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Repairing the Damaged Plasma Membrane of the Cell and the Membrane-Bound Organelles

Introduction to the Plasma Membrane

The human cell is enveloped in a thin, pliable, elastic structure called the cell membrane or the plasma membrane and is only 7.5 to 10 nanometers thick. It is composed almost entirely of proteins and lipids.  There are approximately 5 × 106 lipid molecules in a 1 μm × 1 μm area of lipid bilayer, or about 109 lipid molecules in the plasma membrane of a human cell.

The main purpose of the plasma membrane is to separate the inner contents of the cell from its exterior environment, much like the outer layer of the skin separates the body from its environment.  In addition to providing a protective barrier around the cell, the plasma membrane regulates which materials pass in and out of the cell.

The plasma membrane envelops the human cell and is also found inside the cell in various intracellular membranes, called organelles.  The structure and composition of the plasma membrane are the same for the plasma membrane surrounding the cell as well as for the various intracellular membranes.  The only difference among them is the proportions which vary from one type of membrane to the other.

The formation of plasma membranes is based on the structural organization of bilayers of lipids with associated proteins.  The lipid content of the plasma membrane ranges from 40 to 80% (of dried weight), which is significant.  The two main lipids that predominate quantitatively in the lipid fraction of the plasma membrane are:

  • phosphatidylcholine
  • phosphatidylethanolamine

The lipid molecules in plasma membranes are amphipathic (or amphiphilic)—that is, they have a hydrophilic (“water-loving”) or polar end and a hydrophobic (“water-fearing”) or nonpolar end.

Functions of the Plasma Membrane

In addition to the plasma membrane providing a protective barrier around the cell and the intracellular organelles, it has many essential functions:

  • transporting nutrients into the cell
  • transporting metabolic wastes out of the cell
  • preventing unwanted materials in the extracellular milieu from entering the cell
  • preventing loss of needed metabolites
  • maintaining the proper ionic composition, pH (≈7.2), and osmotic pressure of the cytosol
  • provides cell to cell communication
  • provides hormone sensitivity and utilization
  • support the many enzymatic reactions that occur along their surfaces

These various functions are carried out by specific transport proteins which restrict the passage of certain small molecules.

The plasma membrane actually has a measurable membrane differential which is the voltage across the plasma membrane.  It has been determined that healthy children has a membrane electrical potential up to 90 millivolts, whereas a healthy adult can have up to 70 millivolts.  The membrane electrical potential can decline to around 40 millivolts in an individual with a chronic disease and to as low as 15 millivolts in an individual with advanced cancer.

The Lipids Comprising the Plasma Membrane of the Human Cell

The plasma membrane of the human cell and certain intracellular organelles inside the cell are composed of three categories of lipids:

  • Phospholipids (Glycerophospholipids or Phospholycolipids or Phosphoglycerides and Phosphosphingolipids)
  • Glycolipids
  • Cholesterol

Of the three categories of  lipids, the most abundant membrane lipids are the phospholipids.

The functions of the plasma membrane determines the lipid compositions of the inner and outer monolayers of the cell plasma membrane.  Different mixtures of lipids are found in the membranes of cells of different types.  The two sides of the plasma membrane of the human cell reflect this difference:

Outer Layer (the side on the exterior of the cell)

Consists mainly of phosphatidylcholine and sphingomyelin

Inner Layer (the side on the interior of the cell)

Consists mainly of phosphatidylethanolamine and phosphatidylserine and phosphatidylinositol.  

Figure 12.2. Lipid components of the plasma membrane.

Figure 1.  Lipid components of the plasma membrane

The outer leaflet consists predominantly of phosphatidylcholine, sphingomyelin, and glycolipids, whereas the inner leaflet contains phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol. Cholesterol is distributed in both leaflets. The net negative charge of the head groups of phosphatidylserine and phosphatidylinositol is indicated. (Source:  The Cell: A Molecular Approach. 2nd edition., The Molecular Composition of Cells)

The mitochondria, an intracellular organelle, contains two membranes and consists primarily of phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, and phosphatidic acid.  These phospholipids are asymmetrically distributed between the two halves of the membrane bilayer of the mitochondria.  The inner mitochondrial membrane contains a specific phospholipid called phosphatidylglycerol and is the precursor for cardiolipin.  Cardiolipin is predominantly found in the inner mitochondrial membrane.

Lipids constitute approximately 50% of the mass of most cell membranes, although this proportion varies depending on the type of membrane. Plasma membranes, for example, are approximately 50% lipid and 50% protein.

