Category Archives: Diet and Nutrition

Diet and Nutrition, Histamine and Methylation, Undermethylation

Treat Elevated Histamine, Naturally

Posted on by Epstein
treat elevated histamine naturally
06
Jul

Symptoms of elevated histamine

More and more these days, people suffer from what are simply referred to simply as "allergies." Allergies are reactions by the body to exposure by foods and  other elements that cause the body to release histamine and other biochemical elements such as tryptase, heparin, serotonin and immunoglobulins. The effect of these compounds on the tissues are known as an allergic reaction.

symptoms of mcas mcad high histamine

Treat symptoms of elevated histamine naturally

To treat symptoms of elevated histamine, the best approach is to become familiar with foods and those that contain high levels of histamine or that cause the body to produce high levels of histamine.

High serum levels of histamine lead to common inflammation conditions such as hives, skin rash, diarrhea, runny nose, high stomach acid, nausea, reflux, migraines, irregular menstrual periods, red itchy eyes, etc.

foods high in histamine

Histamine Intolerance and Mast Cell Activation Disorder

Not all histamine reactions are due to allergies. There are a number of conditions that lead to an histamine intolerance. That is true whether the histamines are derived from foods or by our excessive production of, or sensitivity to histamines.

Histamine intolerance, also referred to as histaminosis or HIT or Mast Cell Activation Disorder, may be caused by an increased release or by a lack of histamine degradation enzymes. Histamine intolerance isn't a true allergic reaction. Instead, it refers to a reaction some people experience to foods that have high levels of naturally occurring histamine. The enzymes are required for breaking down ingested or naturally produced histamines.

  • DAO - diamine oxidase. This is the histamine lowering enzyme produced in the intestinal lining and by the kidneys. It circulated through the plasma and serum. Managing histamine intolerance may be addressed by supplementation with enzymes such as DAO
  • HNMT - Histamine N-methyl transferase is a histamine degrading enzyme and it is found within the whole blood cells. Supplements used for symptoms associated with high red blood cell histamine including SAMe and methionine that lower histamine levels.
how SAMe methionine lowers histamine

By treating whole blood histamine with nutrients, serotonin and dopamine levels may be corrected. 

Second Opinion Physician specializes in treating mood disorders and symptoms associated with histamine imbalance within the red blood cells. Because these cells rely on the "methyl" containing enzyme (HNMT), a whole blood histamine level is useful in establishing one's "methylation status." High whole blood histamine indicates undermethylation whereas low blood histamine indicated overmethylation. Presenting his findings at the American Psychiatric Association Conference in 2015, Dr William Walsh, PhD. describes the mood related disorders of high blood histamine and low blood histamine, referring to them as undermethylation and overmethylation respectively.

In managing depression and other symptoms affected by conditions associated with histamine levels we are not specifically treating histamine. We use whole blood histamine blood levels as a measure of over or under methylation status.

Because undermethylators have low functioning levels of serotonin and dopamine, supplementing with methionine and SAMe we can increase the activity of key neurotransmitters. In addition to reducing whole blood levels of histamine, they are important regulators of enzymes involved in serotonin and dopamine reuptake. Overmethylators who, with low whole blood histamine are typically high serotonin depressives. They more frequently benefit from supplements that reduce neurotransmitter activity.

Symptoms of Elevated Whole Blood Histamine

high histamine undermethylation symptoms

Symptoms of Low Whole Blood Histamine

symptoms of low histamine schizophrenia

Test whole blood histamine through this website.

It's a very important test!

Second Opinion Physician offers lab testing for histamine as well as consultations by phone to discuss the results of your lab test. Once ordered you will receive a requisition to take to your nearest Lab Corp.

Related Posts:

Folates are typically not good for depressives with low blood histamine levels.

Low Dose Naltrexone LDN for Symptoms of Histamine Overload

Histamines and The Role They Play in Depression and Methylation

Additional Lab Tests for histamine, allergies, MCAS, histaminosis, and methylation:

mcas histamine lab test online

Other Single Item Tests

Histamine, Plasma (Chilled) or Urine 24hr

$120.00
Methylation Status Lab Test

Biotype Individual Tests

Histamine, Whole Blood

$65.00
parasite testing IgE immunoglobin allergy test

Other Single Item Tests

IgE Immunoglobin E, Total

$84.00
treat elevated histamine naturally

Other Single Item Tests

Tryptase Test – for MCAS (Mast Cell Activation Disorder)

$148.00
Diet and Nutrition, Histamine and Methylation, Walsh Podcasts and Videos

Bulletproof Radio; Dave Asprey Interviews William Walsh PhD

Posted on by Epstein
who is william walsh PhD
15
Feb

  • It’s too late to get healthy once you are already pregnant 00:06:10
  • We can directly affect brain transmitters with nutrients 00:08:00
  • How NAC helps the body and brain 00:10:30
  • We have enough knowledge to use nutrients and diet instead of drugs 00:17:50
  • The ability to edit our genes 00:22:00
  • Nutrients that can cause mischief in the brain 00:47:35
  • The importance of plasma zinc 00:57:00
  • Bigger Ideas:
  • What we can do with diet for young children 00:04:50
  • Why a zero carb diet is not a good idea 00:15:00
  • The next big breakthrough will be preserving the integrity of our DNA 00:19:20
  • Cancer is an event 00:25:00
  • The lay persons’ version of why Bipolar disorder happens 00:35:35
  • How to choose which supplements to take without lab tests 00:54:55

Walsh Protocol Lab Testing

Comprehensive Biotype Panel - The complete set of labs used by Walsh Practitioners for evaluating nutritional biotypes associated with mood disorders.


Click Here

Consultation with Second Opinion Physician

Complete evaluation of Walsh Panel by our Walsh-trained physician including Biotype Report, detailed supplements plan and discussion regarding test results.


Click Here

Links/Resources

Website: walshinstitute.org
Book: Nutrient Power: Heal Your Biochemistry and Heal Your Brain
Facebook: facebook.com/walshresearchinstitute
Twitter: @WalshResearch
YouTube: Walsh Institute Channel
Bulletproof Radio: Gain Control of Your Biochemistry #132

Diet and Nutrition, Histamine and Methylation, Mast Cell Activation Disorder

Foods and Supplements that Lower Plasma Histamine Levels

Posted on by Epstein
treat elevated histamine naturally
04
Feb

Foods and Antigens that Typically Raise Intestinal and Plasma Histamine

Histamine rich foods: Foods that are associated with high histamine levels include fermented foods such as sauerkraut, kombucha, pickles, wine, yogurt, mature cheeses and fermented soy products. It also includes cured, smoked and fermented meats such as salami and sausage, etc. Tomato paste, spinach and canned fish products also have high histamine levels. Citrus foods are histamine liberators which increase histamine release and so should also be avoided.

Histamine is chemically known as a "biogenic amine". Fermented foods have high levels of these biogenic amines. These are foods that are exposed to microbial decomposition as part of the fermentation or in storage. Lactic acid bacteria are the most problematic biogenic amine producers in fermentation. These bacteria break down amino acids into amine-containing compounds. Biogenic amines are commonly found in wines, cider, dairy, meat, fish, beer, spinach, tomatoes and yeast. Biogenic amines in the form of histamine are the product of bacteria breaking down amino acids. Control biogenic amines to treat elevated histamine

Histamine and Lectins
Foods such as potatoes are high in lectins. Lectins can bind the lining of the intestinal wall and cause leaky gut syndrome. Undigested lectins then enter the blood system and lead to antibody formation and which releases histamine. Foods high in lectins include:

·    White potatoes and unmodified potato starch
·    Tomatoes
·    Soy
·    Gluten containing grains
·    Legumes

Histamine and Probiotics
Probiotics in the digestive tract are responsible for producing many compounds in the body. There are bacterial strains that increase histamine as well as intestinal microbes that reduce histamine.

  • Probiotics that increases histamine
    • Lactobacillus casei
    • Lactobacillus reuteri
    • Lactobacillus bulgaricus

Foods, Supplements and Antigens that Lower Intestinal and Plasma Histamine

Histamine and Mast Cells
Histamine is released from “mast cells”. Mast cells are immune cells that line the mucous membranes of the sinuses, digestive tract, the skin, lungs, eyelids, and tissues surrounding blood vessels and nerves. Activation of mast cells plays a key role in asthma, rhinitis, eczema, itching, pain, autoimmunity and hives. Elevated mast cells are associated with female infertility and decreased sperm motility. Stabilize mast cells to treat elevated histamine.

Histamine INTOLERANCE results from a disequilibrium of accumulated histamine and the capacity for histamine degradation. Histamine is a biogenic amine that occurs to various degrees in many foods. In healthy persons, dietary histamine can be rapidly detoxified by amine oxidases, whereas persons with low amine oxidase activity are at risk of histamine toxicity. Diamine oxidase (DAO) is the main enzyme for the metabolism of ingested histamine. It has been proposed that DAO, when functioning as a secretory protein, may be responsible for scavenging extracellular histamine after mediator release. Conversely, histamine N-methyltransferase, the other important enzyme inactivating histamine, is a cytosolic protein that can convert histamine only in the intracellular space of cells. 

