What Is Micro Nutrient Kick - Part 2
continuing on from part 1 of this blog, about What is MNK.
Going over the what vitamins & minerals are in it and a little overview why we put them in this product and what they do.
B Vitamin Complex
Thiamine, also known as vitamin B1, is a water-soluble, B-complex vitamin necessary for the metabolism of proteins, carbohydrates, and fats.
What does it do?
Thiamine is an essential cofactor for numerous enzymes in every cell of your body. It is used by the Kreb cycle to make ATP (our cellular energy currency). Thiamine is a coenzyme in more than 24 enzymes including but not exclusively;
• Pyruvate dehydrogenase (enzyme for energy production in the Krebs cycle),
• Transketolase (enzyme for metabolism of fats and sugar, production of branched-chain amino acids (BCAA), and the production and maintenance of myelin sheath (nerve coating),
• 2-oxo- lucarate dehydrogenase (enzyme for the synthesis of the nerve and brain chemicals acetylcholine, GABA, and glutamate).
Thiamine is required for the Hexose monophosphate shunt, an anabolic pathway used in the adrenal glands and breast gland tissue, and in immune cells leukocytes, erythrocytes. Thiamine is crucial in the central nervous system for energy production from sugar, and also mimics acetylcholine, which may explain its reputation for improving memory, concentration span and cognition in Alzheimer’s disease and other dementias.
Thiamine deficiency is common in the following groups
• Coffee, tea and green tea drinkers (tannins can inhibit thiamine absorption)
• Raw freshwater fish and shellfish deplete thiamine stores. However, cooked fish and seafood are OK
. • Pregnancy
• Those who consume a diet high in simple carbohydrates
• Processed food (sulfites destroy thiamine)
• Alcohol consumption
• Diuretic use
• Eating and digestive disorders
• In 38 % of a group of non-alcoholic psychiatric patients,
• 33-55 %of geriatric populations,
• 30-80 % of alcoholics.
• Thiamine is also depleted in those exposed to formaldehyde. Glyphosate from Round-up and aspartame sweeteners break down to form formaldehyde so you may think you would never drink formaldehyde, well think again.
• Prescription drugs: phenytoin, penicillins, cephalosporins, aminoglycosides, tetracycline derivatives, loop diuretics, fluoroquinolones, sulfonamide derivatives, and trimethoprim.
• Other thiamine deficiency syndromes in critically ill people, alcohol withdrawal, and coma.
• Wernicke's encephalopathy syndrome. Thiamine deficiency disrupts the blood-brain barrier and this results in the cerebral hypoperfusion that create the classic signs of Wernicke's encephalopathy; acute mental confusion, ataxia, and ophthalmoplegia.
• Digestive problems including poor appetite, ulcerative colitis, and ongoing diarrhea, constipation, digestive disturbances, nausea, vomiting,
• Diabetic pain, back pain, myalgia, muscular atrophy, peripheral neuropathy, pain sensitivity, weakness, Neuritis – inflammation of the nerves
• Heart disease, palpitations, bradycardia on rest, tachycardia with sinus arrhythmia on exertion, hypotension,
• Cerebellar syndrome
• Canker sores
Vision problems such as cataracts and glaucoma
• Motion sickness
• Anorexia, weight loss
• Memory loss,
• Dyspnoea, and Sinophobia.
• Emotional instability, mood lability, uncooperative behavior, and fearfulness with agitation
How do I supplement?
Therapeutic supplemental dosages for riboflavin range from 3-400 mg daily. Riboflavin RDAs are 1.2-1.6 mg. Dosages over 20 mg may exceed the carrier-mediated process and absorption is reduced significantly.
Oral (BY MOUTH): For adults: the minimum dose of Thiamine from our diet is 1-2mg daily. Ideal is 5-30 mg daily in either a single dose or divided doses for one month. For severe deficiency doses can be up to 300 mg per day for up to 1 month to correct. MNK has 6.25mg per serve.
Riboflavin is a type of B vitamin. It is water soluble, which means it is not stored in the body. You must replenish the vitamin in your body every day. Riboflavin was identified as a growth factor in 1879 and named vitamin B2 but it wasn't until 1934 that it was isolated from egg whites and synthetic riboflavin arrived shortly after in 1935. Riboflavin is yellow-orange and gives the yellow tinge to egg whites and milk.
What does it do?
Riboflavin and its active coenzymes function as hydrogen carriers in oxidationreduction reactions.
Riboflavin has two active coenzyme forms;
1. Riboflavin 5’-phosphate (R5P; Flavin mononucleotide [FMN]) and 2. Flavin adenine dinucleotide (FAD)
FAD is a cofactor in many energy production reactions, such as sugar and fat metabolism, and amino acid synthesis.
FAD and R5P are also essential for the activation of other vitamins such as folate and B6. Riboflavin is essential for;
• Cofactor for flavocoenzymes, flavoproteins, and metalloproteins to drive enzyme reactions such as; amino acid oxidases, xanthine oxidases, betaoxidation of lipids (fat burning), and dehydrogenase reactions in the citric acid cycle (Krebs cycle).