The lipid composition of different cell membranes also varies:

  Plasma membrane    
Lipid E. coli Erythrocyte Rough endoplasmic reticulum Outer mitochondrial membranes
Phosphatidylcholine 0 17 55 50
Phosphatidylserine 0 6 3 2
Phosphatidylethanolamine 80 16 16 23
Sphingomyelin 0 17 3 5
Glycolipids 0 2 0 0
Cholesterol 0 45 6 <5

Membrane compositions are indicated as the mole percentages of major lipid constituents.

Another source lists the lipid compositions of different cell membranes:

  PERCENTAGE OF TOTAL LIPID BY WEIGHT
LIPID LIVER CELL PLASMA MEMBRANE RED BLOOD CELL PLASMA MEMBRANE MYELIN MITOCHONDRION (INNER AND OUTER MEMBRANES) ENDOPLASMIC RETICULUM E. COLIBACTERIUM
Cholesterol 17 23 22 3 6 0
Phosphatidylethanolamine 7 18 15 25 17 70
Phosphatidylserine 4 7 9 2 5 trace
Phosphatidylcholine 24 17 10 39 40 0
Sphingomyelin 19 18 8 0 5 0
Glycolipids 7 3 28 trace trace 0
Others 22 13 8 21 27 30
(Source: Molecular Biology of the Cell. 4th edition., The Lipid Bilayer; Alberts B, Johnson A, Lewis J, et al. New York: Garland Science; 2002.)
Phospholipids that Compose the Plasma Membrane

Plasma membranes contain 4 major and 1 minor phospholipids:

  • Major phospholipids
    • phosphatidylcholine
    • phosphatidylethanolamine
    • phosphatidylserine
    • sphingomyelin
  • Minor phospholipids
    • phosphatidylinositol

These major phospholipids together account for more than 50% of the lipid in most membranes. Phosphotidylinositol is present in smaller quantities in the plasma membrane but provide important functions like cell signaling.

  Figure 10-12. Four major phospholipids in mammalian plasma membranes.

Figure 2.  Four major phospholipids in mammalian plasma membranes

Note that different head groups are represented by different colors. All the lipid molecules shown are derived from glycerol except for sphingomyelin, which is derived from serine.  (Source: Molecular Biology of the Cell. 4th edition., The Lipid Bilayer; Alberts B, Johnson A, Lewis J, et al. New York: Garland Science; 2002.)

Phosphatidylcholine

Phosphatidylcholine is a vital substance found in every cell of the human body.

Phosphatidylethanolamine

Phosphatidylethanolamines are found in all living cells, composing 25% of all phospholipids. In humans, they are found particularly in nervous tissue such as the white matter of brain, nerves, neural tissue, and in spinal cord, where they make up 45% of all phospholipids.  1

Phosphatidylserine

Phosphatidylserine is a component of the cell membrane. It plays a key role in cell cycle signaling, specifically in relationship to apoptosis.  

Sphingomyelin

Sphingomyelin is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds nerve cell axons. It usually consists of phosphocholine and ceramide, or a phosphoethanolamine head group; therefore, sphingomyelins can also be classified as sphingophospholipids.

Phosphatidylinositol (minor phospholipid)

Phosphatidylinositol forms a minor component on the cytosolic side of eukaryotic cell membranes.

Phosphorylated forms of phosphatidylinositol are called phosphoinositides and play important roles in lipid signaling, cell signaling and membrane trafficking.

Phosphatidylglycerols  (Cardiolipin)

Phosphatidic acid reacts with CTP, producing CDP-diacylglycerol, with loss of pyrophosphate. Glycerol-3-phosphate reacts with CDP-diacylglycerol to form phosphatidylglycerol phosphate, while CMP is released. The phosphate group is hydrolysed forming phosphatidylglycerol.

Two phosphatidylglycerols form cardiolipin, the constituent molecule of the mitochondrial inner membrane.  2

Phosphatidic acid

Phosphatidic acids are the acid forms of phosphatidates, a part of common phospholipids, major constituents of cell membranes.  phosphatidic acids are the simplest diacyl-glycerophospholipids.

The role of phosphatidic acid in the cell can be divided into three categories:

  • Phosphatidic acid is the precursor for the biosynthesis of many other lipids
  • The physical properties of phosphatidic acid influence membrane curvature
  • Phosphatidic acid acts as a signaling lipid, recruiting cytosolic proteins to appropriate membranes

The conversion of phosphatidic acid into diacylglycerol (DAG) by LPPs is the commitment step for the production of phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine. In addition, DAG is also converted into CDP-DAG, which is a precursor for phosphatidylglycerol, phosphatidylinositol and phosphoinositides.

