Taking Daily Essential Nutrients can prevent health problems by ensuring that you get the essential nutrients your body needs. Daily Essential Nutrients has been clinically proven to help improve mood, focus, mental clarity, emotional stability, and sleep quality.*

 

Research shows that we are at risk of being deficient in many essential nutrients at once. The broad spectrum of essential nutrients in Daily Essential Nutrients is critical to prevent metabolic inadequacies and many related health problems.* Learn more.

Yes. The ingredients in Daily Essential Nutrients are shown to: 

Vitamins are carbon-based organic compounds. The human body makes many of its own organic compounds; however, vitamins are required from the diet in small amounts because the body does not make them. Vitamins are used to synthesize substances involved in body functions, such as hormones and neurotransmitters. Learn more.

Yes. The ingredients found in Daily Essential Nutrients are shown to:

Vitamins are needed for normal growth and development and are essential for the healthy maintenance of cells, tissues, and organs. Vitamins enable cells to efficiently use chemical energy provided by food, and to help process the proteins, carbohydrates, and fats required for metabolic function. Although requirements seem small, these molecules are absolutely essential in a healthy diet as deficiency can cause severe problems. Daily Essential Nutrients contains all 13 essential vitamins known to sustain optimal vitality for the body.* Learn more.

Yes. The ingredients in Daily Essential Nutrients have been shown to:

Minerals are inorganic chemical elements that are required from the diet because the body cannot produce them. Minerals are typically from the various families of metals listed in the periodic table. Minerals usually carry a positive electric charge which allows them to act as electrolytes, as co-factors, or as active centers in catalytic enzymes. Learn more.

Minerals are needed for normal growth and development and for the healthy maintenance of cells, tissues, and organs. Minerals enable cells to efficiently use vitamins and other chemical nutrients provided by food for structure and function in the body. Without minerals, there would be no osmotic balance, no electrical impulses in nerve cells, no oxygen transport, and no large-scale structures (like bones). Although requirements differ between certain minerals, they are absolutely essential in a healthy diet as deficiency can cause severe problems. Daily Essential Nutrients contains 17 essential and trace minerals to sustain optimal function for the body.* Learn more.

Yes. The ingredients in Daily Essential Nutrients are shown to:

Yes. The ingredients in Daily Essential Nutrients are shown to:

The Dietary Reference Intakes (DRIs) are used for planning and assessing diets for healthy people. They expand on the Recommended Dietary Allowances (RDAs) which have been published since 1941 by the US National Academy of Sciences. The DRIs comprise a set of six nutrient-based reference values: 

The recommended dietary allowance (RDA) is the minimum daily amount of a vitamin or mineral expected to prevent deficiency in most people. However, getting the RDA each day doesn’t necessarily mean that you will be optimally healthy. The US Institute of Medicine states that intake at the level of the RDA is not expected to be enough for individuals previously undernourished, nor is it adequate for disease states marked by increased requirements. The levels of vitamins and minerals in Daily Essential Nutrients are carefully formulated to supply a safe and optimal level of each nutrient in conjunction with a healthy diet. Learn more.

Yes. Many nutrients play a role in the structure and function of the brain. An impressive amount of research has revealed the powerful influence of high quality essential nutrients on the brain, affecting every aspect of function from mood to body systems and intellectual capacity.* Learn more.

Yes. The proprietary mineral blend in Daily Essential Nutrients has been extensively studied by independent researchers and refined in clinical practice for over 15 years. Its impressive effects on stress and mood have been published in medical journals around the world.* Learn more.

If sufficient scientific evidence is not available to calculate an Estimated Average Requirement (EAR), a reference intake called an Adequate Intake (AI) is provided instead of an RDA. The AI is a value based on experimentally derived intake levels or approximations of observed mean (average) nutrient intakes by a group (or groups) of healthy people.

The Estimated Average Requirement (EAR) is the daily intake value that is estimated to meet the requirement in half of the apparently healthy individuals in a life stage or gender group.