• Builds new red blood cells (erythropoiesis)
• Regulating stress chemicals epinephrine and norepinephrine,
• Amino acid metabolism and conversion to sugar,
• Activation of vitamin B6 by converting pyridoxine to the active form P5P (pyridoxal-5-phosphate),
• Activation of folate; conversion of folate and folic acid to the active form of folate 5-methyltetrahydrofolate (5-MTHF),
• Conversion of tryptophan to niacin (avoid the "tryptophan steal"),
• The synthesis of vitamin B12.
Riboflavin deficiency A riboflavin deficiency is defined as ariboflavinosis. Riboflavin deficiency is prevalent in underdeveloped countries. In developed countries, riboflavin deficiency is common in pregnancy, infancy, alcoholism and the elderly. Rates of deficiency are often proportional with decreased dietary intake of meat and dairy products.
Riboflavin levels are decreased by interactions with certain drugs; tricyclic antidepressants, phenothiazines, oral contraceptives, and anti-malarial drugs. Probenecid decreases the absorption of riboflavin in the gut.
Riboflavin deficiency could result in deficiencies of folate, vitamin B6, and vitamin B12 and manifest those deficiency signs and symptoms also.
Signs and symptoms of deficiency
• Cataracts - Riboflavin deficiency is implicated in the formation of cataracts. Glutathione reductase, the enzyme responsible for the production of glutathione, is decreased in cataracts, and decreased enzymatic activity of glutathione reductase is associated with riboflavin deficiency
. • Hyperhomocysteinemia - Vitamin B6, B12 and folate require riboflavin to work and together they regulate homocysteine levels by controlling transsulfuration and remethylation pathways. Transsulfuration is dependent on vitamin B6 and catabolizes homocysteine to cysteine, while remethylation of homocysteine to methionine is dependent on vitamin B12, folate, and riboflavin.
• Carpal tunnel syndrome
• Angular stomatitis and cheilosis (cracks in lips and corners of mouth)
• Seborrhoea (oily, greasy skin and scalp)
• Glossitis (sore, cracked tongue),
• Scrotal and vulvar dermatitis,
• Seborrheic dermatitis,
• Ocular and visual changes.
How do I supplement?
Therapeutic supplemental dosages for riboflavin range from 3-400 mg daily. Riboflavin RDAs are 1.2-1.6 mg. Dosages over 20 mg may exceed the carriermediated process and absorption is reduced significantly. MNK has 6.25mg per serve.
Niacin and niacinamide are forms of Vitamin B3. Niacinamide, also known as nicotinamide, is a water-soluble amide of nicotinic acid. While niacinamide and niacin both prevent the development of the vitamin B3-deficiency, they have very different pharmacological actions. Vitamin B3 is found in many foods including yeast, meat, fish, milk, eggs, green vegetables, beans, and cereal grains.
What does it do?
Niacinamide acts as an antioxidant by preventing NAD depletion during DNA repair. Niacinamide inhibits free radical formation and protects us from our macrophage toxins. In Type 1 diabetes, it protects pancreatic islet cells from damage and facilitates beta-cell regeneration.
Niacinamide has also been found to stimulate GABA receptors, without binding to the receptor sites, thus creating a benzodiazepine-like effect. Anti-inflammatory action by affecting neutrophil chemotaxis (chemical signals used to attract immune and inflammatory cells) and suppresses cytokine-induced inflammation and oxidative stress.
B3 Deficiency Pellagra, a disease consisting of bilaterally symmetrical lesions on both sides of the body and hands, occurs as a result of a niacin deficiency. The disease is characterized by hyperpigmentation and thickening of the skin, inflammation of the tongue and mouth, and digestive disturbances including indigestion, anorexia, and diarrhea. In the late stages of the disease, irritability, amnesia, and delirium occur. Both niacin and niacinamide are approved by the U.S. Food and Drug Administration (FDA) for the treatment and prevention of niacin deficiency, and certain conditions related to niacin deficiency such as pellagra. Niacinamide is sometimes preferred because it doesn’t cause “flushing,” (redness, itching, and tingling) that is a side effect of using niacin.
In Diabetes; there is a window of opportunity to use high-doses of niacinamide to exert protective effects on beta-cell function in humans. The dose used in diabetic and prediabetic individuals ranges from 1.75- 3.5 grams per day. In diabetic children, a daily dose of 150-300 mg/year of age, up to 3 grams is often used. Refer to the dosing section, and you will see these levels far exceed typical dietary requirements and should be done with guidance and prescription from your healthcare professional.
Niacinamide has been used to treat several types of dermatological pathologies that present with blistering skin conditions or hyperpigmentation in particular. Niacin is commonly used for high cholesterol and triglycerides, but this action still requires further research to test if useful for this. Niacin is also used along with other treatments for circulation problems, migraine headache and dizziness. Niacin is also commonly used for preventing positive urine drug screens in people who take illegal drugs.
How do I supplement?
The recommended daily intake (RDA) is 20 mg per day for an adult. Higher doses are commonly used for masking drug tests, targeting cholesterol, and treating/preventing Type 1 Diabetes but the more massive doses may not be safe and should only be used under the direct supervision of your healthcare professional. Nausea is usually the first side effect noted with niacinamide. Other side effects associated with high-dose niacinamide include heartburn, vomiting, flatulence, and diarrhea. Mild headaches and dizziness have been reported after giving niacinamide parenterally. MNK has 8.77mg per serve.