Phosphatidic acid is essential for lipid synthesis and cell survival, yet, under normal conditions, is maintained at very low levels in the cell.

Glycolipids

The role of glycolipids is to maintain stability of the membrane and to facilitate cellular recognition.  3 

Carbohydrates are found on the outer surface of all eukaryotic cell membranes. They extend from the phospholipid bilayer into the aqueous environment outside the cell where it acts as a recognition site for specific chemicals as well as helping to maintain the stability of the membrane and attaching cells to one another to form tissues.

Figure 3.  Glycolipid attached to lipid residue

The lipid complex is most often composed of either a glycerol or sphingosine backbone, which gives rise to the two main categories of glycolipids:

  • glyceroglycolipids
  • sphingolipids

The heads of glycolipids contain a sphingosine with one or several sugar units attached to it. The hydrophobic chains belong either to:

  • two fatty acids – in the case of the phosphoglycerides, or
  • one fatty acid and the hydrocarbon tail of sphingosine – in the case of sphingomyelin and the glycolipids

Glycolipids occur in all animal cell plasma membranes, where they generally constitute about 5% of the lipid molecules in the outer monolayer. They are also found in some intracellular membranes.

The most complex of the glycolipids, the gangliosides, contain oligosaccharides with one or more sialic acid residues, which give gangliosides a net negative charge.  More than 40 different gangliosides have been identified. They are most abundant in the plasma membrane of nerve cells, where gangliosides constitute 5–10% of the total lipid mass; they are also found in much smaller quantities in other cell types.

Cholesterol

Cholesterol is a sterol, and is biosynthesized by all animal cells, and is an essential structural component of all animal cell membranes; essential to maintain both membrane structural integrity and fluidity. Cholesterol enables animal cells to dispense with a cell wall (to protect membrane integrity and cell viability), thereby allowing animal cells to change shape and animals to move (unlike bacteria and plant cells, which are restricted by their cell walls).

Cell membranes require high levels of cholesterol – typically an average of 20% cholesterol in the whole membrane, increasing locally in raft areas up to 50% cholesterol.  4 

Within the cell membrane, cholesterol also functions in intracellular transport, cell signaling and nerve conduction. Recent studies show that cholesterol is also implicated in cell signaling processes, assisting in the formation of lipid rafts in the plasma membrane, which brings receptor proteins in close proximity with high concentrations of second messenger molecules.  5  

In multiple layers, cholesterol and phospholipids, both electrical insulators, can facilitate speed of transmission of electrical impulses along nerve tissue. For many neuron fibers, a myelin sheath, rich in cholesterol since it is derived from compacted layers of Schwann cell membrane, provides insulation for more efficient conduction of impulses.  6 

Figure 2.47. Insertion of cholesterol in a membrane.

Figure 4.  Insertion of cholesterol in a membrane

Cholesterol inserts into the membrane with its polar hydroxyl group close to the polar head groups of the phospholipids.

Organelles of the Human Cell

An organelle is a specialized sub-unit within a cell that serves a specific function.  Most organelles of the cell are covered by membranes composed primarily of lipids and proteins.

Organelles either have a single-membrane compartment or a double-membrane compartment. 

There are 10 organelles in the human cell that have either a single or double membrane.  There are 3 organelles with double membranes and 7 organelles with single membranes.  The organelles of the cell with membranes are as follows:

Organelle

Function

Membrane Structure

Autophagosome

vesicle that sequesters cytoplasmic material and organelles for degradation

Double membrane

Endoplasmic reticulum

translation and folding of new proteins (rough endoplasmic reticulum), expression of lipids (smooth endoplasmic reticulum)

Single membrane

Golgi apparatus

sorting, packaging, processing and modification of proteins

Single membrane

Lysosomes

breakdown of large molecules (e.g., proteins + polysaccharides)

Single membrane

Melanosome

pigment storage

Single membrane

Mitochondria

energy production from the oxidation of glucose substances and the release of adenosine triphosphate

Double membrane

Nucleus

DNA maintenance, controls all activities of the cell, RNA transcription

Double membrane

Peroxisome

breakdown of metabolic hydrogen peroxide

Single membrane

Vacoule

storage, transportation, helps maintain homeostasis

Single membrane

Vesicle

material transport

Single membrane

Organelles with double membranes are often critical to the function of the cell, each serveing a different purpose.  There are 3 organelles that have double membranes:

  • Mitochondria

  • Nucleus

  • Autophagosome

Mitochondria

A mitochondrion (singular for mitochondria) contains outer and inner membranes composed of phospholipid bilayers and proteins.   Due to the double membrane structure of the mitochondrion, there are five distinct parts to a mitochondrion. They are:

  • the outer mitochondrial membrane
  • the intermembrane space (the space between the outer and inner membranes)
  • the inner mitochondrial membrane
  • the cristae space (formed by infoldings of the inner membrane)
  • the matrix (space within the inner membrane)

The mitochondrial membrane contains the major classes of phospholipids found in all cell membranes, including phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, and phosphatidic acid, as well as phosphatidylglycerol, the precursor for cardiolipin; which is predominantly located in the mitochondria.

The outer mitochondrial membrane, which encloses the entire organelle, has a protein-to-phospholipid ratio similar to that of the human plasma membrane (about 1:1 by weight). It contains large numbers of integral membrane proteins called porins.

In the inner mitochondrial membrane, the protein-to-lipid ratio is 80:20, in contrast to the outer membrane, which is 50:50.  7 

The inner membrane is rich in cardiolipin.  Cardiolipin contains four fatty acids rather than two, and may help to make the inner membrane impermeable.  Unlike the outer membrane, the inner membrane doesn’t contain porins, and is highly impermeable to all molecules.

Nuclear Membrane

The nuclear envelope, otherwise known as nuclear membrane, consists of two cellular membranes, an inner and an outer membrane, arranged parallel to one another and separated by 10 to 50 nanometres (nm). The nuclear envelope completely encloses the nucleus and separates the cell’s genetic material from the surrounding cytoplasm, serving as a barrier to prevent macromolecules from diffusing freely between the nucleoplasm and the cytoplasm. 8   The outer nuclear membrane is continuous with the membrane of the rough endoplasmic reticulum.

Autophagosome

An autophagosome is a spherical structure with double layer membranes. It is the key structure in macro autophagy, the intracellular degradation system for cytoplasmic contents (e.g., abnormal intracellular proteins, excess or damaged organelles) and also for invading microorganisms.

After formation, autophagosomes deliver cytoplasmic components to the lysosomes. The outer membrane of an autophagosome fuses with a lysosome to form an autolysosome. The lysosome’s hydrolases degrade the autophagosome-delivered contents and its inner membrane.  9

Damage and Degradation to the Cell Membrane

When cell membranes are intact their receptor surface is able to perform all necessary functions. Communication between cells, and even within the cell components, flows easily. Once the membrane is damaged this communication is disrupted, and the cell cannot function properly, due to the failure of cellular signaling. 

There are a number ways in which cell membranes can be damaged, which eventually leads to pathology and illness.  This is true of both the cell and its outer membrane barrier or cell membrane, and the membrane structures inside the cell.  Various factors can contribute to damage to the cell membrane, such as:

  • Acetaldehyde
  • Aging
  • Alcohol
  • Excessive Saturated Fatty Acids
  • Lipid peroxidation
  • Oxidization of cell membrane
  • Recreational Drugs
  • Smoking
  • Toxin exposure (toxins stored in the lipid environment)
  • Trans-fatty acids  10  11

Aging causes detrimental changes in membrane phospholipid composition. Phosphatidylcholine is one of the main types of phospholipids in the cell membrane, and its concentration within the cell membrane decreases with age, whereas sphingomyelin and cholesterol both increase with age. 

The changes in the relative amounts of phosphatidylcholine and sphingomyelin are especially great in tissues. Plasma membranes associated with the aorta and arterial wall show a 6-fold decrease in phosphatidylcholine and sphingomyelin ratio with aging. Sphingomyelin also increases in several diseases, including atherosclerosis. The sphingomyelin content can be as high as 70-80% of the total phospholipids in advanced aortic lesion.  12  

Decreased cell membrane fluidity and decomposition of cell membrane integrity, as well as break down of cell membrane repair mechanisms, are associated with various disorders, including liver disease, atherosclerosis, several cancers and ultimately cell death.

Fatty acids within the cell membrane degrade when dietary fats are either oxidized (lipid peroxides can form within the body as well) or contain trans fatty acids.