No. Daily Essential Nutrients supplies essential vitamins, minerals, and other nutrients, but your body needs more than this to stay healthy. Fruits, vegetables, and whole grains also contain fiber, antioxidants and phytochemicals which help keep you healthy.* Learn more.

No, not directly. However, Daily Essential Nutrients can help support healthy weight loss by providing nutrients for healthy metabolism and helping you feel energized.* Learn more.

The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects for almost all individuals in the specified life stage group.

Supplementing with vitamins and minerals can save money through prevention. There’s no question that healthier people incur fewer healthcare costs. They are also more active, more productive, and they enjoy a higher quality of life. In a recent analysis, world-respected economists concluded that supplementing essential nutrients yielded tremendously high benefits compared to costs.* Learn more.

When possible, the Tolerable Upper Intake Level (UL) is based on a no-observed-adverse-effect level (NOAEL), which is the highest intake (or experimental oral dose) of a nutrient at which no adverse effects have been observed in the individuals studied.

If there are no adequate data demonstrating a no-observed-adverse-effect level (NOAEL), then a lowest-observed-adverse-effect level (LOAEL) may be used. A LOAEL is the lowest intake (or experimental oral dose) at which an adverse effect has been identified.

Magnesium stearate has come under some very negative scrutiny of late. There are numerous statements which indicate that magnesium stearate is bad for you, magnesium stearate harms the immune system, and that quality supplements do not contain magnesium stearate. 

These strongly worded positions lacked adequate references and the few that provided references cited one primary source, which will be reviewed in this comprehensive examination. Statements like these can be very concerning and we determined to find where they were coming from. What we found was that none of the comments had any cogency or authority. 

Stearic Acid and Magnesium Stearate

Stearic acid is one of the most common saturated fatty acids found in nature and occurs in many animal and vegetable fats and oils. Cocoa butter and shea butter have the highest stearic acid content at 28–45%. [1]

Magnesium stearate, also called octadecanoic acid magnesium salt, is a salt containing two equivalents of stearate (the stearic acid anion 18:0) and one magnesium cation (Mg2+). It is considered safe for human consumption at levels below 2500 mg/kg per day. [2]

Magnesium stearate [3]

In Supplements

Magnesium stearate is used as a lubricant in the manufacture of medical and supplemental tablets, capsules and powders. Studies have shown that magnesium stearate may affect the release time of the active ingredients in tablets, etc., but that it does not reduce the overall bioavailability of those ingredients. [4,5]

The few milligrams of magnesium stearate in a supplement capsule represent 0.069% of the average daily dietary intake of stearic acid. In other words, based on average daily intake, 99.83% of stearic acid comes from all the other foods we eat every day, even the “healthy” foods.

Making dietary supplements in a high quality way is far more complex than most people realize.  There are several variables involved with nutrients that affect flowing and sticking.  These include particle size of the ingredient, moisture content, chemical nature, solubility, and cohesive nature.  These factors vary based on the ingredients in any product and become more complex as the number of different ingredients in the product increases. We use USP grade stearates derived from vegetable sources.

Did you know?

According to USDA National Health and Nutrition Examination Survey (NHANES 2001-2002) the average intake of stearic acid is 5.7 g/day (8.1% of total fat) for women and 8.2 g/day (8.4% of total fat) for men from all dietary sources. [6]

Stearic acid, or stearate, intake is second only to palmitic acid which accounts for 54.2% of saturated fatty acids (SFAs) (5.8% of total calories) for females and 54.5% of SFAs (6.0% of total calories) for males. [6]

Stearate Facts

·        In 95% lean ground beef, 37% of the saturated fat is stearic acid. [7]

·        One cup of Brazil nuts contains 8.305g of stearate (38.7% of SFAs). [8]

·        One cup of cashew nuts, dry roasted no salt, contains 4.072 g of stearate. [8]