Niacin and niacinamide are LIKELY SAFE for most people when taken by mouth. A typical minor side effect of niacin is a flushing reaction. This might cause burning, tingling, itching, and redness of the face, arms, and chest, as well as headaches. When doses of over 3 grams per day of niacin are taken, more severe side effects may occur; such as liver problems, gout, ulcers of the digestive tract, loss of vision, high blood sugar, irregular heartbeat, and other serious issues. Similar side effects can happen with large doses of niacinamide. Some concern has been raised about stroke risk in people taking niacin. In one extensive study, people who received high doses of niacin had a two-fold higher risk of stroke compared to those not taking niacin. But it is unclear if this outcome was due to niacin or some other unknown factor. Previous research has not identified any stroke risk related to taking niacin.
Pantothenic acid (vitamin B5) is a water-soluble B-complex vitamin originally extracted from the liver, but its name is derived from the Greek word meaning “everywhere” because it is found in so many foods. Even though it is available from so many natural sources most forms of vitamin B5 added to foods and beverages or used in dietary supplements, is made by chemical synthesis.
Food sources include peanuts and peanut butter, liver, kidney, almonds, wheat bran, cheese, shellfish. Refining, freezing, canning and cooking food causes losses of pantothenic acid, so a modern processed food diet would be expected to have lower amounts of vitamin B5 than a whole foods diet
What does it do?
Nature knows best, the vast majority of vitamin B5 in foods is found already incorporated into Coenzyme A (CoA) and as phosphopantetheine. Vitamin B5 / pantothenic acid’s job is to be used in CoA and acyl carrier proteins (ACP), which carry and transfer acetyl and acyl groups.
CoA is an essential cofactor in;
1. Fatty acid oxidation,
2. Lipid elongation,
3. Fatty acid synthesis.
4. The production of many secondary metabolites such as ubiquinone [CoQ10], squalene, and cholesterol
5. Production of steroid molecules (e.g., steroid hormones, vitamin D and bile acids),
6. Acetylated compounds N-acetylglucosamine
7. Acetylated neurotransmitters [e.g. N-acetylserotonin, acetylcholine]),
8. Prostaglandins and prostaglandin-like compounds.
9. Biosynthesis of phospholipids (e.g., phosphatidylcholine, -ethanolamine, -serine, -inositol)
Most plants and microorganisms make pantothenic acid by enzymatically combining pantoic acid with ß-alanine. Mammals lack the enzyme for this synthetic step, so are unable to synthesize pantothenic acid, and we must consume it or supplement
. B5 deficiency has a severe impact on the adrenal glands, and in extreme cases, the damage may be irreversible. In the early stages of deficiency, the adrenal gland hypertrophies (enlarges). The adrenal cortex swells and is depleted of ketosteroids. If the deficiency continues the adrenal gland starts to hypofunction, with an inability to respond appropriately to stress. Eventually, the adrenals atrophy and cell damage occur.
If pantothenic acid is supplied early before adrenal exhaustion occurs, the response to stress can be improved, and changes to the adrenals can be halted and reversed. But once cell damage has happened and you are suffering from clinical adrenal exhaustion, the pantothenic acid administration is no longer sufficient.
• Adrenal exhaustion and dysfunction
• Thymus shrinkage
• Spleen to enlarge
• Immune suppression
• Reduced sperm motility,
• Decreased plasma levels of testosterone and corticosterone.
• Gastrointestinal disturbances (nausea, abdominal cramps, occasional vomiting, increased flatulence, and epigastric burning sensations);
Signs and symptoms of deficiency
• Fatigue (apathy and malaise), headache, and weakness • Weight loss • Reduced growth • Poor grooming • Hair loss • Exudate around the eyes • Diarrhea • Sleep disturbances; • Insomnia • Burning feet syndrome • Infertility • Personality changes and emotional disorders. • Colds and flu • Burning feet
How do I supplement?
The Dietary Reference Intake (DRI) is 5 mg/d of pantothenic acid for males and females 14 years old and over, 6 mg/d during pregnancy, and 7 mg/d during lactation. In mammals, endogenous synthesis of CoA and ACP from pantothenic acid uses magnesium-dependent enzymes and cysteine as a substrate. Therefore, it is essential to have an adequate supply of both magnesium and cysteine for B5 to do its job.
Massive doses are needed to induce toxicity with vitamin B5. In clinical studies, the dose used has varied significantly, and many times the recommended daily intake has been taken for months without toxicity. The low end of dosing has generally been 10 to 100 mg/d with the high end of doses being 10 g/d (10,000mg/ day). MNK has 15mg per serve
Vitamin B6 consists of three pyrimidines: pyridoxine, pyridoxal, and pyridoxamine, and their phosphate esters, such as the active form P5P (pyridoxal-5-phosphate).
What does it do?
Vitamin B6 dependent enzymes are involved in the following reactions:
• decarboxylation of amino acids to yield amines, many of which are important neurotransmitters and hormones
. • transamination of amino acids to keto-acids, which are then oxidized and used as metabolic fuel.
• phosphorolytic cleavage of glycogen (from liver and muscle) to glucose-onephosphate
. • formation of alpha aminolevulinic acid, a precursor to heme.
• decarboxylation of phosphatidylserine to phosphatidylethanolamine in phospholipid synthesis.
