- and N-G,N'-G-dimethyl-arginine from human urine. Today, these substances are known as asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). In their detailed and meticulous publication, Kakimoto and Akazawa speculated about these two compounds: "They may have functional importance in proteins in which they are formed. If they are excreted into the urine as metabolites of body proteins, amounts of these substances in human urine may reflect methylation rate of body proteins and their turnover rates and determination of these substances might be important for the study of various pathological states." The following decades proved them to be right. ADMA, the most potent endogenous nitric oxide synthase (NOS) inhibitor was first found to be elevated in hemodialysis patients. It has been shown to correlate with traditional and nontraditional cardiovascular risk factors. ADMA is also a strong predictor of cardiovascular events and death in both patients with chronic kidney disease (CKD, stage 2-5) and in the general population. Moreover, ADMA predicts the progression of CKD. SDMA, the structural isomer of ADMA, has been shown to be an excellent marker of renal function in human and animal studies. There is emerging evidence that SDMA might also be involved in inflammation and atherosclerosis although it is only thought to be a (weak) indirect inhibitor of NOS. There is burgeoning evidence that these two substances may indeed damage normal physiological functions, or interfere with physiological defense mechanisms in CKD, play a role in the progression of renal disease, induce uremic symptoms, and may even contribute to dialysis-related complications. Hence these compounds are considered uremic toxins. This review summarizes our current concept how these two compounds might play a crucial part in the pathophysiology of uremia, either alone or in their combination. We also allude to the potential physiological role these substances might have.
The discovery of hyperhomocysteinemia as a major factor in the pathogenesis of arteriosclerosis offers new strategies and opportunities for prevention and treatment.
A simple and convenient method using commercially available derivatization reagents is described for the measurement of betaine and N,N-dimethylglycine (DMG) in blood and urine. Precolumn derivatization of plasma or urine is performed directly in acetonitrile without extraction with p-bromophenacyl bromide and crown ether as catalyst. The p-bromophenacyl ester derivatives are then separated by high-performance liquid chromatography, using an isocratic system of acetonitrile and water containing choline. Effluent was monitored at 254 nm. The limit of detection was 5 micromol/L for betaine and 2 micromol/L for DMG. Analytical recovery was >97% for both analytes. Total and within-day CVs were 2.0-4.4% and 0.9-2.2% for DMG. For betaine, the total and within-day CVs were 1.3-5.3% and 0.4-3.8%, respectively. The method is precise and cost-effective and has been used successfully to determine the concentrations of DMG and betaine in human plasma and urine.
High-dose niacin has versatile and substantial efficacy for the treatment of hyperlipidemias, but its utility is compromised by various side effects, the most serious of which is liver damage. It is proposed that this hepatotoxicity reflects the high demand for methyl groups imposed by niacin catabolism, leading to a reduction in hepatic levels of S-adenosylmethionine (SAM). Depletion of the hepatic SAM pool has likewise been shown to mediate, at least in part, the hepatotoxic effects of ethanol, methotrexate, and niacinamide. If niacin does indeed decrease SAM, a likely consequence would be a counterproductive elevation of plasma homocysteine. Conceivably, methyl group deficiency, by altering membrane properties of skeletal muscle, also contributes to niacin-induced insulin resistance. Concurrent betaine supplementation - preferably administered as a complex with equimolar amounts of niacin - may represent the most cost-effective way to prevent niacin-mediated depletion of SAM and thus avoid hepatotoxicity (and possibly other adverse effects) while controlling homocysteine. Betaine also merits evaluation as an adjuvant to methotrexate and niacinamide therapies.