·        One tablespoon of olive oil contains 0.264 g (264 mg) of stearate. [8]

Generally Recognized as Safe

-         Food and Drug Administration

FDA's GRAS (generally recognized as safe) Substances (SCOGS) review states, "There is no evidence in the available information on ... magnesium stearate ... that demonstrates, or suggests reasonable grounds to suspect, a hazard to the public when they are used at levels that are now current and in the manner now practiced, or which might reasonably be expected in the future." [9]

-         World Health Organization

Magnesium stearate has been the subject of study by the Joint FAO/WHO Expert Committee on Food Additives and industry manufacturers for over forty years. The 80th meeting of the Expert Committee was held in Rome, Italy and the technical report was published in 2016. In their report they summarized the history of the review of magnesium stearate.

“At the seventeenth meeting (in 1973), the Committee evaluated salts of palmitic and stearic acids and established ADIs* “not limited”, with notes that palmitic and stearic acids are normal products of the metabolism of fats and that their metabolic fate is well established. Provided that the contribution of cations such as magnesium does not add excessively to the normal body load, there would be no need to consider the use of these substances in any different light to that of dietary fatty acids.”

“At its twenty-ninth meeting (in 1985), the Committee was of the opinion that “ADIs for ionizable salts should be based on previously accepted recommendations for the constituent cations and anions”. The Committee listed ADIs for a number of combinations of cations and anions, including those of magnesium stearate and magnesium palmitate (ADI “not specified”). The Committee was concerned that dietary exposure resulting from the use of magnesium salts as food additives may have a laxative effect. The Committee stated that fatty acids are normal constituents of coconut oil, butter and other edible oils and that they do not represent a toxicological problem. As the Committee had no information on the manufacture or use of the food-grade materials at that time, an ADI for magnesium stearate was not established.”

“At its forty-ninth meeting (in 1997), the Committee evaluated the safety of palmitic acid and stearic acid when used as flavouring agents and concluded that they would not present a safety concern under the proposed conditions of use.”

“In 2010, at the Forty-second Session of CCFA, the deletion of magnesium salts of fatty acids from the INS had been proposed. The International Alliance of Dietary/Food Supplement Associations offered technological justification for the use of this additive.”

The Committee “at its Forty-third Session in 2011 assigned the new INS number 470(iii) to magnesium stearate and asked the Committee to conduct a safety assessment, assess dietary exposure and set specifications for magnesium stearate”

“At its seventy-sixth meeting (in 2012), the Committee established an ADI* “not specified” for a number of magnesium-containing food additives and recommended that total dietary exposure to magnesium from food additives and other sources in the diet should be assessed. This was in the context of the evaluation of magnesium dihydrogen diphosphate, in which the estimated chronic dietary exposure to magnesium from the proposed uses was up to twice the background exposures from food previously noted by the Committee and may be in the region of the minimum laxative effective dose. For the present evaluation, a range of published studies together with three reports on genotoxicity testing of magnesium stearate were submitted to the Committee.”

For the current 2015-2016 evaluation, a range of published studies together with three reports on genotoxicity testing of magnesium stearate were submitted to the Committee. The Committee concluded that there are no differences in the evaluation of the toxicity of magnesium stearate compared with other magnesium salts and confirmed the ADI* “not specified” for magnesium salts of stearic and palmitic acids.

*ADI (Allocation of Acceptable Daily Intakes) ‘not specified’ is a FAO-WHO term for a substance with very low toxicity for which no safe upper-limit of intake is established, or deemed necessary, on the basis of available biochemical, chemical, and toxicological data. [10]

Stearic Acid may have Health Benefits

In a systematic review [11] and a meta-analysis of 60 controlled trials [12] in humans the data clearly (referenced back to 1957) indicate that stearic acid (or its conjugate base stearate) has no effect on cholesterol levels compared to other long-chain saturated fatty acids. In fact the authors of the 2010 systematic review concluded that “LDL cholesterol decreased as dietary stearic acid increased in a statistically significant dose-response relation.”