• as a co-factor for cystathionine synthase and cystathionase
• Anemia. B6 is involved in activation of glycine for heme production
• Carpal tunnel syndrome
• Peripheral neuropathy
• Disrupted GABA and serotonin synthesis
• Elevated homocysteine. Homocysteine, an intermediate in methionine metabolism, can be re-methylated to methionine using folate, B12, and B2, or be channeled down the trans-sulfuration pathway to cysteine, which requires two P5P-dependent enzymes: cystathionine synthase and cystathionase.
• Fatty acid imbalances • Kryptopyrroles (mauve factor)
Signs and symptoms of deficiency
• PMS and PMT
• Premenstrual pain and breast tenderness.
• Stress, anxiety, and depression
• Peripheral nerve pain.
• Heel pain
• Inability to reduce body fat
. • Inadequate fat-loss response to low carbohydrate diet or ketogenic diets.
How do I supplement?
RDA for adults is 2-4 mg daily; the typical therapeutic dose is 5-200 mg/day.
MNK has 12.5mg per serve
The use of supplemental P5P has not been associated with toxicity, although the inactive form, pyridoxine, has been associated with reports of peripheral neuropathy. It is proposed that pyridoxine toxicity is caused by exceeding the liver’s ability to phosphorylate pyridoxine to P5P, resulting in a backlog of pyridoxine which may be directly neurotoxic or may compete with P5P for binding sites, resulting in a relative deficiency
Vitamin B9 - Folic Acid (folate)
What is it?
Folate is an umbrella term that encompasses multiple forms of folates; substituted/unsubstituted, oxidized/reduced and mono/polyglutamate forms of pteroylL-glutamic acid. Folic acid is the synthetic form of oxidized and hydrolyzed folates that is not found in nature but is included as a folate. Folic acid is the form of folate most commonly used in dietary supplements and fortified foods. Folic acid is made when natural folates are degraded during cooking and processing and not found in food. Folic acid is not active and needs to be converted back into the natural folate forms in the body before the body can use it
Folic acid is only found in our diet from the water that you boil or steam your vegetables with, in cups of herbal teas and in frozen vegetables that have been blanched before freezing and this unnatural folic acid comprises only 10 percent or less of folates in the diet. With supplementation and food fortification we can get an excess of folic acid and still be deficient in the natural dietary folate complexes found in the plants and animals.
Overconsumption of folic acid can create problems in the folate conversion pathways and backlog the whole system creating bigger problems. This is worse when the natural folates are deficient as the ratios are so far away from nature that the enzyme conversion pathways cannot cope. Furthermore, any genetic or acquired polymorphisms or enzyme defects in the conversion pathway means the folic acid hits a roadblock that it simply cannot pass and the unconverted folic acid accumulates. This unconverted folic acid is not useful as folate but has a vast array of biological effects of its own that can create side effects and do more harm than good.
The best sources of dietary folate are green, leafy vegetables; sprouts, fruits, brewer’s yeast, liver, and kidney.
In many cases, natural forms of vitamins are promoted to be superior due to superior bioavailability compared to synthetic forms. But that is based on the market perception that "more is better" and "superior absorption must mean superior activity" and "vitamins can only do good things or pass straight through if given in excess" but these beliefs have been proven to be incorrect. The actual fact is that natural forms are often safer and more effective as they have varied bioavailability depending on your body's requirements. Vitamins can be toxic and if made into a form that bypasses our body's natural homeostatic processes to prevent overdose and they are supplied without the necessary cofactors then these synthetic vitamins can do a great deal of harm and not achieve the vitamin function for which they were supplemented.
In the case of folic acid versus natural folate; the natural folate bioavailability can be as low as 25 to 50% of that of the synthetic folic acid and synthetic folic acid has bioavailability of 100% and excellent stability. So, it is easy to see how and why folic acid is used in food fortification, supplements and laboratory testing. Instead of going to the expense of extracting natural folate complexes (as it is impossible to recreate nature synthetically) from plants and trying to preserve them and test for the levels and ratios for the purpose of lab testing / studying or adding to foods or supplements that are going to be warehoused, transported and ultimately cooked before consumption.
The problem here is that folic acid and natural folates have to pass through various enzymes systems to become the required 5-MTHF for absorption and biological activity. These enzyme systems have limited capacity even in the healthiest of populations and in many genetic polymorphisms or those with deficiencies of such things as vitamin C, B2, B12 these enzymes systems can't keep up with high doses of folic acid.
As for the marketing of folic acid's enhanced bioavailability and the added ability for folic acid to be absorbed intact; is not necessarily a good thing. Overloading the systems with folic acid adds an extra burden to the conversion pathways. Folic acid is not necessarily biologically active for methylation processes, but is very active on other cellular targets and has been linked to many side effects such as tongue tie and respiratory problems in offspring, leukemia, and cancers. It backlogs and competes with natural folate and can create folate deficiency signs and symptoms.
If enough folic acid is given orally or if there are deficiencies or genetic defects in the converting enzymes; unaltered folic acid appears in the circulation, is taken up by cells, and is reduced by dihydrofolate reductase to tetrahydrofolate but cannot proceed through to the essential 5-MTHF. This accumulated folic acid is not effective in the methylation cycle but is biologically active in the body.
What does it do?