Diamine Oxidase DAO
This is an important enzyme that naturally lowers intestinal histamine and extracellular plasma histamine. DAO can be provided as a supplement to lower histamine levels. Symptoms of low DAO includes:

  • Skin irritations - hives, itching, rashes, eczema, psoriasis, and acne
  • Headaches/migraines
  • Painful menstrual periods
  • Gastrointestinal symptoms
  • Intolerance to fermented foods and alcohol
  • Mucous in sinuses
  • Asthma

Other supplements that either contain DAO or improve levels of DAO:

  • White Pea
  • Kidney, Placenta and Liver Glandular Extracts
  • Vitamin C
  • Vitamin B6
  • Pancreatic enzymes
  • Benadryl (works only temporarily, more histamine receptors will likely develop, potentially worsening condition.)

Supplements and OTC medicines that stabilize mast cells

  • Cromalyn sodium (Nasalcrom)
  • Quercitin
  • Curcumin (also decreases DAO)
  • Reishi mushroom
  • Yohimbine
  • Adrenaline
  • Eleuthero
  • Rutin
  • Theanine
  • Astragalus

Probiotics can be used to lower intestinal histamine:

Probiotics in the digestive tract are responsible for producing many compounds in the body. There are bacterial strains that increase histamine as well as intestinal microbes that reduce histamine.

  • Decreases histamine
    • Bifidobacterium infantis
    • Bifidobacterium lognum
    • Lactobacillus plantarum

A list of supplements that may be taken to lower plasma histamine and mast cell expression:

  • DAO diamine oxidase from natural sources (kidney glandular, placenta and White Pea are sources of naturally occuring DAO)
  • Probiotics B infantis, B longum, L plantarum
  • Vitamin C 
  • B6 (can also increase histamine carboxylase)
  • Avoid lectin in diet – potatoes and tomatoes
  • Avoid fermented foods
  • Cromolyn sodium– OTC mast cell stabilizer
  • Benadryl (but it lowers DAO and may ultimately cause increased histamine receptor levels)
  • Bromelain and Quercitin
  • Chocamine  – mast cell stabilizer
  • Improve adrenals with herbal and glandular supplements
  • Curcumin (also decreases DAO)
  • NAC N-acetyl cysteine
  • Catechins (green tea etc)
  • Fatty Acids (long chain and 
  • Micronutrients- Calcium, Iron, Magnesium Zinc, Phosphorus, B12, B6, Vitamin C, 
  • Various glandulars
  • Various herbs
  • White Pea
  • Reishi Mushrooms

Biotype Nutrients is a source for purchasing supplements to manage elevated histamine and MAST Cell disorder. The site offers many top name brands and quality sources.

DISCLAIMER - This is a site developed and owned by Second Opinion Physician for the benefit of persons treating elevated histamine and related conditions.

Tests for evaluating MCAS, Histaminosis, Methylation and Allergies

mcas histamine lab test online

Other Single Item Tests

Histamine, Plasma (Chilled) or Urine 24hr

$120.00
Methylation Status Lab Test

Biotype Individual Tests

Histamine, Whole Blood

$65.00
parasite testing IgE immunoglobin allergy test

Other Single Item Tests

IgE Immunoglobin E, Total

$84.00
treat elevated histamine naturally

Other Single Item Tests

Tryptase Test – for MCAS (Mast Cell Activation Disorder)

$148.00

Diet and Nutrition, Histamine and Methylation, Mast Cell Activation Disorder

LDN Low Dose Naltrexone for High Histamine

Posted on by Epstein
treat elevated histamine naturally
04
Feb

Low Dose Naltrexone LDN for Symptoms of Histamine Overload

Very low dosages of the pharmaceutical drug naltrexone is being used for histamine intolerance and other inflammatory conditions with great success. It is more commonly recommended in full strength, as an opiate receptor stimulator/blocker for pain syndromes. Because it is a receptor agonist and antagonist, it has a unique characteristic of treating pain without the risk of narcotic overdose. It is also used for treating heroin and other opiate overdoses its receptor antagonist effect allows it to bind some of the opiate receptors sites and block the effects of opiates. As a overdose treatment, most states allow over the pharmacy counter sales for a single, low dose therapy.

Below is a excerpt from a research publication that describes the mechanism of action and treatment benefits of naltrexone.

The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain
Jarred Younger,corresponding author Luke Parkitny, and David McLain

"Naltrexone, given at low dosages (in the range of 3–5 mg), has been demonstrated to reduce symptom severity in a small number of chronic conditions, including fibromyalgia (1), Crohn's disease (2, 3), multiple sclerosis (4, 5), and pruritus associated with systemic sclerosis (6). The use of naltrexone at this dosage range is typically referred to as low‐dose naltrexone (7). As an orally available compound that is structurally similar to naloxone, naltrexone may work to reduce disease severity by attenuating inflammatory processes (8). This antiinflammatory effect is distinct from the better‐known effect of naltrexone in the blockade of neuronal opioid receptors and may instead involve the antagonism of immune cell receptors, including microglia in the central nervous system (9, 10).

Microglia are the resident macrophages of the central nervous system, and the primary form of immune defense in the brain and spinal cord. The cells normally exist in a resting (ramified) state but are activated by a range of triggers, including cell death, peripheral inflammation, and infection (11). Once activated, microglia undergo drastic morphologic changes and produce proinflammatory factors, such as cytokines, excitatory amino acids, and nitric oxide (12). These inflammatory factors can interact with neurons via multiple channels (13) to cause hyperalgesia, fatigue, and other symptoms (14). The behavioral symptoms of activated microglia (classically called sickness behaviors) are very similar to the primary complaints of fibromyalgia, suggesting that activated microglia may underlie the condition. Fibromyalgia may therefore represent a state of hypersensitive microglial activity and heightened inflammation in the central nervous system. Compounds such as naltrexone, which are known to suppress microglial activity, may therefore be helpful in treating fibromyalgia. By antagonizing microioglial activity (likely via action on Toll‐like receptor 4), naltrexone may suppress the release of proinflammatory factors and thereby reduce pain and other symptoms of fibromyalgia."

Most functnal medicine practitioners are familiar with this LDN low dose naltrexone therapy and prescribe it via a compounding pharmacy. Cost ranges from $75-150 for a prescription. To save costs, some will take a single full strength Naloxone tablet of 50mg and dissolve in water and take 1/30th of this volume on a nightly basis.  This is not recommended as stability and consistency are not predictable. It is advisable to contact your physician for a properly prepared prescription.

What are Histamines and How Are They Related To Depression and Methylation

Food and Supplements that Lower Plasma Histamine

Treat Elevated Histamines Naturally

Tests available for histamine, immunoglobin, methylation and mast cell evaluation disorder MCAD:

mcas histamine lab test online

Other Single Item Tests

Histamine, Plasma (Chilled) or Urine 24hr

$120.00
Methylation Status Lab Test

Biotype Individual Tests

Histamine, Whole Blood

$65.00
parasite testing IgE immunoglobin allergy test

Other Single Item Tests

IgE Immunoglobin E, Total

$84.00
treat elevated histamine naturally

Other Single Item Tests

Tryptase Test – for MCAS (Mast Cell Activation Disorder)

$148.00
Diet and Nutrition, Epigenetics

Epigenetic Benefits of ALA in Treatment of Cancer

Posted on by Epstein
epigenetics.alpha.lipoic.acid
29
Aug

Extensively published researcher and clinician, Dr Berkson utilizes high doses of racemic ALA (IV and Orally) along with HCA to inhibit tumor cell formation.

Dr Berksen is doing awesome work reversing cancer by utilizing nutrients to effect epigenetics, inflammation and mitrochondrial activity. Utilizes high doses of racemic ALA (IV and Orally) along with HCA to inhibit ATP-citrate lyase, which is important in Acetyl CoA production. In tumor cells this plays a role in fatty acid formation which is vital to tumor growth.

His cancer protocol utilizes another exciting therapy – LDN – Low Dose Naltrexone – which helps regulate inflammation via the immune system through activation of microglia and endorphins. Full protocol also includes selenomethionine, HCA Garcinia Camboglia, Silamaryn and high doses of Vitamin C.

The Long-Term Survival of a Patient With Stage IV Renal Cell Carcinoma Following an Integrative Treatment Approach Including the Intravenous α-Lipoic Acid/Low-Dose Naltrexone Protocol

Burton M. BerksonMD, MS, PhD, Francisco Calvo Riera, MD,

First Published December 19, 2017 

The first key component in the patient’s treatment protocol was lipoic acid (ALA). IV ALA can reach much higher plasma levels than the oral form, with the oral capsules maintaining levels in between IV infusions. ALA has multiple activities; for instance, it is a powerful antioxidant and heavy metal chelator.9 It appears that 3 of its actions are relevant in this case: its anti-inflammatory activity, the effect on mitochondrial metabolism, and its epigenetic activity.