Researchers from the Netherlands even evaluated hydrogenated linoleic acid (to produce stearic acid) and found that there was no difference in the serum lipid profiles compared to “natural” stearic acid. [13]

Molecular basis for the immunosuppressive action of stearic acid on T cells

The common reference used to demonstrate harm caused by magnesium stearate was published in 1990. The experiment entitled “Molecular basis for the immunosuppressive action of stearic acid on T cells” [14] is research that many people have used as evidence that magnesium stearate is harmful to human T cells.

It is clear that anyone referring to this study to claim magnesium stearate is toxic to humans hasn’t actually read it.

The researchers were specifically looking to determine the mechanism by which stearic acid (stearate) causes T cell suppression in mice, but in order for the experiment to work the scientists had to remove the immune cells from mice. The T cells then had to be incubated on rabbit anti-mouse immunoglobulins in order to be isolated and purified. The lymphocytes were cultured in medium containing 0.2% NaHCO3, penicillin, streptomycin and 5% fetal bovine serum.

The T cells were then stimulated with phytohaemagglutinin or with lipopolysaccharide. These are plant and bacterial factors that start the process of activating the T cells (mitosis).

At this point stearic acid combined with bovine serum albumin and diatomaceous earth (80-90% silica, 2-4% aluminum oxide, and 0.5-2% iron oxide) were added to the T cells. The T cells began to incorporate stearate into their membranes which resulted in inactivation of the T cell. B cells, also from mice, examined in the same way had no issues because they have an enzyme that desaturates the stearate molecule. 

Yes, this experiment worked in mouse T cells. However, it had to be done in a petri dish (in vitro) to create the environment where it could happen. To quote directly from the authors; “If the effects of 18:0 (stearate) on T cells could be retained in vivo (in the living organism), the fatty acid could effectively and rapidly immunosuppress cell-mediated responses, but without the serious side-effects of cyclosporin.” In other words, the effect is not observed in the living mouse.

The researches were trying to see if there was a way that stearate could be used as a potential immune suppressing drug, but could only get it to work in conditions far removed from normal physiological conditions. Human T lymphocytes have a desaturase enzyme unlike the mouse T cell. [15] This means that human T cells can modify stearate by enzymatic desaturation and cannot be inactivated by stearate consumption.

References

[1] Beare-Rogers, J.; Dieffenbacher, A.; Holm, J.V. (2001). "Lexicon of lipid nutrition (IUPAC Technical Report)". Pure and Applied Chemistry 73 (4): 685–744.

[2] D. Søndergaarda, O. Meyera and G. Würtzena (1980). "Magnesium stearate given peroprally to rats. A short term study". Toxicology 17 (1): 51–55. doi:10.1016/0300-483X(80)90026-8. PMID 7434368

[3] "Magnesium stearate" by Edgar181 - Own work. Licensed under Public Domain via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:Magnesium_stearate.png#/media/File:Magnesium_stearate.png

[4] Alija Uzunović, Edina Vranić; "Effect Of Magnesium Stearate Concentration On Dissolution Properties Of Ranitidine Hydrochloride Coated Tablets"; Bosnian Journal Of Basic Medical Sciences, 2007, 7(3): 279-283.

[5] Natalie D. Eddington, Muhammad Ashraf, Larry L. Augsburger, James L. Leslie, Michael J. Fossler, Lawrence J. Lesko, Vinod P. Shah, Gurvinder Singh Rekhi; "Identification of Formulation and Manufacturing Variables That Influence In Vitro Dissolution and In Vivo Bioavailability of Propranolol Hydrochloride Tablets"; Pharmaceutical Development and Technology, Volume 3, Issue 4 November 1998 , pages 535–547.

[6] U.S. Department of Agriculture, Agricultural Research Service. What We Eat in America, NHANES 2001-2002, individuals 2 years and over (excluding breast-fed children). Nutrient Intakes: Mean Amount Consumed Per Individual, One Day.