Plasma membranes are one of the preferential targets of reactive oxygen species which cause lipid peroxidation. This process modifies membrane properties such as fluidity, a very important physical feature known to modulate membrane protein localization and function.  13  

Numerous reports have established that lipid peroxidation contributes to cell injury by altering the basic physical properties and structural organization of membrane components. Oxidative modification of polyunsaturated phospholipids has been shown, in particular, to alter the intermolecular packing, thermodynamic, and phase parameters of the membrane bilayer.  14  15

Damage to the Double Membrane Structure of the Mitochondria

Damage to mitochondrial components, especially the delicate inner mitochondrial membrane, leads to the release of toxic proteins, including caspases and other enzymes. These proteins are normally confined in the mitochondria, but once released these proteins go through several steps that trigger the formation of a potent inflammatory molecular complex called an inflammasome.

New evidence has placed inflammasomes at the center stage of complex diseases like metabolic syndrome and cancer, as well as the regulation of the microbial ecology in the intestine and the production of ATP.  16 

Once the inner membrane of the mitochondria is damaged, its core ability to produce energy in the form of ATP and to maintain optimal mitochondrial nutrient uptake and utilization necessary for ATP production are impaired.

The inner mitochondrial membrane is also one of the most sensitive membranes of the cell to oxidative damage. This is because of its unique membrane structure and the presence of a very oxidation-sensitive phospholipid, cardiolipin. Cardiolipin is functionally required for the electron transport system. 

When mitochondrial cardiolipin and to a lesser degree other phosphatidyl phospholipids are damaged by oxidation, the chemical/electrical potential across the inner mitochondrial membrane is altered due to an increasingly “leaky” membrane that allows protons and ions to move across the membrane. This occurs because the oxidized membrane phospholipids no longer form a tight ionic/electrical “seal” or barrier.

Significant oxidative damage to mitochondrial membranes represents the point-of-no-return of programmed cell death pathways that culminate in apoptosis or regulated cell death leading to necrosis.  17

Repairing the Damaged Cell Membrane with Lipid Replacement Therapy®

The good news is that damaged lipids can be replaced.  In fact, a young healthy cell usually replaces damaged lipids in its membranes.  However, due to aging, eating a poor diet, exposure to environmental toxins, getting infections and certain illnesses, it becomes necessary to proactively replace the damaged lipids with new lipids. 

This can be done using Lipid Replacement Therapy (LRT®), which provides for the consumption of lipids that are the same as found in the cell membrane and organelle membranes. 

A product developed and manufactured by Nutritional Therapeutics Inc., called NTFactor®, is intended to reverse the damage done to our cells and mitochondria by oxidative stress through the process of Lipid Replacement Therapy®.

The NTFactor® formula is a unique combination that allows the healthy phospholipids to stay intact during transport through the body.

NT Factor Lipids® is based on U.S. Patent No. 8,877,239.  The lipid blend of NTFactor® includes:

  • Phosphatidic acid (PA)
  • Phosphatidyl-choline (PC)
  • Phosphatidyl-ethanolamine (PE)
  • Phosphatidyl-glycerol(PG) – (precursor for cardiolipin (CL))
  • Phosphatidyl-inositol (PI)
  • Phosphatidyl-serine (PS)
  • Digalactosyldiacylglyceride (DGDG)
  • Monoglactosyldiacylglyceride (MGDG)

NTFactor® uses a form of a stable oral supplement that emulates the amount and composition of the mitochondrial lipids assures that inappropriate oxidative membrane damage is prevented, damaged membrane phospholipids are replaced and mitochondrial membrane permeability is maintained in the optimal range.

Obtaining Phospholycolipids through Diet

Phospholycolipids can be obtained generally in the diet from meat, egg yolks, fish, turkey, chicken and beef.  Organ meats and egg yolks are among the best food sources of phosphoglycolipids, however, one would have to consume large portions of these foods at every meal to obtain the benefit of lipid replacement, which is unlikely and unhealthy.

The various lipids can be found in the following foods:

Phosphatidylcholine

Phosphatidylcholine can be obtained from egg yolk or soybeans.  Phosphatidylcholine is a major component of egg, soy and sunflower lecithin. 

Lecithin’s are mostly phospholipids, composed of phosphoric acid with choline, glycerol or other fatty acids usually glycolipids or triglyceride. Glycerophospholipids in lecithin include phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, and phosphatidic acid.

Phosphatidylethanolamine

Phosphatidylethanolamine is primarily found in lecithin.

Phosphatidylinositol

Phosphatidylinositol can be found in lecithin. 

Phosphatidylserine

Phosphatidylserine can be found in meat and fish. Only small amounts of phosphatidylserine can be found in dairy products or in vegetables, with the exception of white beans and soy lecithin.