Folate is essential for;
1. DNA metabolism
2. Methylation reactions.
3. Metabolism of several amino acids including, methionine, cysteine, serine, glycine, and histidine.
4. Folic acid has no biological activity unless converted into a folate.
DNA metabolism Folate plays a crucial role in DNA metabolism through two main actions.
(1) The synthesis of DNA from its precursors (thymidine and purines) is dependent on folate coenzymes.
(2) The synthesis of methionine from homocysteine, and subsequent conversion of methionine into S-adenosylmethionine (SAMe). SAMe is our universal methyl donor used in most biological methylation reactions, including within DNA, RNA, proteins, and phospholipids. The methylation of DNA plays a role in controlling gene expression and is critical during cell differentiation, defects in DNA methylation have been linked to cancer.
NO NEED FOR METHIONINE SUPPLEMENTATION
Methionine is an "essential amino acid" but supplementation is not usually necessary as it is abundant in dietary proteins (in developed countries the average diet provides 60% more methionine than is actually needed for protein synthesis and its other functions). The sulfur-containing amino acids, methionine and homocysteine, can be converted into each other but neither can be synthesized in humans.
The excess methionine is degraded via the methylation cycle to homocysteine (refer to the section on homocysteine to see how toxic this compound and ultimately how toxic methionine can potentially be). The synthesis of methionine from homocysteine is catalyzed by methionine synthase, an enzyme that requires not only folate (as 5-methyltetrahydrofolate) but also vitamin B12. Thus, folate (and/or vitamin B12) deficiency can result in decreased synthesis of methionine and an accumulation of homocysteine
It is important to note that over-consumption and supplementation with methionine can also backlog the pathway and cause homocysteine to accumulate. There is no need to supplement with methionine. Elevated blood homocysteine has been considered for many years to be a risk factor for some chronic diseases, including cardiovascular disease, and dementia.
Folate for methylation
5-MTHF can only be channeled to the methylation cycle to supply S-adenosylmethionine (SAM), which acts as our main methyl donor to a wide range of methyltransferases for methylation reactions. These enzymes methylate a wide range of substrates including lipids, hormones, DNA, proteins, xenoestrogens, endocrine disrupting chemicals, other toxins etc. For example;
• Methylation of myelin basic protein, which acts as insulation for nerves cells; resulting in a neuropathy which leads to ataxia, paralysis, and, if untreated, ultimately death
• Down-regulate DNA and suppress cell division, an important step in cancer prevention
• Neurotransmitter methylation via COMT to control brain chemistry
• Methylation of hydroxylated estrogens for efficient detoxification and elimination of both endogenous and xeno-estrogens
• Degrade methionine into toxic homocysteine. Excess methionine is degraded via the methylation cycle to create homocysteine
The DNA and methylation cycles both regenerate tetrahydrofolate. However, there is a considerable amount of wasted and lost folate. Therefore, there is a constant need to replenish the body’s folate content from the diet.
Reduced DNA biosynthesis thereby slowing cell division. This leads to;
• Decreases in red blood cell production i.e. anemia.
• Cells derived from bone marrow also decrease, leading to low white blood cells i.e. leucopoenia and thrombocytopenia.
• Reduction in cell division in the gut wall creating increased intestinal permeability, IBS, IBD, digestive and immune dysfunction.
• Therefore, reduction in the DNA cycle results in an increased susceptibility to infection, allergies, intolerances, cancer, a decrease in blood coagulation, and secondary malabsorption.
The methylation cycle is decreased leading to;
• Elevation in plasma homocysteine due to a decreased availability of new methyl groups provided as 5-methyltetrahydrofolate,
• Demyelination and neuropathy known as subacute combined degeneration of the spinal cord and peripheral nerves.
• Ataxia, paralysis, and ultimately death. Such neuropathy is not usually associated with short term folate deficiency but is seen if folate deficiency is very severe and prolonged and is more aggressive if combined with a B12 deficiency
Folate dependant pathways;
Folic acid is reduced in cells by the enzyme dihydrofolate reductase to the di- and tetrahydro forms This takes place within the intestinal mucosal cells, and 5-methyltetrahydrofolate is released into the plasma. Natural folates found in foods are all conjugated to a polyglutamyl chain containing different numbers of glutamic acids depending on the type of food. This polyglutamyl chain is removed in the brush border of the mucosal cells by the enzyme folate conjugase, and folate monoglutamate is subsequently absorbed. The primary form of folate entering human circulation from the intestinal cells is 5-methyltetrahydrofolate monoglutamate.
Low folate status may be caused by
• Low dietary intake of natural folate.
• Poor absorption of ingested folate.
• Low stomach acid.
• Altered folate metabolism due to genetic defects in the MTHFR gene, and
• Drug interactions e.g. methotrexate.
Signs and symptoms of folate deficiency
• Reducing homocysteine,
• Reducing the occurrence of neural tube defects,
• Preventing cervical dysplasia
, • Protecting against neoplasia in ulcerative colitis,
• Gum inflammation,
• Neurological disorders,
• Cognitive disorders
, • Nerve pain; peripheral neuropathy, myelopathy, and restless legs syndrome,
• Dementia and forgetfulness,
• Irritability, anxiety or depression,
• Psychosis, and schizophrenia-like syndromes,
• Low levels of white blood cells and infections,
• Gut dysfunction and leaky gut wall,
• Allergies and intolerances
How do I supplement?