[7] U.S. Department of Agriculture, Agricultural Research Service, 2006. USDA Nutrient Database for Standard Reference, Release 19.

[8] U.S. Department of Agriculture, Agricultural Research Service, 2014. USDA National Nutrient Database for Standard Reference. Release 27.

[9] FDA's SCOGS Database; Report No. 60; ID Code: 557-04-0; http://www.accessdata.fda.gov/scripts/fcn/fcnDetailNavigation.cfm?rpt=scogsListing&id=198

[10] http://apps.who.int/iris/bitstream/10665/204410/1/9789240695405_eng.pdf

[11] Hunter JE, Zhang J, Kris-Etherton PM. Cardiovascular disease risk of dietary stearic acid compared with trans, other saturated, and unsaturated fatty acids: a systematic review. Am J Clin Nutr. 2010 Jan;91(1):46-63.  Review. PubMed PMID: 19939984.

[12] Mensink RP, Zock PL, Kester AD, Katan MB. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr. 2003 May;77(5):1146-55. PubMed PMID: 12716665.

[13] Zock PL, Katan MB. Hydrogenation alternatives: effects of trans fatty acids and stearic acid versus linoleic acid on serum lipids and lipoproteins in humans. J Lipid Res. 1992 Mar;33(3):399-410. PubMed PMID: 1569387.

[14] Tebbey PW, Buttke TM. Molecular basis for the immunosuppressive action of stearic acid on T cells. Immunology. 1990 Jul;70(3):379-84. Erratum in: Immunology 1990 Oct;71(2):306.

[15] Anel A, Naval J, González B, Uriel J, Piñeiro A. Fatty acid metabolism in human lymphocytes. II. Activation of fatty acid desaturase-elongase systems during blastic transformation. Biochim Biophys Acta. 1990 Jun 14;1044(3):332-9.

Titanium dioxide is the naturally occurring oxide of titanium, chemical formula TiO₂. It is used to provide whiteness and opacity to foods and medicines, and in our case, the veggie capsule.

The US Code of Federal Regulations Title 21 (revised April 2014) states;

(c) Uses and restrictions. The color additive titanium dioxide may be safely used for coloring foods generally, subject to the following restrictions:

(1) The quantity of titanium dioxide does not exceed 1 percent by weight of the food.

(2) It may not be used to color foods for which standards of identity have been promulgated under section 401 of the act unless added color is authorized by such standards.

(d) Labeling. The label of the color additive and any mixtures intended solely or in part for coloring purposes prepared therefrom shall conform to the requirements of 70.25 of this chapter.

(e) Exemption from certification. Certification of this color additive is not necessary for the protection of the public health and therefore batches thereof are exempt from the certification requirements of section 721(c) of the act. [1]

The most current evidence indicates that titanium dioxide is not toxic and is relatively inert in biological systems. [2,3,4] Nanoscale range particles have different physical properties and are not suitable as a pigment. Nanoscale titanium dioxide is not currently approved as a food additive.

It is very clear from the literature that there is a distinction in health effects between nano-sized mineral oxides, including titanium dioxide, and larger sized particles of the exact same material. 

Nano-particles of many different mineral oxides--including iron oxide[5], magnesium oxide[6], copper oxide[7], silicon dioxide[8], manganese oxide[9], etc. can pass through cell membranes undigested remaining predominantly as inorganic oxides and not as mineral ions or ions chaperoned by other organic molecules.  This distinction also applies to certain non-mineral ingredients as well.  For example, nanoparticles of microcrystalline cellulose [10] are clearly harmful while the larger particle sizes are not.

Many of the inorganic mineral oxides cause oxidative stress when they are nano-sized.  Yet the same substances are not harmful if the particles are large enough that they would normally pass through the bowel and do not enter the cell undigested.