This article provides an update about catecholamine metabolism, with emphasis on correcting common misconceptions relevant to catecholamine systems in health and disease. Importantly, most metabolism of catecholamines takes place within the same cells where the amines are synthesized. This mainly occurs secondary to leakage of catecholamines from vesicular stores into the cytoplasm. These stores exist in a highly dynamic equilibrium, with passive outward leakage counterbalanced by inward active transport controlled by vesicular monoamine transporters. In catecholaminergic neurons, the presence of monoamine oxidase leads to formation of reactive catecholaldehydes. Production of these toxic aldehydes depends on the dynamics of vesicular-axoplasmic monoamine exchange and enzyme-catalyzed conversion to nontoxic acids or alcohols. In sympathetic nerves, the aldehyde produced from norepinephrine is converted to 3,4-dihydroxyphenylglycol, not 3,4-dihydroxymandelic acid. Subsequent extraneuronal O-methylation consequently leads to production of 3-methoxy-4-hydroxyphenylglycol, not vanillylmandelic acid. Vanillylmandelic acid is instead formed in the liver by oxidation of 3-methoxy-4-hydroxyphenylglycol catalyzed by alcohol and aldehyde dehydrogenases. Compared to intraneuronal deamination, extraneuronal O-methylation of norepinephrine and epinephrine to metanephrines represent minor pathways of metabolism. The single largest source of metanephrines is the adrenal medulla. Similarly, pheochromocytoma tumor cells produce large amounts of metanephrines from catecholamines leaking from stores. Thus, these metabolites are particularly useful for detecting pheochromocytomas. The large contribution of intraneuronal deamination to catecholamine turnover, and dependence of this on the vesicular-axoplasmic monoamine exchange process, helps explain how synthesis, release, metabolism, turnover, and stores of catecholamines are regulated in a coordinated fashion during stress and in disease states.
The goal of this study was to identify and validate novel serum markers of human colorectal cancer as potential candidates for noninvasive detection of early colorectal neoplasm.
Employing two-dimensional gel electrophoresis and mass spectrometry, we analyzed 16 matched colorectal cancer and adjacent normal tissue samples. Proteins found to be elevated in cancer tissue were further validated by generating antibodies which were used for immunoblotting of tissue samples and for the development of highly sensitive immunoassays for assessment of serum samples.
In total, 735 different proteins were identified in colon tissue. Strong elevation in colorectal cancer for five proteins was confirmed by immunoblot analysis: transforming growth factor-beta induced protein ig-h3 (betaIG-H3), nicotinamide N-methyltransferase (NNMT), nucleoside diphosphate kinase A (nm23-H1), purine nucleoside phosphorylase (PNPH), and mannose-6-phosphate receptor binding protein 1 (M6P1). Elevated levels of NNMT, which is not predicted to be secreted but is known as a cytoplasmic protein, were found in serum from patients with colorectal cancer. Employing a receiver-operating characteristic curve based on the measurement of 109 patients with colorectal cancer and 317 healthy controls, we obtained an area under the curve of 0.84 for NNMT, which was superior to the established tumor marker carcinoembryogenic antigen with an area under the curve of 0.78.
It is proposed that NNMT serum levels may have significance in the early detection and in the management of patients with colorectal cancer.
Betaine serves as a methyl donor in a reaction converting homocysteine to methionine, catalysed by the enzyme betaine-homocysteine methyltransferase. It has been used for years to lower the concentration of plasma total homocysteine (tHcy) in patients with homocystinuria, and has recently been shown to reduce fasting and in particular post-methionine load (PML) tHcy in healthy subjects.
Betaine exists in plasma at concentrations of about 30μmol/L; it varies 10-fold (from 9 to 90μmol/L) between individuals, but the intra-individual variability is small. Major determinants are choline, dimethylglycine and folate in plasma, folic acid intake and gender.
Recent studies have demonstrated that plasma betaine is a stronger determinant of PML tHcy than are vitamin B
To conclude, betaine status is a component of an individual's biochemical make-up with ramifications to one-carbon metabolism. Betaine status should be investigated in pathologies related to altered metabolism of homocysteine and folate, including cardiovascular disease, cancer and neural tube defects.
Forty male weanling albino rats were divided into 4 groups and fed 20% casein diets of high fat (40% ) or low fat (5% ) content with adequate or exces sive quantities of niacin. The niacin content of both the high and low fat diets was increased by supplementing the diets with 0.1% of niacin. Two control groups, one fed high fat and the other low fat, containing adequate (0.5 mg/100 g) quantities of niacin, were fed the diet simultaneously. Blood samples were collected for pyridine nucleotide determinations on the twenty-first and the forty-second day of the experi ment. The animals were killed after 44 days and the livers analyzed for pyridine nucleotide concentration, fatty acid oxidase activity, and proximate composition. Re sults from this study indicate that excess niacin enters metabolic pathways to produce at least 2 unrelated effects, increased concentrations of pyridine nucleotides in blood and liver and increased levels of fat in the liver. The first effect occurs regardless of the level of fat in the diet, but the second occurs only in conjunction with a high level of dietary fat. The possibility that an increased consumption of niacin and fat increases the animals' requirement for choline is discussed.