First, ALA may discourage the growth of cancer cells by its action involving the pro-inflammatory transcription factor, nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB).10

Unmitigated NF-κB activation can produce proliferation, angiogenesis, mutagenesis, metastasis, and chemo-radio resistance in malignant cells and leave them resistant to apoptosis.11 Patients with advanced cancer exhibit greatly elevated markers of oxidative stress and an unrelenting inflammatory process in part due to NF-κB activation.11 ALA inhibits NF-κB, blunting these deleterious effects and discouraging the unbridled growth of cancer cells.

Another significant interaction of ALA is with the pyruvate dehydrogenase enzyme complex (PDHC) and its regulatory enzyme pyruvate dehydrogenase kinase (PDK). PDHC consists of 3 mitochondrial enzymes that sit in the intersection of cytoplasm and mitochondria, glycolysis and the Krebs cycle, and anaerobic and aerobic energy metabolism. PDHC converts cytoplasm-generated pyruvate into acetyl CoA, which then enters the Krebs cycle. ALA is the necessary cofactor for PDHC, and without ALA there is no energy produced in the mitochondria.

PDK phosphorylates and inhibits PDHC, regulating its activity. ALA inhibits PDK, and by doing so it further increases PDHC activity.12,13

These enzymes are involved in a metabolic peculiarity of cancer cells, the so-called Warburg effect, also called “aerobic glycolysis,” a phenotype rather common to malignancies: cancer cells preferentially metabolize glucose and pyruvate into lactic acid, even in the presence of oxygen.14 This increase in glycolysis might favor the formation of amino acid and nucleotide precursors, important for a rapidly proliferating cell, whose importance might offset the disadvantage of a reduced ATP production.15,16

McFate et al17 have shown that inhibition of PDHC activity contributes to the Warburg metabolic and malignant phenotype in human head and neck squamous cell carcinoma. This inhibition occurred by an enhanced expression of pyruvate dehydrogenase kinase (PDHK). Knockdown of PDHK restored pyruvate dehydrogenase (PDH) activity, reverted the Warburg metabolic phenotype, decreased invasiveness, and inhibited xenograft tumor growth in nude mice.

Clear cell RCC is characterized by the constitutive upregulation of the hypoxia inducible factor-1.18 Hypoxia inducible factor-1 has been shown to promote the Warburg effect in several cancers, including clear cell RCC,18 in part due to the activation of PDHK (one of its target genes19), and subsequent inhibition of PDH. Recently, Lim et al20 demonstrated that in this type of cancer, most of the 10 tumor samples studied had an elevated PDHK enzyme level, and a decreased PDHC activity, when compared with patient-matched normal tissue.

Schell et al21 furthered this idea by implying that the inhibition of the Warburg effect in colon cancer cells was associated with decreased cancer cell xenograft growth in nude mice.

Studying a related issue concerning these enzymes, Kaplon et al22 demonstrated that PDH is a crucial mediator of malignant cell senescence induced by BRAFV600E, a protein kinase and oncogene that is often mutated in melanoma and other cancers. This BRAFV600E-induced senescence was accompanied by simultaneous inhibition of PDHK. Enforced normalization of PDHK inhibited PDH and abolished oncogene-induced senescence, thereby allowing BRAFV600E-driven melanoma growth.

Since ALA inhibits PDHK and activates PDHC, the metabolic peculiarity of cancer cells described by Warburg may be mitigated, and it is likely that the overall cancer growth program may be altered. It is also possible, according to Kaplon’s work, that tumor cell senescence may also be promoted by ALA’s action on these enzymes.

Another potential antineoplastic action of ALA concerns its epigenetic activity. ALA can inhibit histone deacetylase (HDAC) activity in human tumor cells.23,24 Histone acetylation and deacetylation are important components in gene regulation.

An active avenue of cancer research involves inhibitors of HDACs, with drugs such as vorinostat.

Recently, it has been found that PDH, thought to be an exclusive mitochondrial enzyme, is also present and functional in the nucleus, probably translocated from the mitochondrion.25 Inhibition of nuclear PDH in isolated nuclei decreased the acetylation of histone lysine residues. This nuclear PDH has also lipoic acid as cofactor, so ALA provides a source for nuclear acetyl-CoA synthesis required for histone acetylation and epigenetic regulation.

These epigenetic modifications give ALA the capacity of influencing, at a genetic level, tumor behavior and growth. In other words, cancer is not only a genetic disease but is also a metabolic disease. ALA seems to address both of these components.

IV vitamin C was also part of the patient’s treatment protocol. Integrative medical doctors have administered this agent for many years with some positive case history reports. Some of these results include reversal of pulmonary metastases from RCC and from hepatocellular carcinoma.26,27

HCA is an extract from the citrus fruit, Garcinia cambogia. Not only it inhibits pancreatic α-amylase and intestinal α-glucosidase, but also inhibits ATP-citrate lyase,28 a cytoplasmic enzyme that catalyzes the generation of acetyl-CoA from mitochondrial-generated citrate.29 Acetyl-CoA is a vital building block for the endogenous biosynthesis of fatty acids, cholesterol, and isoprenoids.

Find out more about the work and practice of Dr Beckson here 

 

 

Diet and Nutrition

Scientific Article on Zinc Deficiency

Posted on by Epstein

treating zinc deficiency

Excellent Open Access Scientific Article on Zinc Deficiency

The article was reformatted so that Item 5 goes after 1, as deficiency is the question of concern here. As much as 1/3 of the worlds population is believed to be deficient in zinc. Toxicity is not a common problem as described below.

Int. J. Environ. Res. Public Health 2010, 7(4), 1342-1365; doi:10.3390/ijerph7041342

Review
The Essential Toxin: Impact of Zinc on Human Health
Laura M. Plum , Lothar Rink and Hajo Haase *
Institute of Immunology, Medical Faculty, RWTH Aachen University, Pauwelstrasse 30, 52074 Aachen, Germany; E-Mails: lplum@ukaachen.de (L.M.P.); lrink@ukaachen.de (L.R.)
*
Author to whom correspondence should be addressed; E-Mail: hhaase@ukaachen.de; Tel.: +49-241-808-0205; Fax: +49-241-808-2613.
Received: 27 January 2010; in revised form: 8 March 2010 / Accepted: 10 March 2010 /
Published: 26 March 2010

Abstract

Compared to several other metal ions with similar chemical properties, zinc is relatively harmless. Only exposure to high doses has toxic effects, making acute zinc intoxication a rare event. In addition to acute intoxication, long-term, high-dose zinc supplementation interferes with the uptake of copper. Hence, many of its toxic effects are in fact due to copper deficiency. While systemic homeostasis and efficient regulatory mechanisms on the cellular level generally prevent the uptake of cytotoxic doses of exogenous zinc, endogenous zinc plays a significant role in cytotoxic events in single cells. Here, zinc influences apoptosis by acting on several molecular regulators of programmed cell death, including caspases and proteins from the Bcl and Bax families. One organ where zinc is prominently involved in cell death is the brain, and cytotoxicity in consequence of ischemia or trauma involves the accumulation of free zinc. Rather than being a toxic metal ion, zinc is an essential trace element. Whereas intoxication by excessive exposure is rare, zinc deficiency is widespread and has a detrimental impact on growth, neuronal development, and immunity, and in severe cases its consequences are lethal. Zinc deficiency caused by malnutrition and foods with low bioavailability, aging, certain diseases, or deregulated homeostasis is a far more common risk to human health than intoxication.

Keywords:

toxicity; zinc; essential trace element

1. Introduction

In the periodic table of the elements, zinc can be found in group IIb, together with the two toxic metals cadmium and mercury. Nevertheless, zinc is considered to be relatively non-toxic to humans [1]. This is reflected by a comparison of the LD50 of the sulfate salts in rats. According to the Toxnet database of the U.S. National Library of Medicine, the oral LD50 for zinc is close to 3 g/kg body weight, more than 10-fold higher than cadmium and 50-fold higher than mercury [2]. An important factor seems to be zinc homeostasis, allowing the efficient handling of an excess of orally ingested zinc, because after intraperitoneal injection into mice, the LD50 for zinc was only approximately four-fold higher than for cadmium and mercury [3]. In contrast to the other two metals, for which no role in human physiology is known, zinc is an essential trace element not only for humans, but for all organisms. It is a component of more than 300 enzymes and an even greater number of other proteins, which emphasizes its indispensable role for human health. Optimal nucleic acid and protein metabolism, as well as cell growth, division, and function, require sufficient availability of zinc [4].

In this review, we will give a brief summary of zinc homeostasis, followed by a description of the effects of acute zinc intoxication and the consequences of long-term exposure to elevated amounts of zinc. Besides systemic intoxication, there exists evidence for a physiological involvement of endogenous zinc in toxicity on the cellular level, e.g., regulating apoptosis in many different cell types, and having a prominent role in neuronal death. In the end, we will also briefly discuss the detrimental effects of zinc deficiency, because, unless they are exposed to zinc in the workplace or by accident, healthy individuals are at far greater risk of suffering from the adverse effects associated with zinc deficiency than from those associated with intoxication.