Thus, the dangers to health are due to the size rather than the substance and titanium dioxide is not unique in this.

Titanium dioxide content is less than or equal to 1% of the weight of the empty capsule. We use the titanium dioxide for one reason and that is because the raw materials we use can sometimes have varying shades of color depending on harvesting, original moisture content etc. and it distresses individuals when the color is different between batches, even if it does not change the nutritional content. We also regularly evaluate the state of the evidence for many ingredients and make changes or improvements accordingly.

There is a lot of recent press on titanium dioxide. It appears that origins of the carcinogenic findings come from a 2010 publication of the International Agency for Research on Cancer (IARC), a branch of the World Health Organization. [11]

The IARC found that all the human studies analyzed do not suggest an association between occupational exposure to titanium dioxide as it occurred in recent decades in Western Europe and North America and risk for cancer. There was no evidence of an exposure–response relationship.

In animal studies oral, subcutaneous and intraperitoneal administration did not produce a significant increase in the frequency of any type of tumor in mice or rats. Inhalation studies did show an increase in lung tumors in rats breathing fine titanium dioxide dust at a concentration of 250 mg/m3 for two years. That is equal to breathing in and average of 30 grams of the particulate over two years.

The IARC concluded;

“Cancer in Humans: There is inadequate evidence in humans for the carcinogenicity of titanium dioxide.

Cancer in experimental animals: There is sufficient evidence in experimental animals for the carcinogenicity of titanium dioxide.

Overall evaluation: Titanium dioxide is possibly carcinogenic to humans (Group 2B).”

There are four IARC classification groups. [12]

Group 1: carcinogenic to humans (currently – 118 agents). There is enough evidence to conclude that it can cause cancer in humans.

Group 2A: probably carcinogenic to humans (currently – 79 agents). There is strong evidence that it can cause cancer in humans, but at present it is not conclusive.

Group 2B: possibly carcinogenic to humans (currently – 290 agents). There is some evidence that it can cause cancer in humans but at present it is far from conclusive.

Group 3: not classifiable as to carcinogenicity in humans (currently – 501 agents). There is no evidence at present that it causes cancer in humans.

Group 4: probably not carcinogenic to humans (currently – 1 agent). There is strong evidence that it does not cause cancer in humans.

There are two items to point out. First, the conclusion that titanium dioxide is possibly carcinogenic to humans comes from experimental animals exposed to incredibly high doses of inhaled material. Ingestion, or eating, did not increase the frequency of any types of cancer. 

It is almost like saying that rats died when breathing in water therefore water is possibly harmful to humans. The statement may be accurate but it is very ambiguous.

Second, the categories are all worded in such way that cancer is a certainty or a probability. This too is ambiguous.

To be fair if humans breathed in the equivalent amount of titanium dust we would likely get lung tumors also. The human equivalent would be 2.1 kg or 4.6 pounds over two years.

On October 26, 2015, the IARC reported that consumption of processed meat (e.g., bacon, ham, hot dogs, sausages) was a Class 1 carcinogen, and that red meat was a Class 2A carcinogen ("probably carcinogenic to humans"). [13]

Therefore based on their own criteria titanium dioxide carries less cancer risk than red meat and far less risk than processed meats. 

 

References

[1] http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=73.575

[2] Skocaj M, Filipic M, Petkovic J, Novak S. Titanium dioxide in our everyday life; is it safe? Radiol Oncol. 2011 Dec;45(4):227-47.

[3] Ophus EM, Rode L, Gylseth B, Nicholson DG, Saeed K. Analysis of titanium pigments in human lung tissue. Scand J Work Environ Health. 1979 Sep;5(3):290-6.

[4] Lindenschmidt RC, Driscoll KE, Perkins MA, Higgins JM, Maurer JK, Belfiore KA. The comparison of a fibrogenic and two nonfibrogenic dusts by bronchoalveolar lavage. Toxicol Appl Pharmacol. 1990 Feb;102(2):268-81.