The silent information regulator (SIR) genes (sirtuins) comprise a highly conserved family of proteins, with one or more sirtuins present in virtually all species from bacteria to mammals. In mammals seven sirtuin genes - SIRT1 to SIRT7 - have been identified. Emerging from research on the sirtuins is a growing appreciation that they are a very complicated biological response system that influences many other regulator molecules and pathways in complex manners. Part 1 of this article provided an overview of the mammalian sirtuin system, discussed the dietary, lifestyle, and environmental factors that influence sirtuin activity, and summarized research on the importance of vitamin B3 in supporting sirtuin enzyme activity, as well as the role specifically of the amide form of this vitamin - nicotinamide - to inhibit sirtuin enzyme activity. In Part 2 of this review, clinical situations where sirtuins might play a significant role, including longevity, obesity, fatty liver disease, cardiovascular health, neurological disease, and cancer are discussed. Research on the ability of nutritional substances, especially resveratrol, to influence sirtuin expression and function, and hence alter the courses of some clinical situations, is also reviewed.
The silent information regulator (SIR) genes (sirtuins) comprise a highly conserved family of proteins, with one or more sirtuins present in virtually all species from bacteria to mammals. In mammals seven sirtuin genes - SIRT1 to SIRT7 - have been identified. Emerging from research on the sirtuins is a growing appreciation that the sirtuins are a very complicated biological response system that influences many other regulator molecules and pathways in complex manners. Responses of this system to environmental factors, as well as its role in health and disease, are currently incompletely characterized and at most partially understood. This article reviews the mammalian sirtuin system, discusses the dietary, lifestyle, and environmental factors that influence sirtuin activity, and summarizes research on the importance of vitamin B3 in supporting sirtuin enzyme activity, as well as the role specifically of the amide form of this vitamin - nicotinamide - to inhibit sirtuin enzyme activity. Polyphenols, especially resveratrol, influence sirtuins. Existing evidence on these nutritional compounds, as they relate to the sirtuin system, is reviewed. In Part 2 of this review, clinical situations where sirtuins might play a significant role, including longevity, obesity, fatty liver disease, cardiovascular health, neurological disease, and cancer, are discussed.
This review examines how the sympathetic nervous system plays a major role in the regulation of cardiovascular function over multiple time scales. This is achieved through differential regulation of sympathetic outflow to a variety of organs. This differential control is a product of the topographical organization of the central nervous system and a myriad of afferent inputs. Together this organization produces sympathetic responses tailored to match stimuli. The long-term control of sympathetic nerve activity (SNA) is an area of considerable interest and involves a variety of mediators acting in a quite distinct fashion. These mediators include arterial baroreflexes, angiotensin II, blood volume and osmolarity, and a host of humoral factors. A key feature of many cardiovascular diseases is increased SNA. However, rather than there being a generalized increase in SNA, it is organ specific, in particular to the heart and kidneys. These increases in regional SNA are associated with increased mortality. Understanding the regulation of organ-specific SNA is likely to offer new targets for drug therapy. There is a need for the research community to develop better animal models and technologies that reflect the disease progression seen in humans. A particular focus is required on models in which SNA is chronically elevated.
Cardiovascular disease is the most common cause of mortality in the Western world and accounts for up to a third of all deaths worldwide. Cardiovascular disease is multifactorial and involves complex interplay between lifestyle (diet, smoking, exercise, ethanol consumption) and fixed (genotype, age, menopausal status, gender) causative factors. The initiating step in cardiovascular disease is endothelial damage, which exposes these cells and the underlying cell layers to a deleterious inflammatory process which ultimately leads to the formation of atherosclerotic lesions. Intrinsic to lesion formation is cellular oxidative stress, due to the production of damaging free radicals (reactive oxygen and nitrogen species) by many cell types including endothelial cells, vascular smooth muscle cells and monocytes/macrophages. Exogenous factors such as smoking and the existence of other disease states such as diabetes also contribute to oxidative stress and are strong risk factors for cardiovascular disease. In this review we describe this role of free radicals in atherosclerosis and discuss the mechanisms and cellular systems by which these radicals are produced. We also highlight recent technological advances which have added to the vascular biologist's armoury and which promise to provide new insight into the role of reactive oxygen species in cardiovascular disease.