5. Zinc Deficiency

As discussed above, systemic zinc toxicity is not a major health problem. On the other hand, due to its essentiality, a lack of this trace element leads to far more severe and widespread problems. Both, nutritional and inherited zinc deficiency generate similar symptoms [164], and clinical zinc deficiency causes a spectrum from mild and marginal effects up to symptoms of severe nature (Figure 2) [165].

Human zinc deficiency was first reported in 1961, when Iranian males were diagnosed with symptoms including growth retardation, hypogonadism, skin abnormalities, and mental lethargy, attributed to nutritional zinc deficiency [166]. Later studies with some Egyptian patients showed remarkably similar clinical features [167]. Additional studies in the ongoing years manifested zinc deficiency as a potentially widespread problem in developing as well as in industrialized nations [168].

Severe zinc deficiency can be either inherited or acquired. The most severe of the inherited forms is acrodermatitis enteropathica, a rare autosomal recessive metabolic disorder resulting from a mutation in the intestinal Zip4 transporter [169]. Symptoms of this condition include skin lesions, alopecia, diarrhea, neuropsychological disturbances, weight loss, reduced immune function, as well as hypogonadism in men, and can be lethal in the absence of treatment [170].

Acquired severe zinc deficiency has been observed in patients receiving total parental nutrition without supplementation of zinc, following excessive alcohol ingestion, severe malabsorption, and iatrogenic causes such as treatment with histidine or penicillamine [165]. The symptoms are mostly similar to those arising during acrodermatitis enteropathica.

Some reports indicate the existence of another group of inherited disorders of zinc metabolism. They lead to baseline zinc plasma levels above 300 μg/100 mL, more than three times the physiological level, while iron and copper levels stay normal [171–173]. Even though this exceeds the amount normally found in serum after zinc intoxication, symptoms range from none to severe anemia, growth failure, and systemic inflammation, and resemble zinc deficiency rather than chronic or acute intoxication [172–175]. The elevated zinc levels have been attributed to excessive binding to serum proteins, e.g., by albumin [171,173], or to overexpression of the zinc-binding S100 protein calprotectin [172,174]. Hence, the large amounts of zinc in the serum of these patients are sequestered by proteins, potentially even depleting biologically available zinc [175].

Clinical manifestations of moderate zinc deficiency are mainly found in patients with low dietary zinc intake, alcohol abuse, malabsorption, chronic renal disease, and chronic debilitation. Symptoms include growth retardation (in growing children and adolescents), hypogonadism in men, skin changes, poor appetite, mental lethargy, delayed wound healing, taste abnormalities, abnormal dark adaptation, and anergy [165].

Moderate zinc deficiency can also occur as a consequence of sickle cell disease [176]. Hyperzincuria and a high protein turnover due to increased hemolysis lead to moderate zinc deficiency in these patients, which causes clinical manifestations typical for zinc deficiency, such as growth retardation, hypogonadism in males, hyperammonemia, abnormal dark adaptation, and cell-mediated immune disorder [177] connected with thymic atrophy [178].

In mild cases of zinc deficiency, slight weight loss, oligospermia and hyperammonemia were observed [165]. One population in which mild zinc deficiency occurs with high prevalence, even in industrialized countries, are the elderly. Here, a significant proportion has reduced serum zinc levels, and zinc supplementation studies indicate that this deficiency contributes significantly to increased susceptibility to infectious diseases [44].

The overall frequency of zinc deficiency worldwide is expected to be higher than 20% [179]. In developing countries, it may affect more than 2 billion people [166,180–182]. Furthermore, it has been estimated that only 42.5% of the elderly (≥71 years) in the Unites States have adequate zinc intake [183]. This widespread occurrence combined with the variety of clinical manifestations makes zinc deficiency a serious nutritional problem, which has a far greater impact on human health than the relatively infrequent intoxication with zinc.

6. Conclusions

Zinc is an essential trace element, and the human body has efficient mechanisms, both on systemic and cellular levels, to maintain homeostasis over a broad exposure range. Consequently, zinc has a rather low toxicity, and a severe impact on human health by intoxication with zinc is a relatively rare event.

Nevertheless, on the cellular level zinc impacts survival and may be a crucial regulator of apoptosis as well as neuronal death following brain injury. Although these effects seem to be unresponsive to nutritional supplementation with zinc, future research may allow influencing these processes via substances that alter zinc homeostasis, instead of directly giving zinc.

Whereas there are only anecdotal reports of severe zinc intoxication, zinc deficiency is a condition with broad occurrence and potentially profound impact. Here, the application of “negative zinc”, i.e., substances or conditions that deplete the body of zinc, constitute a major health risk. The impact ranges from mild zinc deficiency, which can aggravate infections by impairing the immune defense, up to severe cases, in which the symptoms are obvious and cause reduced life expectancy.

 

2. Zinc Homeostasis

The human body contains 2–3 g zinc, and nearly 90% is found in muscle and bone [5]. Other organs containing estimable concentrations of zinc include prostate, liver, the gastrointestinal tract, kidney, skin, lung, brain, heart, and pancreas [6–8]. Oral uptake of zinc leads to absorption throughout the small intestine and distribution subsequently occurs via the serum, where it predominately exists bound to several proteins such as albumin, α-microglobulin, and transferrin [9].

On the cellular level, 30–40% of zinc is localized in the nucleus, 50% in the cytosol and the remaining part is associated with membranes [4]. Cellular zinc underlies an efficient homeostatic control that avoids accumulation of zinc in excess (see also Figure 1a). The cellular homeostasis of zinc is mediated by two protein families; the zinc-importer (Zip; Zrt-, Irt-like proteins) family, containing 14 proteins that transport zinc into the cytosol, and the zinc transporter (ZnT) family, comprising 10 proteins transporting zinc out of the cytosol [10].

Ijerph 07 01342f1 1024
Figure 1. Cellular zinc homeostasis and its impact on cytotoxicity (A) Cellular zinc homeostasis is mediated by three main mechanisms. First, by transport through the plasma membrane by importers from the Zip-family, and export proteins from the ZnT-family. Second, by zinc-binding proteins such as metallothionein. Third, by transporter-mediated sequestration into intracellular organelles, including endoplasmic reticulum, Golgi, and lysosomes. Tight control of zinc homeostasis is required for maintenance of cellular viability, whereas deregulation leads to cell death. (B) A particular role in intracellular zinc homeostasis is played by the metallothionein/thionein-system. Free and loosely bound zinc ions are bound by the apo-protein thionein (Tred), to form metallothionein (MT). Elevated levels of free zinc ions can bind to zinc finger structures of the metal-regulatory transcription factor (MTF)-1, thus inducing the expression of thionein. Additionally, oxidation of thiols by reactive oxygen (ROS) or nitrogen (RNS) species triggers the formation of the oxidized protein thionin (Tox) with concomitant release of zinc.Click here to enlarge figure

The same transporter families also regulate the intracellular distribution of zinc into the endoplasmic reticulum, mitochondria, and Golgi. In addition, many mammalian cell types also contain membrane-bound vesicular structures, so-called zincosomes. These vesicles sequester high amounts of zinc and release it upon stimulation, e.g., with growth factors [11,12].

Finally, metallothioneins (MTs) play a significant role in zinc homeostasis by complexing up to 20% of intracellular zinc (Figure 1b) [13,14]. MTs are ubiquitous proteins, characterized by a low-molecular weight of 6–7 kDa, high cysteine content, and their ability to complex metal ions. One MT molecule can bind up to seven zinc ions. Through different affinities of the metal ion binding sites, it can act as a cellular zinc buffer over several orders of magnitude [15]. Dynamic regulation of cellular zinc by MT results from the synthesis of the apo-form thionein (T) in response to elevated intracellular zinc levels by triggering the metal response element-binding transcription factor (MTF)-1 [16]. In addition, oxidation of cysteine residues can alter the number of metal binding thiols, connecting redox and zinc metabolism. An in-depth discussion of this complex subject can be found in a recent review [17].

3. Exposure to Zinc

There are three major routes of entry for zinc into the humn body; by inhalation, through the skin, or by ingestion [18]. Each exposure type affects specific parts of the body (Figure 2) and allows the uptake of different amounts of zinc.