[5] Pelclova D, Zdimal V, Kacer P, Fenclova Z, Vlckova S, Syslova K, Navratil T, Schwarz J, Zikova N, Barosova H, Turci F, Komarc M, Pelcl T, Belacek J, Kukutschova J, Zakharov S. Oxidative stress markers are elevated in exhaled breath condensate of workers exposed to nanoparticles during iron oxide pigment production. J Breath Res. 2016 Feb 1;10(1):016004. PMID: 26828137

[6] Mangalampalli B, Dumala N, Perumalla Venkata R, Grover P. Genotoxicity, biochemical, and biodistribution studies of magnesium oxide nano and microparticles in albino wistar rats after 28-day repeated oral exposure. Environ Toxicol. 2018 Apr;33(4):396-410. PMID: 29282847

[7] Xu P, Xu J, Liu S, Yang Z. Nano copper induced apoptosis in podocytes via increasing oxidative stress. J Hazard Mater. 2012 Nov 30;241-242:279-86. PMID: 23063557

[8] Passagne I, Morille M, Rousset M, Pujalté I, L'azou B. Implication of oxidative stress in size-dependent toxicity of silica nanoparticles in kidney cells. Toxicology. 2012 Sep 28;299(2-3):112-24. PMID: 22627296

[9] Sárközi K, Papp A, Horváth E, Máté Z, Hermesz E, Kozma G, Zomborszki ZP, Kálomista I, Galbács G, Szabó A. Protective effect of green tea against neuro-functional alterations in rats treated with MnO2 nanoparticles. J Sci Food Agric. 2017 Apr;97(6):1717-1724. PMID: 27435261

[10] Endes C, Camarero-Espinosa S, Mueller S, Foster EJ, Petri-Fink A, Rothen-Rutishauser B, Weder C, Clift MJ. A critical review of the current knowledge regarding the biological impact of nanocellulose. J Nanobiotechnology. 2016 Dec 1;14(1):78. PMID: 27903280

[11] http://monographs.iarc.fr/ENG/Monographs/vol93/

[12] http://monographs.iarc.fr/ENG/Classification/

[13] http://www.iarc.fr/en/media-centre/pr/2015/pdfs/pr240_E.pdf

Nickel, as well as magnesium, is an activator of an enzyme called calcineurin, which in turn activates another enzyme called calmodulin. Together these enzymes move calcium into cells. This action has influences in the immune response and inflammation, metabolism, apoptosis, smooth muscle contraction, intracellular movement, short-term and long-term memory, and helps modulate neuronal development and plasticity. [1]

Function

Nickel serves as a cofactor or structural component of specific metalloenzymes of various functions, including hydrolysis and redox reactions and gene expression (Andrews et al., 1988; Kim et al., 1991; Lancaster, 1988; Przybyla et al., 1992). Nickel also serves as a cofactor facilitating ferric iron absorption or metabolism (Nielsen, 1985). Nickel is an essential trace element in animals, as demonstrated by deficiency signs reported in several species. Rats deprived of nickel exhibit retarded growth, low hemoglobin concentrations (Schnegg and Kirchgessner, 1975), and impaired glucose metabolism (Nielsen, 1996). Nickel may interact with the vitamin B12- and folic-acid dependent pathway of methionine synthesis from homocysteine (Uthus and Poellot, 1996). [2]

Superoxide Dismutase

The superoxide ion, (O2-) is generated in biological systems by reduction of molecular oxygen. It has an unpaired electron, so it behaves as a free radical. It is a powerful oxidising agent. These properties render the superoxide ion very toxic and are deployed to advantage by phagocytes to kill invading microorganisms. Otherwise, the superoxide ion must be destroyed before it does unwanted damage in a cell. The superoxide dismutase enzymes perform this function very efficiently. [3]