Folic acid side effects
Folic acid is the form used in food fortification and in most supplements; it is very different to naturally occurring folates in our diet because it is in the oxidized state and contains only one conjugated glutamate residue. The naturally occurring dietary folates that are used in our body are all in the reduced form (tetrahydrofolates; THF) and contain multiple conjugated glutamate residues (polyglutamate)
. Synthetic folic acid competes with natural folate but has an unnatural advantage.Synthetic folic acid has a substantially higher stability and bioavailability than do natural folates, being rapidly absorbed across the intestine. This synthetic folic acid competes with the reduced active forms of folate and interferes with the conversion, transport, and functions.
For example, the folate receptor binds stronger with folic acid than for 5-MTHF; the main active form of folate that does the work. Folates are delivered to the brain by this folate receptor, and so an accumulation folic acid in the blood inhibits the transport of 5-MTHF into the brain. Transport into cells can also occur via the folate receptor with several transporters. Folic acid competes with 5-MTHF for transport. In humans, folic acid supplementation leads to elevated blood concentrations of unmetabolized folic acid.
The high blood concentrations of folic acid may lead to
• Decreased natural killer cell cytotoxicity
• Reduced response to antifolate drugs used against malaria, rheumatoid arthritis, psoriasis, and cancer.
• Increased risk of cognitive impairment
• In pregnant women, it may increase risk of tongue tie, insulin resistance and obesity in their offspring
• Cardiovascular disease
• Folates will activate but folic acid will inhibit several folate-dependent enzymes and related enzymes.
• Protection against cancer initiation but also stimulation of established cancer growth.
The Vitamin C Story
Vitamin C has been one of the most studied nutraceutical ingredients, yet it is still so misunderstood in the public domain with the consumer driving the product development process and marketing. The new scientific discoveries and knowledge generated is available in the public domain but is not being heard or believed. The consumer is chasing more for less; stronger doses with the belief that more is better, megadoses as it can't possibly be bad, after all, it is vitamin C, we all know we need it. More, more, more!!! So of course, "the man" and "big pharma" will happily supply what you want to buy. Why would they push the education and let you know that the new research suggests you don't need so much and it doesn't work for everything you are taking it for. Yes, it is essential, without it; you will die. But that doesn't mean taking extra will make you live longer
The general public seem to have a belief that vitamins are essential and can only do good things and have no negative side effects or toxicities at supraphysiological doses. The "more is better" philosophy is encouraged by retailers and manufacturers. High doses of various forms of vitamin C are readily purchased over the counter and with encouragement or prescription from healthcare professionals they are consumed by the general public with the assumption that it is without risk and free of side effects. The negative effects are usually dismissed or attributed to something else.
Interestingly and it is kind of crazy that there has been so much research on vitamin C over so many years showing negligible effects from supplementation using large doses; beyond what is necessary to correct deficiencies, the standard doses used by the general population far exceed what the science says we need. Yet we all still do it, and healthcare professionals keep recommending it based on belief and faith in what they heard and the real science cannot be heard amongst all of that noise.
Furthermore, research shows that vitamin C supplementation greater than 100-250mg per day for disease prevention and at "high" doses as "low" as 500mg daily can contribute negligible positive results and in some cases, worse results for cardiovascular disease, cancer, aging, and may even increase all-cause mortality. With the average adult supplement recommending 1000 to 6000mg per day and infant supplements recommending 150 to 250mg per day it is worth the effort to investigate what the high doses will do and embark on an education campaign to inform the consumer of the new knowledge generated and how best to use vitamin C.
The earliest symptom of scurvy is subtle and was described by James Lind in 1753 in his treatise on the scurvy as lassitude. It was a predictable affliction of sailors who developed the disease after a month or two at sea. In its early stage, sailors lost initiative and the will to work, became fatigued and apathetic but were capable of working if motivated. The initial lassitude was followed by changes to gums, hair follicles, and poor wound healing.
The official signs and symptoms of scurvy initially are associated with defective catecholamine (adrenalin and noradrenalin) levels followed by the changes associated with defective collagen synthesis.
Scurvy is now rare but in full form presents with striking signs and symptoms. These include; • hypochondriasis and depression; • perifollicular hyperkeratosis with coiled hairs; • swollen and friable gingivae; • anemia, • petechial hemorrhage, • erythema, and purpura; • arthralgia and/or joint effusions; • breakdown of old wounds; bleeding into the skin, subcutaneous tissues, muscles, joints, and subperiosteal hemorrhages; • fever; • shortness of breath; • infections; • and confusion. Untreated, the condition is fatal.
Anti-scorbutic Vitamin C
• The term "ascorbic acid" is derived from "anti-scorbutic," meaning anti-scurvy compound.
• Vitamin C deficiency was linked to low intake due to poor food choices (lack of education), poor farming practices and food processing techniques. Humans have a particular error in our carbohydrate metabolism stopping us from making vitamin c from sugar like other animals. Most of the vitamin C we consume goes to the brain and neuroendocrine tissues such as the adrenal gland. Vitamin C has a reputation for enhancing immune function because the vitamin C concentration of 1-4mM in immune cells (lymphocytes, neutrophils, and monocytes) is 10- to 100-fold higher than the concentration in plasma.