Figure 2. Comparison of the effects of zinc intoxication versusdeficiency. Intoxication by excessive exposure to, or intake of, zinc (left hand side), and deprivation of zinc by malnutrition or medical conditions (right hand side), have detrimental effects on different organ systems. Effects that could not be attributed to a certain organ system or affect several organs are classified as systemic symptoms.Click here to enlarge figure

3.1. Exposure by Inhalation

Inhalation of zinc-containing smoke generally originates from industrial processes like galvanization, primarily affecting manufacture workers. In addition, military smoke bombs contain zinc oxide or zinc chloride, making soldiers a group in which several cases of inhalation of zinc-containing fumes were described. For example, Homma and colleagues reported a case of two soldiers who developed adult respiratory distress syndrome (ARDS) upon exposure to a zinc chloride-containing smoke bomb [19]. The two men died 25 and 32 days after the accident, respectively. Another soldier was exposed to concentrated zinc chloride for several minutes during military training [20]. He also developed ARDS 48 h after exposure. After tracheal intubation and mechanical ventilation for eight days, he left the hospital, and four months after the incident he returned to work without any respiratory disorder [20]. There are a few additional reports of related incidents with smoke bombs having similar effects on the respiratory tract [21,22].

However, in none of the incidents there was unequivocal evidence that zinc was the main cause for the respiratory symptoms. Not only was no information about the concentrations available, but also the inhaled smoke contained several other ingredients besides zinc chloride. In addition, zinc chloride is generally caustic, so the effects could have risen from the specific properties of the compound, rather than being a direct effect of zinc intoxication.

The most widely known effect of inhaling zinc-containing smoke is the so-called metal fume fever (MFF), which is mainly caused by inhalation of zinc oxide. This acute syndrome is an industrial disease which mostly occurs by inhalation of fresh metal fumes with a particle size <1 μm in occupational situations such as zinc smelting or welding [23]. Symptoms of this reversible syndrome begin generally a few hours after acute exposure and include fever, muscle soreness, nausea, fatigue, and respiratory effects like chest pain, cough, and dyspnea [24]. The respiratory symptoms have been shown to be accompanied by an increase in bronchiolar leukocytes [23]. In general, MFF is not life-threatening and the respiratory effects disappear within one to four days [25].

Development of MFF is connected to the exposure level, but very little data is available concerning the zinc concentrations that trigger this syndrome [26]. Two volunteers developed MFF as a consequence of acute inhalation (10–12 minutes) of 600 mg zinc/m3 as zinc oxide [27]. Hammond and colleagues reported about workers who had shortness of breath and chest pain 2–12 hours following exposure to 320–580 mg zinc/m3 as zinc oxide [28]. Only small changes in forced expiratory flow were observed after exposure to 77 mg zinc/m3 (15–30 minutes) as zinc oxide [29]. Several reports of exposures to lower concentrations of zinc oxide (14 mg/m3 for eight hours, 8–12 mg zinc/m3 for up to three hours and 0.034 mg zinc/m3 for six to eight hours) did not result in symptoms of metal fume fever [28,30,31]. Today, the permissible exposure limit according to the Occupational Safety and Health Administration (OSHA) is 5 mg/m3 for zinc oxide (dusts and fumes) in workplace air during an 8-hour workday, 40-hour work week [32].

3.2. Dermal Exposure

Dermal absorption of zinc occurs, but the number of studies is limited and the mechanism is still not clearly defined. Agren and colleagues pointed out that the pH of the skin, the amount of zinc applied, and its chemical speciation influence the absorption of zinc [33,34].

In a study in which a 25% zinc oxide patch (2.9 mg/cm2) was placed on human skin for 48 hours, there was no evidence of dermal irritation [33]. In another study comparing the dermal effect of different zinc compounds in mice, rabbits, and guinea pigs, zinc chloride was clearly the strongest irritant, followed by zinc acetate, causing moderate, and zinc sulfate, causing low irritations. Consistent with the study by Agren, zinc oxide did not show any irritant effect on skin [35].

As mentioned above, zinc chloride is caustic, and the irritation does not necessarily indicate a toxic effect of zinc. In contrast to a potentially harmful effect of zinc on skin, it should be noted that zinc is a well-known supplement for topical treatment of wounds and several dermatological conditions [34,36–38]. Based on the existing data, it can be concluded that dermal exposure to zinc does not constitute a noteworthy toxicological risk.

3.3. Oral Exposure

Due to its nature as an essential trace element, oral uptake of small amounts of zinc is essential for survival. The recommended dietary allowance (RDA) for zinc is 11 mg/day for men and 8 mg/day for women [39]. Lower zinc intake is recommended for infants (2–3 mg/day) and children (5–9 mg/day) because of their lower average body weights [39]. This is significantly below the LD50 value, which has been estimated to be 27 g zinc/day humans based on comparison with equivalent studies in rats and mice [18]. In general, uptake of such an amount is unlikely, because approximately 225–400 mg zinc have been determined to be an emetic dose [40]. However, there is one published report of a woman who died after oral intake of 28 g zinc sulfate. After ingestion, she started vomiting and developed tachycardia as well as hyperglycemia. She died five days later of hemorrhagic pancreatitis and renal failure [41].

Immediate symptoms after uptake of toxic amounts of zinc include abdominal pain, nausea, and vomiting. Additional effects include lethargy, anemia, and dizziness [42]. Particular effects of excessive oral zinc exposure are discussed in detail below.

Gastrointestinal Effects

The gastrointestinal tract is directly affected by ingested zinc, before it is distributed through the body. Therefore, multiple gastrointestinal symptoms after oral uptake of zinc have been reported. Brown et al.described several cases in which high zinc ingestion resulted from storage of food or drink in galvanized containers. Ingestion was caused by the moderately acidic nature of the food or drink, enabling the removal of sufficient zinc from the galvanized coating. The resulting symptoms included nausea and vomiting, epigastric pain, abdominal cramps, and diarrhea [40].

In a study by Samman and Roberts, symptoms such as abdominal cramps, vomiting and nausea occurred in 26 of 47 healthy volunteers following ingestion of zinc sulfate tablets, containing 150 mg elemental zinc, for six weeks [43]. However, similar doses have been used in several other zinc supplementation studies without comparable side effects [44].

In addition to zinc sulfate, other zinc compounds like zinc oxide and zinc gluconate also have a similar impact on the gastrointestinal system [45–47]. A 39-year-old man showed nausea, vomiting, and abdominal pain six hours after ingesting 150 g of a 10% zinc oxide lotion, but without signs of systemic toxicity. Furthermore, he developed gastroduodenal corrosive injury. The symptoms persisted for three days and on the fifth day of admission, the corrosive injury showed regression without cicatrization [47].

Zinc-Induced Copper Deficiency

Taking up large doses of supplemental zinc over extended periods of time is frequently associated with copper deficiency [48–50]. This correlation seems to be caused by the competitive absorption relationship of zinc and copper within enterocytes, mediated by MT. The expression of MT is upregulated by high dietary zinc content, and MT binds copper with a higher affinity than zinc. Consequently, available copper ions are bound by MT and the resulting complex is subsequently excreted [51,52]. Oestreicher and Cousins stated that the dietary intake of different doses of copper and zinc did not significantly alter the absorption of the other metal, as long as they were given at the same ratio, irrespective if 1 mg/kg copper and 5 mg/kg zinc, or up to 36 mg/kg copper together with 180 mg/kg zinc were given [53]. Nevertheless, copper absorption is depressed when zinc is given in high excess over copper [54].

Frequent symptoms of copper deficiency include hypocupremia, impaired iron mobilization, anemia, leukopenia, neutropenia, decreased superoxide dismutase (SOD) (particularly erythrocyte SOD (ESOD)), ceruloplasmin as well as cytochrome-c oxidase, but increased plasma cholesterol and LDL:HDL cholesterol and abnormal cardiac function [55–57].

Furthermore, Irving and colleagues reported the case of a 19-year old woman who was supplemented with two doses of 50 mg zinc per day as part of a treatment of Hallervorden–Spatz syndrome, leading to a total daily intake of about 121.25 mg of zinc for more than 5 years, corresponding to approximately 15 times the RDA. Her daily intake of copper was 2 mg, which was approximately twice the RDA. As a result, she was markedly anemic and had severe neutropenia. Zinc-induced copper deficiency was confirmed by elevated serum zinc and low copper and ceruloplasmin serum levels. Four weeks after zinc therapy was stopped, all hematological and trace-metal parameters showed strong trends toward normalization and were normal after eight months [58].

Prasad and colleagues reported several cases of patients with sickle cell anemia who received 150 mg zinc/day and consequently showed low plasma copper, low ceruloplasmin, leukopenia, and anemia [59]. Another case report described a 31-year-old schizophrenic man who had been ingesting coins for 10 years [60]. He entered the hospital with symptoms including nausea, vomiting, and abdominal pain. Furthermore, profound anemia, neutropenia, and virtually absent serum copper and ceruloplasmin levels together with elevated zinc levels were diagnosed. Upon X-ray examination a large number of coins (totaling $22.50) were identified and surgically removed. Following the surgery, anemia and copper deficiency rapidly resolved. His copper deficiency was attributed to the ingestion of pennies, which since 1982 are composed of 98% zinc and 2% copper [60]. Several additional reports of zinc-induced copper deficiency leading to anemia and several other cytopenias were reviewed by Fiske and colleagues [55].