In biology this type of reaction is called a dismutation reaction. It involves both oxidation and reduction of superoxide ions. The superoxide dismutase group of enzymes, abbreviated as SOD, increase the rate of reaction to near the diffusion limited rate. The key to the action of these enzymes is a metal ion with variable oxidation state which can act as either an oxidizing agent or as a reducing agent. [4]

 In human SOD the active metal is copper, as Cu2+ or Cu+, coordinated tetrahedrally by four histidine residues. This enzyme also contains zinc ions for stabilization and is activated by copper chaperone for superoxide dismutase (CCS). Other isozymes may contain iron, manganese or nickel. Ni-SOD is particularly interesting as it involves nickel (III), an unusual oxidation state for this element. The active site Ni geometry cycles from square planar Ni (II), with thiolate (Cys2 and Cys6) and backbone nitrogen (His1 and Cys2) ligands, to square pyramidal Ni (III) with an added axial His1 side chain ligand. [5]

Calcineurin

Calcineurin is a protein phosphatase [6] consisting of a catalytic subunit, calcineurin A, which contains an active site dinuclear metal center, and a tightly associated, Ca (2+)-binding subunit, calcineurin B. This enzyme has a wide variety of biological responses including Ca (2+) and calmodulin* dependent signal transduction, lymphocyte activation, neuronal and muscle development, neurite outgrowth, and morphogenesis of vertebrate heart valves. [7] Research dating to the early 1980’s has identified that nickel is an activator of the calcineurin enzyme. [8-14]

*Calmodulin is a calcium binding protein that mediates many crucial processes such as inflammation, metabolism, apoptosis, smooth muscle contraction, intracellular movement, short-term and long-term memory, and the immune response. Calmodulin is expressed in many cell types and can have different subcellular locations, including the cytoplasm, within organelles, or associated with the plasma or organelle membranes. Many of the proteins that Calmodulin binds are unable to bind calcium themselves, and use Calmodulin as a calcium sensor and signal transducer.

References

[1] Wayman GA, Lee YS, Tokumitsu H, Silva AJ, Soderling TR. Calmodulin-kinases: modulators of neuronal development and plasticity. Neuron. 2008 Sep 25;59(6):914-31. PMID: 18817731

[2] Food and Nutrition Board, Institute of Medicine.  Dietary Reference Intakes: Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. National Academy Press, Washington, D.C., 2001.

[3] Packer, L. (editor) (2002). Superoxide Dismutase: 349 (Methods in Enzymology). Academic Press. ISBN 0-12-182252-4.

[4] Heinrich, Peter; Georg Löffler; Petro E. Petrides (2006). Biochemie und Pathobiochemie (Springer-Lehrbuch) (German Edition). Berlin: Springer. pp. 123.

[5] Barondeau, D.P.; Kassmann C.J.; Bruns C.K.; Tainer J.A.; Getzoff E.D. (2004). "Nickel superoxide dismutase structure and mechanism". Biochemistry 43 (25): 8038–8047.

[6] Liu L, Zhang J, Yuan J, Dang Y, Yang C, Chen X, Xu J, Yu L. Characterization of a human regulatory subunit of protein phosphatase 3 gene (PPP3RL) expressed specifically in testis. Mol Biol Rep. 2005 Mar;32(1):41-5.

[7] Rusnak F, Mertz P. Calcineurin: form and function. Physiol Rev. 2000 Oct;80(4):1483-521. Review.

[8] King MM, Huang CY.; Activation of calcineurin by nickel ions. Biochem Biophys Res Commun. 1983 Aug 12;114(3):955-61.

[9] Raos N, Kasprzak KS.; Allosteric binding of nickel(II) to calmodulin. Fundam Appl Toxicol. 1989 Nov;13(4):816-22.

[10] Mukai H, Ito A, Kishima K, Kuno T, Tanaka C.; Calmodulin antagonists differentiate between Ni(2+)- and Mn(2+)-stimulated phosphatase activity of calcineurin. J Biochem (Tokyo). 1991 Sep;110(3):402-6.

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