Nicotinamide N-methyltransferase (NNMT) catalyses the conversion of nicotinamide to 1-methylnicotinamide and plays an important role in hepatic detoxification reactions. Here we show that, in addition to the liver, 3T3-L1 adipocytes as well as human and murine adipose tissue explants express high amounts of enzymatically active NNMT. NNMT mRNA levels and enzyme activity increased in 3T3-L1 cells in a differentiation-dependent manner. Homocysteine, the atherogenic product of the NNMT-catalyzed reaction, was secreted from 3T3-L1 cells or adipose tissue cultures. Homocysteine release increased during 3T3-L1 differentiation and was reduced when adipose tissue was treated with the NNMT inhibitor 1-methylnicotinamide. Nicotinic acid (NA), a widely used drug to lower elevated plasma lipid levels, induced NNMT enzyme activity in white adipose tissue of mice. In tissue culture nicotinamide treatment led to an increase in adipose tissue homocysteine secretion. These data support the concept that adipose tissue NNMT contributes to the increased plasma homocysteine levels in patients treated with NA.
By using the GI tube technique, niacin was shown to be equally well absorbed from the stomach and the upper small intestine. The maximum plasma niacin concentrations occurred 10-20 and 5-10 min, respectively, after instillation. Thus, the physiological prerequisites for a physically retarded niacin preparation were established.
This brief review summarizes recent literature about plasma catecholamines as indices of sympathetic nervous and sympathoadrenomedullary activity in clinical cardiologic disease states. Many reports have described high plasma levels of norepinephrine, the neurotransmitter of the sympathetic nervous system, in acute myocardial infarction, congestive heart failure, the mitral valve prolapse syndrome, and early essential hypertension. Fewer studies have reported values for plasma epinephrine, which is the product of sympathoadrenomedullary secretion. The relationship between circulating catecholamine levels and activity of the sympathetic nervous system is obscured by ignorance about catecholamine removal mechanisms and regionalization of sympathetic outflow. Further, whether increased sympathetic outflow increases cardiovascular risk or reflects compensatory recruitment or a non-specific stress response is poorly understood.
Nicotinamide is being used in trials to prevent or delay the development of clinical IDDM. A related compound, niacin, has been shown to cause insulin resistance in normal subjects, resulting in increased insulin secretion. This study was designed to answer the question: Does the short-term administration of nicotinamide cause insulin resistance in subjects who have a high risk of developing IDDM? Eight islet cell antibody-positive (ICA+) relatives of IDDM patients were given nicotinamide at a dose of 2 g/day for 2 weeks. Measurements of first-phase insulin release, insulin sensitivity, glucose effectiveness, and the constant for glucose disappearance (Kg) were measured at baseline, at the end of 2 weeks of therapy, and after subjects had been off therapy for at least 2 weeks. Nicotinamide administration caused a 23.6% decrease in insulin sensitivity (P = 0.02). This decrease was associated with a fall in Kg despite increased insulin secretion. Our data suggest that the use of nicotinamide in subjects who are at risk of developing IDDM may be complicated by the drug's effects on insulin sensitivity. By inducing insulin resistance, a therapeutic effect of nicotinamide on the diabetes disease process may be missed, and the interpretation of insulin secretion measurements that are obtained during the intervention trials using nicotinamide may be complicated by the changes in insulin secretion that are caused by the increased insulin resistance. Therefore, we strongly support the recommendation that at least one subgroup of subjects enrolled in clinical trials to prevent IDDM have regular measurements of both insulin sensitivity and insulin secretion performed. This subgroup should be randomly assigned and large enough for statistical analysis to interpret properly the changes in insulin secretion that may occur.