The mechanism by which copper deficiency induces anemia is based on the requirement of copper for several enzymes involved in iron transport and utilization and, therefore, in heme synthesis. For example, ceruloplasmin is a ferroxidase that binds copper and converts ferrous to ferric iron, allowing it to bind to transferrin and be transported. Cytochrome-c oxidase is also dependent on copper, and is required for the reduction of ferric iron to be incorporated into the heme molecule [61–63]. In addition to interference with heme synthesis, copper deficiency causes approximately 85% reduction of ESOD in the red blood cell (RBC) membrane, decreasing RBC survival time [64].

Whereas a recent meta-analysis found no general effect of zinc supplementation on serum lipoproteins [65], it may occur as a consequence of disturbed copper homeostasis. Copper deficiency is related to alterations of serum cholesterol levels [57]. In healthy men, a daily intake of 160 mg zinc/day decreased HDL cholesterol significantly [66,67]. Also, young women who ingested 100 mg zinc/day showed a reduction in HDL cholesterol [68]. A study with 24 men who were fed omnivorous diets that were deficient in copper (0.89 mg) and high in zinc (21.4 mg), i.e., a Zn:Cu ratio of 23.5, showed low plasma copper, ESOD and HDL cholesterol, while LDL cholesterol was elevated [69]. This study was stopped after 11 weeks because four participants experienced cardiac abnormalities. Klevay and colleagues fed one man an omnivorous diet providing a Zn to copper ratio ≥ 16 for 105 days. Plasma copper and ceruloplasmin decreased, whereas total cholesterol and LDL cholesterol increased [70]. This experiment was ended when arrhythmia was detected. Taking into account several additional studies, Sandstead suggested that cardiac abnormalities were associated with Zn to copper ratios ≥16 [57].

Zinc Supplementation and Cancer

Whereas several other metals are well-known carcinogens, zinc is not generally considered to be a causative agent for cancer development. In contrast, displacement of zinc from zinc-binding structures, e.g., finger structures in DNA repair enzymes, may even be a major mechanism for carcinogenicity of other metals such as cadmium, cobalt, nickel, and arsenic [71].

One well investigated example in which an involvement of zinc in cancer development was suggested is prostate cancer. Notably, zinc levels in prostate adenocarcinoma are significantly lower than in the surrounding normal prostate tissues, suggesting an implication of zinc in the pathogenesis and progression of prostate malignancy [72–74]. This is based on a down regulation of the zinc transporter Zip1, which is responsible for zinc uptake and accumulation in prostate cells [75,76].

Men with moderate to higher zinc intake may have a lower risk for prostate cancer, but the opposite may be true at extremely high doses and long-term supplementation [77]. A study by Leitzmann and colleagues examined the association between supplemental zinc intake and prostate cancer risk among 46,974 U.S. men. During 14 years, 2901 new cases of prostate cancer were observed, of which 434 were diagnosed as advanced cancer. Supplemental zinc intake at doses of up to 100 mg/day did not cause a higher prostate cancer risk, whereas long-term supplementation with higher doses increased the relative risk 2.9-fold [78]. This increased risk may not be due to direct carcinogenicity of zinc, because it is known that immunosuppression significantly increases the incidence of cancer, and, as discussed in the following paragraph, high doses of zinc can be immunosuppressive.

Immunological Effects

Sufficient availability of zinc is of particular importance to the immune system. Thereby, it plays a key role in multisided cellular and molecular mechanisms [79,80]. For instance, zinc influences the lymphocyte response to mitogens and cytokines, serves as a co-factor for the thymic hormone thymulin, and is involved in leukocyte signal transduction [81–83]. An influence of zinc excess on T cell function was observed in several in vitro studies. In cell culture, very high zinc concentrations (above 100 μM) in a serum-free culture medium stimulate monocytes to secrete pro-inflammatory cytokines [84], but actually inhibit T cell functions. In general, T cells have a lower intracellular zinc concentration and are more susceptible to increasing zinc levels than monocytes [85,86]. Also, in vitro alloreactivity was inhibited in the mixed lymphocyte reaction (MLC) after treatment with more than 50 μM zinc [87]. A similar inhibition was observed when the MLC was done ex vivo with cells from individuals that had been supplemented with 80 mg zinc per day for one week, indicating that zinc supplementation has the potential to suppress the allogeneic immune response at relatively low doses [88].

An in vivo study supported the finding that zinc excess can affect lymphocyte function. 83 healthy volunteers ingested 330 mg zinc/ day in three doses for a month. The treatment had a small but significant influence on the lymphocyte response to the mitogens phytohemagglutinin (PHA) and Concanavalin A (Con A). Interestingly, it was observed that zinc had an immuno-regulatory influence, i.e., it decreased the lymphocyte response in high responders and had an enhancing effect on low responders [89].

4. The Role of Zinc in Cell Death

In addition to the systemic toxic effects of zinc, this metal is also involved in the regulation of live and death decisions on the cellular level. First, we will discuss its role in apoptosis. Second, we will focus on an organ where zinc toxicity has been investigated in great detail, the brain.

4.1. Impact of Zinc on Apoptosis

The exact role of zinc in the regulation of apoptosis is ambiguous. A variety of studies indicate that, depending on its concentration, zinc can either be pro- or anti-apoptotic, and both, zinc deprivation and excess, can induce apoptosis in the same cell line [90–93].

The induction of apoptosis by high levels of intracellular zinc has been shown in different tissues and cell types [93–95]. Reports indicate that accumulation of intracellular zinc, either as a consequence of exogenous administration or release from intracellular stores by reactive oxygen species or nitrosation, activates pro-apoptotic molecules like p38 and potassium channels, leading to cell death [93,96–98]. Increased intracellular zinc levels may also induce cell death by inhibition of the energy metabolism [99,100].

Sensitive targets of zinc toxicity are the anti-apoptotic Bcl-2-like and pro-apoptotic Bax-like mitochondrial membrane proteins. In context of its apoptosis-inducing properties, zinc has been shown to increase the expression of Bax, leading to a decrease in the Bcl-2/Bax ratio [101]. As a consequence, dissipation of the mitochondrial membrane potential leads to the release of cytochrome-c from mitochondria into the cytosol [96,102–105].

The anti-apoptotic properties of zinc likely comprise two main mechanisms. First, zinc limits the extent of damage induced during oxidative stress, thereby suppressing signaling pathways resulting in apoptosis. Second, zinc directly affects several proteins and pathways that regulate apoptosis.

Consistent with the first issue, zinc deficiency has been shown to induce oxidative stress [106–108]. Mechanisms by which the redox-inert zinc protects cells against oxidative damage seem to include its property to protect sulfhydryl groups in proteins from oxidation [109]. Furthermore, by stabilizing lipids and proteins, zinc can preserve cellular membranes and macromolecules from oxidative damage. On the other hand, it has to be noted that elevated availability of zinc may also induce oxidative stress, and its impact on redox homeostasis may either be protective or promoting, depending on its availability [17].

With regard to the second mechanism, interaction of zinc with several apoptosis-regulating molecules has been reported. Zinc is a potent caspase-3 inhibitor [110] with an IC50 below 10 nM [111]. Furthermore, inhibition of caspases-6, -7, and -8 at low zinc concentrations was also shown, with caspase-6 being the most sensitive of the three [112].

Zinc deficiency can also induce apoptosis by disrupting growth factor signaling molecules such as ERK and Akt [113]. Other molecular targets for zinc are the anti-apoptotic Bcl-2-like and pro-apoptotic Bax-like mitochondrial membrane proteins. Zinc has been shown to increase the Bcl-2/Bax ratio, thereby increasing the resistance of the cells to apoptosis [114]. Consistent with this, in a study by Zalewski and colleagues apoptosis was induced in premonocytic cells by treatment with hydrogen peroxide. Supplementation with 1 mM zinc increased the ratio of Bcl-2 to Bax resulting in the inhibition of active caspase-3 and reduction of apoptosis [115]. Zinc-mediated apoptosis is abrogated by chelation with TPEN [116]. This is not undisputed, because it has also been shown in another study that zinc can increase the expression of Bax, leading to an decreased Bcl-2/Bax ratio and the release of cytochrome-c from mitochondria [101].

The influence of zinc on apoptosis is very complex and data are in part even contradictory. Amongst others, variables in this complex network are tissue and cell type, zinc concentration, expression of zinc transporters and zinc-binding proteins, other environmental circumstances like oxidative or nitrosative stress, and the involvement of multiple molecular targets with opposing functions.

4.2. Role of Zinc in Neuronal Death

A prominent and well investigated example for the control that zinc exerts on survival on the cellular level is the brain. This will now be discussed in more detail as an example of the mechanisms by which zinc can influence cellular survival.

Normally, homeostatic mechanisms should prevent zinc from accumulating in the brain to reach toxic concentrations as a result of excessive oral ingestion. However, there are reports of neurological symptoms following zinc intoxication, e.g., of a boy who showed lethargy and focal neurological deficits three days after he ingested 12 g of metallic zinc [117].