What does it do?
The actions of vitamin C are accounted for by a single chemical property: ascorbic acid is an electron donor and thus a reducing agent. Through this mechanism it works as an enzyme cofactor in hydroxylation reactions to produce the following;
Hydroxyproline and hydroxylysine which are crucial for the production of collagen. Common symptoms of scurvy include wound dehiscence, poor wound healing, and loosening of teeth, all pointing to defects in connective tissue. Collagen provides connective tissue with structural strength. Vitamin C catalyzes the reactions on procollagen to produce and secrete adequate amounts of structurally normal collagen.
Vitamin C is involved in the catabolism of tyrosine. Ascorbate deficiency leads to impaired tyrosine catabolism and increased plasma concentrations of tyrosine.
Production of carnitine from the essential amino acids lysine and methionine. The enzyme requires iron, alpha-ketoglutarate, and a reductant, of which ascorbate is the most optimal.
Noradrenalin and hydroxylation of tryptophan in serotonin biosynthesis.
Vitamin C is needed during the production of steroid hormones for the adrenal glands and in the activation of many peptide hormones, including hypothalamic and gastrointestinal hormones to make them biologically active; such as gastrin, cholecystokinin, calcitonin, vasopressin, and oxytocin.
As a reducer - Folate
metabolism Vitamin C participates in biosynthesis of tetrahydrofolic acid, a crucial step in folate metabolism and activation pathways
Joint repair and inflammation
Vitamin C is involved in the production of hyaluronic acid involved in joint and cartilage regeneration and repair and prostaglandins associated with the inflammatory cascade.
Vitamin C as an antioxidant
Chemically, vitamin C is an electron donor or reducing agent, and electrons from ascorbate account for all of its known physiological effects. Vitamin C is easily and reversibly oxidized into dehydro- L-ascorbic acid, creating a redox system which allows it to deactivate multiple ROS. It regenerates vitamin E used up during similar processes. Vitamin C is a powerful antioxidant, and as it is water soluble, it is the main antioxidant defense localized in the hydrophilic compartment of cells and antioxidant of extracellular fluids.
Vitamin C as a pro-oxidant
Vitamin C acts as an antioxidant because electrons from vitamin C can reduce oxidized species or oxidants. However, the same electrons from vitamin C can reduce metals such as copper and iron, creating pro-oxidants, superoxide and hydrogen peroxide, and their subsequent generation of ROS (reactive oxidant species). This is how, under some circumstances, ascorbate, is a pro-oxidant instead of antioxidant.
Liver detoxification by stimulating the synthesis of cytochrome P450. Vitamin C also takes part in detoxification of xenobiotics thereby reducing the associated ROS.
Vitamin c enhances intestinal iron absorption by reducing nearly non-absorbable Fe3+ to more easily absorbable Fe2+. It also helps by inhibiting the production of insoluble iron-tannin (tannins are the compounds found in green and black tea that inhibit iron absorption) and iron-phytate (compounds found in fiber that can inhibit iron absorption) complexes. Vitamin C also increases iron transfer from the iron transporting protein transferrin to the iron storage protein ferritin.
Vitamin C and stress
Vitamin C is proposed as a neuromodulator of glutamatergic, dopaminergic, cholinergic and GABAergic transmission and related behaviors. It is involved in the production of noradrenaline and serotonin. The adrenal gland has high levels and highly active uptake of vitamin C. It was once believed that vitamin C was involved in cortisol production and that supplementation can reverse adrenal exhaustion or adrenal fatigue, but this has been disproven. In the adrenal gland, vitamin C works to make norepinephrine (aka noradrenaline; the neurotransmitter responsible for our nervous response to stress) from dopamine in the nervous system and in the adrenal glands. This occurs in both the chromaffin cell system of the adrenal medulla and adrenal cortex. The adrenal medulla is necessary for the synthesis of norepinephrine from dopamine in the nervous system and in the adrenal glands. Vitamin C also stimulates catecholamine release via NO-induced mechanism. During stress vitamin c helps to modulate the hepatic and adrenal CYP450 in particular CYP45011B that regulates aldosterone production and release for regulating sodium levels; this is the mechanism by which vitamin C can cause sodium retention and depletion of potassium. During times of excess physical and mental demand, extra vitamin C may be beneficial for the above-mentioned actions; fuelling our nervous survival response to stress, as well as for the antioxidant effects of vitamin C that are protective to cell structures during increased physical and mental demand.
Vitamin C and immunity
An immunological function of vitamin C is indicated originally because the vitamin C concentration of immunocompetent cells (lymphocytes, neutrophils, and monocytes) is 10- to 100-fold higher than the concentration in plasma. The immune system requires appropriate energy and nutrient supplies. Energy and nutrient supplies are especially important for the immune system because its individual components are characterized by high turnover rates, leading to a higher substrate requirement compared to most other body systems. Only if all essential nutrients are supplied in appropriate amounts can the immune system work optimally. Therefore, our immunocompetence is reliant on the availability of essential vitamins, minerals, and certain fatty acids.