Various psychosocial factors have been implicated in the etiology and pathogenesis of certain cardiovascular diseases such as atherosclerosis, now considered to be the result of a chronic inflammatory process. In this article, we review the evidence that repeated episodes of acute psychological stress, or chronic psychologic stress, may induce a chronic inflammatory process culminating in atherosclerosis. These inflammatory events, caused by stress, may account for the approximately 40% of atherosclerotic patients with no other known risk factors. Stress, by activating the sympathetic nervous system, the hypothalamic-pituitary axis, and the renin-angiotensin system, causes the release of various stress hormones such as catecholamines, corticosteroids, glucagon, growth hormone, and renin, and elevated levels of homocysteine, which induce a heightened state of cardiovascular activity, injured endothelium, and induction of adhesion molecules on endothelial cells to which recruited inflammatory cells adhere and translocate to the arterial wall. An acute phase response (APR), similar to that associated with inflammation, is also engendered, which is characterized by macrophage activation, the production of cytokines, other inflammatory mediators, acute phase proteins (APPs), and mast cell activation, all of which promote the inflammatory process. Stress also induces an atherosclerotic lipid profile with oxidation of lipids and, if chronic, a hypercoagulable state that may result in arterial thromboses. Shedding of adhesion molecules and the appearance of cytokines, and APPs in the blood are early indicators of a stress-induced APR, may appear in the blood of asymptomatic people, and be predictors of future cardiovascular disease. The inflammatory response is contained within the stress response, which evolved later and is adaptive in that an animal may be better able to react to an organism introduced during combat. The argument is made that humans reacting to stressors, which are not life-threatening but are "perceived" as such, mount similar stress/inflammatory responses in the arteries, and which, if repetitive or chronic, may culminate in atherosclerosis.
We have previously speculated that elevated levels of nicotinamide N-methyltransferase (NNMT), the primary catabolic enzyme of nicotinamide, may result in reduced Complex I activity in idiopathic Parkinson's disease (IPD) in two ways: (1) reduction in the levels of nicotinamide available for nicotinamide adenine dinucleotide synthesis; and (2) increased methylation of compounds such as tetrahydroisoquinolines and beta-carbolines, which are potent Complex I inhibitors. Expression of NNMT was assessed in 91 cerebella (53 IPD, 38 control) using immunohistochemistry coupled with quantitative digital image analysis. Control cerebella showed a distribution of expression ascribed to low, intermediate and high expressors with ratios of 1:2:1 categories. Expression in the parkinsonian cerebella was significantly higher than in the control group (control group median expression 17%, mean expression 16.6%, range 0-51%, standard deviation 11.4%, standard error 1.9%; IPD group median expression 46%, mean expression 53.7%, range 21-100%, standard deviation 23.4%, standard error 3.2%; P<0.0001; unpaired t-test with Welch correction (parametric) and Mann-Whitney U-test (non-parametric)). These results confirm that NNMT expression is elevated in IPD, which may ultimately lead to neurodegeneration via a reduction in Complex I activity.
Metabolism of oxygen by cells generates potentially deleterious reactive oxygen species (ROS). Under normal conditions the rate and magnitude of oxidant formation is balanced by the rate of oxidant elimination. However, an imbalance between prooxidants and antioxidants results in oxidative stress, which is the pathogenic outcome of oxidant overproduction that overwhelms the cellular antioxidant capacity. The kidney and vasculature are rich sources of NADPH oxidase-derived ROS, which under pathological conditions play an important role in renal dysfunction and vascular damage. Strong experimental evidence indicates that increased oxidative stress and associated oxidative damage are mediators of renovascular injury in cardiovascular pathologies. Increased production of superoxide anion and hydrogen peroxide, reduced nitric oxide synthesis, and decreased bioavailability of antioxidants have been demonstrated in experimental and human hypertension. These findings have evoked considerable interest because of the possibilities that therapies targeted against free radicals by decreasing ROS generation or by increasing nitric oxide availability and antioxidants may be useful in minimizing vascular injury and renal dysfunction and thereby prevent or regress hypertensive end-organ damage. This article highlights current developments in the field of ROS and hypertension, focusing specifically on the role of oxidative stress in hypertension-associated vascular damage. In addition, recent clinical trials investigating cardiovascular benefits of antioxidants are discussed, and some explanations for the rather disappointing results from these studies are addressed. Finally, important avenues for future research in the field of ROS, oxidative stress, and redox signaling in hypertension are considered.
By comparative proteome analysis we searched for characteristic alterations of human stomach adenocarcinoma tissue and paired surrounding normal tissue. Selected differential protein spots were identified with peptide mass fingerprinting based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) and database searching. We identified protein alterations in 18 stomach cancer tissues compared with normal controls, comprising elevated levels of eight proteins, including 14-3-3 zeta, calcyclin, keratin, apolipoprotein A-1 precursor, proteasome activator complex subunit, nucleoside diphosphate kinase, nicotinamide N-methyltransferase, and pyridoxal kinase. Five proteins (CA11, prohibitin, peroxiredoxin 4, serum amyloid P component, and NADH-ubiquinone oxidoreductase 23 kDa subunit) were decreased. These data are valuable for identification of differentially expressed proteins involved in stomach cancer carcinogenesis, providing biomarker candidates to develop diagnostic and therapeutic tools.