Many studies indicate that zinc acts as a neuromodulator [118–121]. On the other hand, experimental evidence indicates that endogenous zinc might be a relatively potent, rapidly acting neurotoxin, and, to a lesser extent, also a gliotoxin [122–126].

Zinc is stored in and released from vesicles in presynaptic terminals of a specific subset of neurons that also releases glutamate. Therefore, these neurons are defined as “gluzinergic” neurons [119, 127]. Zinc can be released from presynaptic terminals during synaptic transmission, enabling it to enter postsynaptic somata and dendrites of cells via zinc-permeable ion channels [105]. These channels include NMDA (N-methyl-D-aspartate)-gated channels [128], voltage-gated calcium channels [129,130] and the calcium-permeable AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)/kainate channel [131,132].

In addition to being sequestered in vesicles of presynaptic terminals in the gluzinergic neurons, zinc can also be bound to MT, especially MT-III, in perikarya as well as being taken up by mitochondria [133]. The MT-III isoform is found only in the brain and it is abundant in the gluzinergic neurons [134,135].

Exposure to 300–600 μM zinc for 15 minutes results in extensive neuronal death in cortical cell culture [136]. Considering that neurons store high amounts of free zinc in their terminals [137] that are released upon depolarization [138,139], zinc may play an active role in neuronal injury. Furthermore, membrane depolarization, which is associated with acute brain injury [140], greatly increases the potency of zinc to act as a neurotoxin [141]. Weiss et al. confirmed this by showing that depolarization with high concentrations (25 mM) of potassium media requires just a five minute-exposure to 100 μM zinc to kill all neurons in cortical cell culture [131].

Zinc has been described as a critical component of the excitotoxic cascade occurring after ischemia, seizures, and head trauma [141–143]. The first study providing evidence that zinc accumulation may play a role in the selective death of dentate hilar neurons after global ischemia in rats was done by Tonder and colleagues [144]. In the meantime, zinc accumulation in dying or dead neurons has not only been shown in the hippocampal hilar region, but also in all brain regions damaged in global ischemia such as hippocampal CA1, neocortex, thalamus, and striatum [145]. Consistent with the hypothesis that zinc-accumulation may lead to neuronal cell death, this event was prevented by the intraventricular injection of the zinc-chelating agent CaEDTA [145].

Zinc release and accumulation of zinc ions was also observed in a rat model of traumatic brain injury, where Suh and colleagues showed that trauma is associated with loss of zinc from presynaptic boutons and appearance of zinc in injured neurons. Again, neuroprotection occurred by intraventricular administration of a zinc chelator [146].

For some time, vesicular zinc was thought to be the only releasable pool of zinc in the brain [127]. This led to the assumption that the zinc ions accumulating in injured neurons must be entirely of presynaptic origin [127], but when ZnT-3 knock-out mice were investigated, which lack histochemically reactive zinc in synaptic vesicles, they still showed zinc accumulation in degenerating neurons, pointing toward sources other than synaptic vesicular zinc [147]. Alternative dynamic zinc sources might be MT-III as well as mitochondrial stores in the postsynaptic neurons [148,149].

Although zinc is redox-inactive in biological systems and exists only as a bivalent cation, there is evidence that zinc toxicity in neurons is mediated mainly by oxidative stress [141]. Zinc-induced cell death is associated with increased levels of reactive oxygen species in neurons [150,151]. In addition, free-radical-generating enzymes like NADPH oxidase are induced and activated by exposure to zinc [152]. Finally, zinc-induced cell death has been shown to be attenuated by various antioxidant interventions [96,153].

Besides oxidative stress, nitrosative stress can also affect zinc-induced neuronal injury. Nitric monoxide plays a crucial role in zinc toxicity by releasing zinc ions from MT [154], and inhibition of nitric oxide synthase significantly reduces zinc release from brain slices during oxygen and glucose deprivation [155]. Consistent with this, Frederickson and colleagues observed that nitric oxide also rapidly releases zinc from presynaptic terminals [156].

In addition to the impact of zinc on apoptosis discussed above, zinc-induced apoptosis in neurons might be based on two additional mechanisms. First, zinc-exposed neurons show an induction of the neutrophin receptor p75NTR and p75NTR-associated death executor (NADE) [157], a combination that can trigger caspase activation and apoptosis [158]. Second, high intracellular zinc concentrations trigger dysfunction of neuronal mitochondria, resulting in the release of pro-apoptotic proteins such as cytochrome-c and apoptosis-inducing factor (AIF) [148].

Although the release of intracellular zinc triggers neuronal apoptosis [96,159,160], indicators of necrosis such as cell body swelling and destruction of intracellular organelles have also been observed [96,150], indicating that zinc-induced neuronal cell death might encompass both apoptotic and necrotic mechanisms [143]. Taken together, alterations of neuronal zinc homeostasis have a profound influence on cellular survival during acute insults, and zinc chelators are discussed as potential therapeutic agents for the treatment of stroke [161].

It seems likely that zinc is also involved in neurodegenerative diseases, e.g., zinc and a deregulated zinc homeostasis could be important to onset and progression of Alzheimer’s disease [162]. Here, the use of metal chelators such as clioquinol to restore normal neuronal zinc homeostasis has shown promising results in vivo [163].

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Diet and Nutrition

Good Foods During Pregnancy

Posted on by Epstein
foods high in methionine
23
May

 We are all either undermethylators, overmethylators or normal methylators.

Many persons with depression are under or over methylators. Depressed women during pregnancy are frequently undermethylators. The good news is, there are many foods that provide #methionine to reverse the deficiency and lift depression. 

This published study in the Psych Congress Journal suggests that women who have maternal depression and are undermethylated, often give birth to children who experience depression due to their own ensuing condition of #undermethylation.

Whole blood histamine test is a lab that indicates methylation status. An excellent natural therapy may be methionine or SAMe supplements or foods that are high in methionine. If you have high blood histamines you may be undermethylated. Persons with seasonal allergies are frequently undermethylated. I recommend you get your levels tested before indulging in high methionine foods because your depression may in fact be associated with overmethylation, which requires an opposite approach, to lower methionine.

In consideration of the the study below, know your methylation status, particularly if you are depressed, and to combat during pregnancy, eat foods high in methionine and or take supplements. It won’t just make the mother feel better, but improves chance child won’t end up with depression.

Maternal Depression Linked to #dna Methylation Changes in Offspring

by Will Boggs MD, Psych Congress

By Will Boggs MD

Maternal depression is associated with widespread changes in DNA methylation in their offspring that may persist into adulthood, researchers from Canada report.

“These data further demonstrate the potential long-term consequences of maternal depression for the health of future generations and the importance of mental health and social support of mothers and would be mothers for the physical health of newborn and children,” Dr. Moshe Szyf from McGill University in Montreal, Quebec, told Reuters Health by email. “What is remarkable is that the mental state of a mother causes changes in DNA methylation in the newborns in the immune system, not just the brain.”

Maternal mood disorders and stress during pregnancy can result in attention learning deficits during childhood and mood disorders during adulthood for their offspring. Evidence suggests these consequences may be mediated by modifications of DNA methylation levels.

Dr. Szyf’s team investigated possible associations between maternal depression and DNA methylation changes in T lymphocytes from neonatal cord blood and in hippocampal brain tissues from adults with or without histories of maternal depression.

Offspring of depressed mothers, however, showed significant differences in DNA methylation from those of nondepressed mothers in 145 T lymphocyte CG sites. Most (75.5%) were hypomethylated in the maternal depression group compared with the control group.

“One of the main surprises was that we found a larger effect of maternal depression on the babies’ DNA methylation than the maternal DNA methylation,” Dr. Szyf said. “The second surprise was that it seems that the effect is a consequence of lifelong depression rather than depression only around the pregnancy period.”

“For healthy babies to develop into healthy adults it is important to have healthy mothers,” Dr. Szyf said. “And this involves not only physical and metabolic health but also mental and social wellbeing. This hopefully will be an important pillar in prenatal care as well as public policy relating to preconception health.”

“The #epigenetic consequences of maternal depression might suggest using epigenetic interventions for prevention and reversal of the impacts of maternal depression on the offspring,” Dr. Szyf added. “One clinical potential of the data is the possibility of developing biomarkers of maternal depression that might serve as predictors of lifelong health risks and guide early interventions.”

Dr. Joanne Ryan from University of Melbourne’s Murdoch Childrens Research Institute, Australia, who recently reviewed #epigenetics and depressive disorders, told Reuters Health by email, “An important next step in this research is to determine whether these methylation differences and associated with health outcomes in the infants/children. Maternal depression during pregnancy has been associated with long-term negative outcomes in the child — the data from this study should be used to determine whether such effects can be mediated by differential DNA methylation.”