Phosphatidylserine (PS) content in different foods

Food

PS Content in mg/100 g

Bovine brain

713

Atlantic mackerel

480

Chicken heart

414

Atlantic herring

360

Eel

335

Offal (average value)

305

Pig‘s spleen

239

Pig’s kidney

218

Tuna

194

Chicken leg, with skin, without bone

134

Chicken liver

123

White beans

107

Soft-shell clam

87

Chicken breast, with skin

85

Mullet

76

Veal

72

Beef

69

Pork

57

Pig’s liver

50

Turkey leg, without skin or bone

50

Turkey breast without skin

45

Crayfish

40

Cuttlefish

31

Atlantic cod

28

Anchovy

25

Whole grain barley

20

European hake

17

European pilchard (sardine)

16

Trout

14

Rice (unpolished)

3

Carrot

2

Ewe‘s Milk

2

Cow‘s Milk (whole, 3.5% fat)

1

Potato

1

 (Source:  Souci SW, Fachmann E, Kraut H (2008). Food Composition and Nutrition Tables. Medpharm Scientific Publishers Stuttgart)

Sphingomyelin

Sphingomyelin can be obtained from eggs or bovine brain.

Cholesterol

All animal-based foods contain cholesterol in varying amounts.  Cholesterol can be obtained from cheese, egg yolks, beef, pork, poultry, fish, and shrimp.  Cholesterol is not found in plant-based foods.   

#29 Garth Nicolson: How to Repair Mitochondria with Lipid Replacement

The Potent Compounds of Salvia militorrhiza (Danshen)

Salvia miltiorrhiza, also known as red sage, Chinese sage, tan shen, or danshen, is a perennial plant in the genus SalviaSalvia miltiorrhiza is native to China and Japan where it grows at 90 to 1,200 m (300 to 3,940 ft) elevation, preferring grassy places in forests, hillsides, and along stream banks. The specific epithet miltiorrhiza means “red ochre root” as can be seen in the photo below:

DanshenRoot

Salvia militorrhiza BUNGE (Danshen) roots

Scientist have identified over 80 compounds in Danshen, both water soluble and fat soluble:  1  2  3

  • 50 water soluble compounds
    • Salvianolic acid B
    • Danshensu (Salvianolic acid A)
    • Protocatechuic aldehyde
  • 30 fat soluble compounds
    • Tanshinones
      • Tanshinone I
      • Tanshinone IIA 
      • Cryptotanshinone

The two compounds that show the most pharmalogical significance is the Salvianolic acids, Salvianolic acid A (danshensu) and the tanshinones, Tanshinone I and Tashinone IIA.

Salvianolic acid B is a potent antioxidant and has been investigated for its ability to protect against cerebrovascular disorders.  4  5

The Tanshinones (Dihydrotanshinone, tanshinone I, and tanshinone IIA) are currently being investigated for their anti-cancer effects.  6  7

The Table below lists the active compounds that have been studied for their therapeutic benefits in human health with references to various scientific studies for each compound:

Active Compounds in Salvia miltorrhiza Bunge

Compounds in Salvia miltorrhiza Bunge Clinical ApplicationsFunctions and UsesReferences
Cryptotanshinone1. Coronary heart disease and sugar diabetes; 2. Anti-infections; 3. To treat hepatitis and lepra disease.Cryptotanshinone is a major tanshinone isolated from Salvia miltiorrhiza that uses in many different fields. It has a good effection cardiovascular disease resisting fungus, also been effective to inhibit bacterium and diminish inflammation.1 2 3
Danshensu sodium1. Anti-bacterial 2. Anti-atherosclerotic 3. Enhancing immune1. Prevention for cardiac muscle, inhibit platelet aggregation; 2. Prevention for nerve cell and hepatic fibrosis; 3. Anti-bacterial, anti-inflammatory, anti-atherosclerotic and anticoagulation. Hypolipidemic effect and enhancing immune1 2 3
Danshensu/Salvianic Acid A1. Coronary heart disease 2. Anti-platelet aggregation 3. Protection for heartDanshensu is mainly used as raw material for clearing heat, anti-inflammation, detumescence and increasing coronary flow.1 2 3
Dihydroanshinone1. Antibacterium 2. Antifungal activity 3. Anti-thromboticSome inhibitory effects on Staphylococcus aureus, human-type Mycobacterium tuberculosis, Mycobacterium, leather bacteria etc. Inhibit platelet aggregation, anti-oxidants and expansion of coronary activity. Applied in medicine, healthcare food, food additive1 2 3 4 5 6
Magnesium Lithospermate B1. Anti-oxidative junction 2. Protection for heart 3. Protection for brain 4. Prevention for hepatic fibrosis 5. Anti-aging and anti-tumorPromoting blood circulation and removing blood stasis, Stimulate the menstrual flow and activate the collaterals. It is used for apoplexy and the angina caused by coronary artery disease. Anti-fibrosis of liver. Mainly applied in Medicine, healthcare food, food additive.1 2 3 4 5 6 7 8
Protocatechuic aldehyde1. Anti-inflammation 2. anti-prostaglandin 3. anti-lipid peroxidationIt has a strong effect on antithrombotic, improving the blood circulation and anti-oxidant. Applied in medicine, healthcare food, food additive.1 2 3 4
Salvianolic Acid B1. Anti-oxidative junction 2. Protection for heart 3. Protection for brain 4. Prevention for hepatic fibrosis 5. Anti-aging and anti-tumorPromoting blood circulation and removing blood stasis, Stimulate the menstrual flow and activate the collaterals. It is used to cure apoplexy and the angina caused by coronary artery disease. Anti-fibrosis of liver. Mainly applied in Medicine, healthcare food, food additive.1 2 3 4 5 6 7 8
Sodium tanshinoneⅡA sulfonate1. To ease postpartum pain 2.To remove goreSodium tanshinoneⅡA sulfonate is used to remove blood stasis and relieve pain, promote the flow of blood and stimulate menstrual discharge, expand blood vessels. It has a good effect on abnormal menstruation.1 2 3 4 5 6
Tanshinone I1. To depress pains in bodies 2. Promote the secretion of estrogen 3. Against angina pectoris1.It has a strong inhibition on human strains of Mycobacterium and is for the treatment of acne, and angina pectoris; 2. It is effective on the treatment of hepatitis and lepra disease. Applied in medicine, healthcare food, food additive.1 2 3 4 5 6 7 8
Tanshinone IIA1. To expend vessel 2. Depress blood pressure 3. Anti-thrombotic 4 AntioxidantUsed in medicine, healthcare food, food additive.1 2 3 4 5 6 7 8
Source of Columns 1, 2 and 3 is Xi 'an Honson Biotechnology Co., Ltd.
References provided by BioFoundations.org

 


Oxaloacetate Reduces Neuroinflammation

Neuroinflammation is inflammation of the brain and nervous tissue. The common causes of chronic neuroinflammation include:

  • Aging
  • Air pollution
  • Autoimmunity
  • Microbes
  • Passive smoke
  • Toxic metabolites
  • Traumatic brain injury
  • Viruses

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls:

  • cell survival
  • cytokine production
  • transcription of DNA

NF-kB is an important factor in the inflammation pathway and if there is excessive or overly activated NF-kB, then this reaction can result in chronic inflammation not only in the nervous tissue but throughout the body.

NF-κB is involved in cellular responses to stimuli such as:

  • bacterial or viral antigens
  • cocaine
  • cytokines
  • free radicals
  • isoproterenol
  • oxidized LDL
  • stress
  • ultraviolet irradiation
  • tumor necrosis factor alpha (TNFα),
  • interleukin 1-beta (IL-1β)

NF-κB has been shown to have diverse functions in the nervous system.  Activated NF-κB can be transported retrogradely from activated synapses to the nucleus to translate short-term processes to long-term changes such as axon growth, which is important for long-term memory. 1

In glia, NF-κB is inducible and regulates inflammatory processes that exacerbate diseases such as autoimmune encephalomyelitis, ischemia, and Alzheimer’s disease. In summary, inhibition of NF-κB in glia might ameliorate disease. 2

NF-KBPathway

Abating or lowering the NF-kB protein trans-location to the nucleus when inflammation is present is one of the strategies to reducing neuroinflammation and chronic inflammation in general.

A study from December 2014 published in the Journal Human Molecular Genetics, entitled “Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis”, found among other things, that oxaloacetate reduces neuroinflammation.

Oxaloacetic acid (also known as oxalacetic acid or oxaloacetate ) is a metabolic intermediate in many processes that occur in humans and other animals. Oxaloacetate takes part in many systems within the body, such as:

  • amino acid synthesis
  • citric acid cycle
  • fatty acid synthesis
  • gluconeogenesis
  • glyoxylate cycle
  • urea cycle
Oxaloacetic_acid

Oxaloacetic acid molecule

In the December 2014 study, the researchers assessed the effects of Oxaloacetate (OAA) administration on brain inflammation.  They measured the mRNA levels for two inflammation-related genes, tumor necrosis factor α (TNFα) and C–C motif chemokine 11 (CCL11).