More is not better
You only need to supply enough Vitamin C to fill the micronutrient requirements. Extra high doses will not stimulate the immune system any further. A single oral dose of Vitamin C increases the ascorbate levels of immune cells monocytes and neutrophils quickly and then plateus off, and the cells can not take on any more once they are full (Fig. 2). In adults, a vitamin C intake of approximately 100 mg/day results in complete intracellular saturation of immune cells.
Relevance of antioxidant action in immunity.
Activated phagocytes synthesize high amounts of Reactive Oxygen Species (ROS). Reactive oxygen compounds kill microbes’ function in the elimination of bacteria. However, although they are essential for the immune system, reactive oxygen compounds also damage immune cells such as phagocytes, impairing their function. Therefore, Vitamin C plays a pivotal role in the integrity of phagocytes because it acts as an effective water-soluble antioxidant, protecting immune cells against damage. Macrophages consume extra vitamin C during phagocytosis as the most important antioxidants localized in the water parts of cells and between cells.
Significance of Vitamin C for the Functional Integrity of Phagocytes and T Cells.
Vitamin C affects the activity of phagocytic immune cells but not the number. Phagocytosis (the engulfing of foreign particles and infectious organism for destruction and removal) activity is reduced by vitamin C deficiency. A decline of the intracellular vitamin C concentration in leucocytes is associated with impaired immune activity. Again, low doses regularly are more effective as the high doses seem to have the opposite effect. Maintaining optimal doses for weeks to months’ increases immune cell production, whereas unnatural supraphysiological concentrations as seen with intravenous and mega dosing in acute infection show inhibiting effects on immune cell production.
Vitamin C and Nitric Oxide (NO) synthesis
NO (Nitric oxide) induces vasodilation to enhance oxygenation and blood flow for the purpose of energy metabolism, waste removal, immune and inflammatory processes. Vitamin C deficiency can lead to resistance to NO-induced vasodilation. Tetrahydrobiopterin (BH4) is a cofactor of inducible NO synthase (NOS) that oxidizes arginine via multiple steps generating citrulline and NO. Ascorbate increases NO synthesis.
How much do I need?
Research shows approximately 200mg per day is the optimal dosage of vitamin C for the average adult. When reviewing the adverse reactions associated with “high doses”; please note that the average retail vitamin C supplement is 1000mg per serve and it is common practice for healthcare practitioners and retailers to recommend from 1000mg to 6000mg per day. In children, it is common for 150 to 250mg per serve and a recommendation of 1000 to 3000mg per day. The “high doses” listed in the literature are as low as 500 to 1000mg per day. MNK has 37.38mg per serve.
Large doses, 500 mg per day or more can cause nausea, pyrosis, and diarrhea enhanced urination with a feeling of burning. Large doses, 500mg per day or more can cause Erythrocyte hemolysis in people suffering with glucose-6-phosphate dehydrogenase (G-6-PD) and vitamin B12 deficiency. Large doses, 500mg per day or more can increase your risk of kidney stones as it may impair the excretion of weak acids and bases, which may result in the precipitation of cystinate and urate depositions in the urinary tract, leading to the formation of renal calculi. 1000mg per day can elevate blood and urinary oxalic acid concentrations to a degree increasing the risk of calculi formation from calcium oxalate. Large doses >500mg per day should not be administered in chronic renal failure, cystinuria, predisposition to gout, urate and oxalate calculosis. By acidifying the urine, it can lead to the crystallization of urine excreted p-aminosalicylic acid and sulphonamides.
Vitamin C increases amphetamine derivative and tricyclic antidepressant drug elimination by inhibiting their reabsorption in renal tubules. Vitamin C should not be taken around the time of pathology testing as it can create false results in the determinations of bilirubin, glucose, or creatinine concentrations, and LDH or AspAT activity. High doses of vitamin C inhibit copper absorption and inhibit copper-containing ceruloplasmin and the powerful antioxidant superoxide dismutase (Cu, Zn-SOD) activities.
Vitamin C enhances iron absorption to the harmful degree in those with increased blood iron concentration, and with hemochromatosis, sideroblastic anemia or thalassemia (where the symptoms exacerbate). Vitamin C can also lead to the release of iron from its tissue resources, i.e., stored in ferritin. The excess unbound iron accumulates in your tissues, liver, and skin, irritates gastrointestinal mucosa, causes intoxication, and contributes to the pro-oxidant effects of vitamin C. Vitamin C-induced pro-oxidant effects can occur mainly due to the reduction of metals, in particular, iron and copper. Reduced ions of the metals contribute to generating extremely potent (ROS) reactive oxygen species such as hydrogen peroxide. Those reactions can repeat cyclically; they lead to the generation of large concentrations of ROS which stimulate free radical reactions and show mutagenic and neurotoxic activity. This is the reason why this vitamin should not be used along with iron and copper salts
High dose strategies for vitamin C orally or intravenously are used specifically to induce the pro-oxidant action to blast tissues with reactive oxygen species. This is a strategy used in treatments for HIV and AIDS, cancer and chronic viral infections but further research is needed to test efficacy and safety. High doses of vitamin C orally or IV are not loading up antioxidant defense systems as often promoted for. It is used this way specifically for its pro-oxidant effects. Taking large doses of vitamin C may lead to vitamin C tolerance or even dependency. The withdrawal from such doses may result in deficiency symptoms, including scurvy; therefore, the doses must be reduced gradually to avoid withdrawl symtpoms.
part 3 coming soon