To find out more about good foods during pregnancy to help with low methionine, we checked with our favorite food resource.

https://nutritiondata.self.com/

foods.high.in.methionine

5 Biotypes of Depression, Diet and Nutrition, Walsh Protocol

Treating Depression Naturally

Posted on by Epstein
22
May

…by gaining control over your brain’s biochemistry

Dr. William J. Walsh, PhD is the president of the Walsh Research Institute, an organization “dedicated to unraveling the biochemistry of mental disorders and [the] development of improved clinical treatments through scientific research”.  Dr. Walsh received his PhD in Chemical Engineering, but while working as a prison volunteer he was given the opportunity to study the brain chemistry of convicts and violent offenders and, because of the astounding discoveries made, decided to devote the rest of his career to Nutrient Based Psychiatry & Nutritional Medicine.  Dr. Walsh is very influential and highly regarded in his field, and has become a major proponent of treating depression naturally, as well as using Nutritional Therapy to combat many other mental and behavioral disorders.

Around 1965-1975, there was a revolution in mental health happening around the world.  Psychiatry was shifting its focus from a Freudian-based one, which speculated that children were born as a “blank slate” whose behavior and personality were then formed by their experiences and environment, into a paradigm which acknowledged family history, chemical imbalances, neurotransmitters, and the overall molecular biology of the brain as major factors in “bad behavior”, mental illness, #schizophrenia, etc.  Dr. Walsh wondered if this molecular biology could explain much of what was driving the violence and/or mental illness of the convicts that he was working with at the time.  This inquiry led to years upon years of experiments and the accumulation of massive amounts of data, all pointing towards a surprising conclusion… chemical imbalances, and improper levels of trace metals in particular, do indeed account for many of the tendencies of violent criminals and the expression of mental and behavioral disorders.

One example Dr. Walsh gives of a trace metal that has a huge impact on brain function is copper.  Copper is a key factor in the transition of dopamine to norepinephrine, so not having the right amount of copper in your system will lead to unhealthy levels of norepinephrine.  Additionally, it is very important that our bodies have the ability to regulate these levels by flushing excess copper from our system.  Some people do not have these regulatory abilities, and Dr. Walsh was surprised to discover that almost all of the convicts/offenders he was working had copper imbalances… those with who had episodic violent tendencies had very high copper levels, and the sociopathic types had very low copper levels.  This is just one example of the remarkable and pervasive findings of these revolutionary studies.

Additionally surprising was the fact that an entire group of convicts that Dr. Walsh had worked with, when subjected to blood tests in order to assess brain chemistry, returned almost identical results.  All the convicts had Pyrrole Disorder, were dramatically zinc deficient, and all were under methylated (high blood histamine).  Dr. Walsh recalls saying “they’re all the same!” upon receiving results.  This was incredibly surprising news… but also exciting, as these types of imbalances are easily treated with the proper Nutritional Therapy.  These discoveries and more prompted Dr. Walsh to initiate a study of over 500 people, starting with violent offenders and then eventually also taking on children who exhibited violent tendencies.  The treatments were extremely beneficial to the adults, but many would stop compliance after a period of time, thereby negating the positive outcomes.  The children, on the other hand, had extremely high levels of success, with very long-lasting beneficial effects.

One major focus of Dr. Walsh’s is depression.  According to Dr. Walsh, there is a major misconception around depression in the world of Psychiatry.  Depression is usually treated as a “single disorder” whose major foundational factor is low activity in serotonin receptors.  But not all depressions are alike, as Dr. Walsh’s data has shown him.  He points to “five completely different disorders called ‘depression’, only two of which have to do with serotonin”.  It is perfectly logical to conclude that treating depression naturally, thru Nutritional Therapy, could bypass much of the hardship and mishaps which are proliferated by treating each person and each brain as if it were the same… a dangerous approach, as it turns out that undermethylated patients respond very differently to SSRIs (Selective Serotonin Reuptake Inhibitors, most often prescribed for depression) then overmethylated patients, who respond very poorly.  Dr. Walsh even points to school shooting as one of the devastating offshoots of this type of blanket treatment offered for depression, as 40 out of the 50 school shootings of the past 3 decades have been carried out by young men who had functioned quite normally thru life before being put on SSRI antidepressant medications.  Dr. Walsh speculates that a simple blood test may have helped guide the prescribing physicians towards more appropriate treatment, as it could indicate whether or not a patient was overmethylated and therefore at high risk for adverse effects from the SSRIs.

Dr. Walsh believes that “we’re on the verge of a new era of psychiatry where we’ll be able to fix all these psychiatric problems without foreign molecules.  We’ll be able to normalize the brain, without drugs.  That is the era that is just beginning… and my group is trying to speed that up”.  As a matter of fact, his group at one point studied 700 violent children and adults, treated their specific chemical imbalances thru Nutritional Therapy (thereby “normalizing brain chemistry”) and then published the resulting changes in their violent activity.  91% of the families said that violent episodes had diminished, and 58% reported that violent episodes had completely disappeared.  Astounding results.

Dr. Walsh is very clear in pointing out that he is “not opposed to drugs… psychiatric medications have helped millions of people.  It was the best they had for the last 50 years… but now we’re learning how to do things better and without side effects … normalizing the brain instead of putting powerful foreign molecules into the brain.  As science advances, the need for psychiatric drugs will fade away”.

Second Opinion Physician agrees! And we believe that need for drugs is already fading.  SOP is trained in the Walsh Protocol and can advise patients on ways to use Nutritional Therapy and Supplements to combat mental and behavioral disorders, including highly effective ways of treating depression naturally.

Diet and Nutrition, Medications

Treatment for Depression without Medication

Posted on by Epstein
treatment for depression without medications
15
May

It is estimated that 13.1 to 14.2 million American adults suffer from clinical #depression and that 32 million will face the disease at some point in their life.  Only roughly 57% ever receive treatment, but those that do seem to find relief in antidepressant medications, such as SSRIs, #tricyclics, and MAO inhibitors.  However, whether or not it is actually the medication which is supplying that relief is up for debate.  And this is exactly the debate that is bravely addressed by psychology researcher Irving Kirsch, in his book The Emperor’s New Drugs: Exploding the Antidepressant Myth, and which is addressed in Newsweek’s article “Why Antidepressants Are No Better Than Placebos”, by Sharon Begley.
Backed by Kirsch’s research, Begley writes that “Yes, the drugs are effective, in that they lift depression in most patients. But that benefit is hardly more than what patients get when they, unknowingly and as part of a study, take a dummy pill—a #placebo. As more and more scientists who study depression and the drugs that treat it are concluding, that suggests that antidepressants are basically expensive Tic Tacs.”

The placebo effect, “a medical benefit you get from an inert pill or other sham treatment” continues Begley, “rests on the holy trinity of belief, expectation, and hope.”

Begley goes on to point out that some researchers even wonder if “antidepressants are ‘a triumph of marketing over science’” and points out that “even defenders of antidepressants agreed that the drugs have ‘relatively small’ effects.”  Kirsch’s study indicated that “patients on a placebo improved about 75 percent as much as those on drugs. Put another way, three quarters of the benefit from antidepressants seems to be a placebo effect.”
Further, it appears to that those small effects are really only evident in patients which exhibit severe levels of depression, not for the mild to moderate cases.  Although any amount of depression is incredibly difficult, vastly overwhelming, and often simply unbearable, it seems that those suffering from the more mild to moderate levels could very well benefit greatly from treatment for depression without medication.  Which begs the question… why then, since this study, has “the number of Americans taking antidepressants doubled in a decade, from 13.3 million in 1996 to 27 million in 2005”?

Psychology researcher Steven Hollon of Vanderbilt University reaffirms the pervasiveness of this placebo effect when he states that “many have long been unimpressed by the magnitude of the differences observed between treatments and controls… […] what some of our colleagues refer to as ‘the dirty little secret.’”

This is undoubtedly difficult for patients and doctors to hear.  A doctor who has witnessed improvement in a patient wants to believe that the treatment they are prescribing is the basis for that improvement… otherwise, how does one really quantify or measure the efficacy of one treatment over another?  But should this desire for standardization get in the way of a patient knowing the truth about his or her treatment options or prescriptions?

Psychotherapists could be excited at the prospect of an upsurge in talk therapy as opposed to medication.  It has been shown that #psychotherapy is actually more effective than both pills and placebos, and carries a lower rate of relapse for sufferers of depression.  Unfortunately, most people that currently seek treatment for depression are receiving such from their primary-care doctors, not from psychiatrists (as many do not accept insurance).  Psychotherapy is just not a viable option for many patients.

Depression is devastating for the individual ensnared in its net, as well as often debilitating to the healthy functioning of entire families.  If a pill provides some semblance of relief, even if only by way of a placebo effect, is that really such a bad thing?  Perhaps not.  But one must take into consideration the side-effects which often accompany antidepressant medications, the high cost for prescriptions, the high potentiality for relapse, as well as the difficult and painful symptoms which may arise with withdrawal from that particular medication.  Could there be a better way?  Are there other viable treatment for depression without medication?

Second Opinion Physician believes so. 

 

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See full article from Newsweek

Link to The Emperor’s New Drugs: Exploding the Antidepressant Myth, by Irving Kirsch

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