To explore the involvement of enzymes of drug metabolism in renal cell carcinoma we analyzed the gene expression profiles of tumor and nontumor tissues from the same patient by DNA macroarray. The enzyme nicotinamide N-methyltransferase was selected for further evaluation.
Nicotinamide N-methyltransferase mRNA expression was investigated in paired tissue samples from cancerous and noncancerous parts of the kidneys of 30 patients with clear cell renal cell carcinoma who underwent tumor nephrectomy. Measurements were performed by semiquantitative reverse transcriptase-polymerase chain reaction and quantitative real-time polymerase chain reaction. Paired tissue samples were also obtained from 1 patient with chromophobe renal cell carcinoma and from another with oncocytoma to compare the specificity of changes in nicotinamide N-methyltransferase expression among tumors that are related to different renal epithelial cell types. Western blot analysis and catalytic activity assay were also performed to study nicotinamide N-methyltransferase expression. Expression correlated with tumor characteristics.
A marked increased expression in tumor tissue was found for nicotinamide N-methyltransferase, which is an enzyme involved in the biotransformation of many drugs and xenobiotic compounds. Differential gene expression measurements in tumor vs normal tissue revealed up-regulation in all clear cell renal cell carcinomas at between 3 and 294-fold (mean 41). In contrast, in chromophobe renal cell carcinoma and oncocytoma nicotinamide N-methyltransferase expression did not increase. In addition, nicotinamide N-methyltransferase expression significantly correlated inversely with tumor size.
Our results indicate that a marked nicotinamide N-methyltransferase increase is a peculiar feature of clear cell renal cell carcinoma. Additional studies may establish the role of nicotinamide N-methyltransferase in tumor formation and progression.
The development of vascular disease has its origins in an initial insult to the vessel wall by biological or mechanical factors. The disruption of homeostatic mechanisms leads to alteration of the original architecture of the vessel and its biological responsiveness, contributing to acute or chronic diseases such as stroke, hypertension, and atherosclerosis. Endothelial dysfunction, macrophage infiltration of the vessel wall, and proliferation and migration of smooth muscle cells all involve different types of reactive oxygen species produced by various vessel wall components. Although basic science and animal research have clearly established the role of reactive oxygen species in the progression of vascular disease, the failure of clinical trials with antioxidant compounds has underscored the need for better antioxidant therapies and a more thorough understanding of the role of reactive oxygen species in cardiovascular physiology and pathology.
To gain an understanding of the molecular pathogenesis of thyroid cancer, we used DNA microarray to study the expression profiles of 10 different human thyroid carcinoma cell lines. These included papillary lines BHP 2-7, BHP 7-13, BHP 10-3, BHP 18-21, NPA 87, and TPC1; anaplastic lines ARO 81-1 and DRO 90-1; follicular line WRO 82-1; and medullary line HRO 85-1. Among the genes with increased expression in the cancer cell lines, a gene coding for nicotinamide N-methyltransferase (NNMT) was identified for being highly expressed only in the papillary cell lines. NNMT catalyzes N-methylation of nicotinamide and other structurally related compounds and is highly expressed in the human liver. The results were further confirmed by semiquantitative RT-PCR and Northern blot analysis. NNMT catalytic activities were determined in all of the cells described above and in additional cell lines. Significantly higher NNMT enzyme activities were detected in eight of 10 of the papillary lines and three of six of the follicular cell lines tested. Normal thyroid tissue, thyroid primary cultures, anaplastic cancer cells, and medullary cancer cells showed no or low enzyme activity. Immunohistochemical staining for NNMT of human thyroid specimens showed strong and abundant cytoplasmic reactions in the sections of papillary carcinomas, and weak or scanty reaction in the normal thyroid tissues. These results indicate that NNMT is a potential biomarker for papillary thyroid carcinoma.
High expression of nicotinamide N-methyltransferase in patients with idiopathic Parkinson's disease
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26 Parsons RB, Smith SW, Waring RH, Williams AC, Ramsden DB. High expression of nicotinamide N-methyltransferase in patients with idiopathic Parkinson's disease. Neurosci Lett 2003; 342: 13–16.