While hippocampal TNFα levels were comparable across the groups, hippocampal CCL11 mRNA levels were 44% lower in the group receiving 2 g/kg/day than they were in the control group (Figure 1).

The amount of nuclear factor κB (NFκB) protein was lower in the nucleus of the combined OAA treatment group (by 50%), after two weeks of OAA supplementation, and in both OAA treatment groups the nucleus-to-cytoplasm ratio was ∼70% lower than it was in the control group.  3 

 

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Figure 1:  Effect on inflammation. (A) TNFα mRNA levels were comparable. (B) CCL11 mRNA was lower in the 2 g/kg/day OAA group. (C) Nuclear NFκB protein was lower in the combined OAA group. Although the ANOVA was not significant, on post hoc analysis nuclear NFκB protein was lower in the 1 g/kg/day OAA group. (D) The NFκB nucleus:cytoplasm ratio was lower in the 1 g/kg/day, 2 g/kg/day and combined OAA groups. Values shown are relative group means ± SEM. *P < 0.05; **P < 0.005; #ANOVA comparison was not significant, but the post hoc LSD test between the specified treatment group and the control group was significant at P < 0.05.  (Source:  Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis, Hum Mol Genet. 2014 Dec 15; 23(24): 6528–6541. Published online 2014 Jul 15. doi:  10.1093/hmg/ddu371)

The researchers concluded that:

When activated, NFκB’s restraint is removed and it moves to the nucleus. Since NFκB promotes the CCL11 gene, reduced NFκB may account for lower CCL11 expression. OAA, therefore, could prove useful for treating brain diseases in which neuroinflammation occurs.”  4


 

Resources:

benaGene by benaGene

Advanced Orthomolecular Research AOR Benagene Capsules, 30 Count

 


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Balancing Your Neurotransmitter Systems Naturally

A balanced and healthy nervous system requires a sufficient level of neurotransmitters. 

There are a number of neurotransmitters that have been identified and are typically classified as:

  • Amino acids
  • Monoamines
  • Peptides

Another classification of neurotransmitters is whether they are inhibitory or stimulatory.  For purposes of this article, four main neurotransmitters are examined:

  • Stimulatory
    • Acetylcholine
    • Dopamine
  • Inhibitory
    • GABA
    • Serotonin

The Table below lists the four major neurotransmitters and their certain characteristics:

Neurotransmitter Systems

SystemAcetylcholineDopamineGABASerotonin
SystemCholinergicCathecholamineGABAergicSerotonergic
TypeStimulatoryStimulatoryInhibitoryInhibitory
Lobe of the BrainParietal lobesFrontal lobesTemporal lobesOccipital lobes
BrainwaveAlphaBetaThetaDelta
Brain MeasurementSpeedVoltageBalance (Calm)Synchrony (Rest)
CharacteristicsLubricant to neuronsPowerCalmnessHealing
BalancedCreativeBlood pressureStabilityNourishment
Fast thinkingMetabolismEven moodSatisfied feelings
Feelings of wellbeingDigestionMake good decisionsSleep deeply
Voluntary movementThink rationally
Intelligence
Abstract thought
Goal setting
Long term planning
CharacteristicDecreased brain speedDecreased brain powerHeadachesDepression
DeficiencyBrain fogFatiguePalpitationsSleep disorders
DementiaAddictionSeizuresEating disorders
AlzheimersLoss of attentionAnxietySensory processing
dysfunction
Dietcholine-rich: almonds; artichokes; lean beef; broccoli; Brussels sprouts; cabbage; fish; pine nuts; tomato paste; wheat bran; toasted wheat germ.high-protein: meat, poultry, cottage cheese, wheat germ; eggs; yogurt; walnuts; dark complex carbohydrates: Brown rice; broccoli; lentils; almonds; bananas; whole grain oats; oranges; spinach; walnuts; whole grain wheat..tryptophan-rich: turkey; chicken; sausage; avocados; cheese; cottage cheese; ricotta; eggs; granola; oat flakes; luncheon meats; wheat germ; whole milk; yogurt.
Supplementsphospatidylcholine powder; choline powder; huperzine A; phosphatidylserine; dopa bean; Ginkgo biloba; piracetam; omega-3 fish oil; pregnenolone. Phenylalanine; tyrosine; methionine; rhodiola; pyroxidine; B complex; DHEA; phosphatidylserine; Ginkgo biloba; green tea extract. Inositol powder; thiamine; tryptophan; passionflower; melatonin; magnesium; glutamic acid; niacinamide; pyridoxine; valerian root.tryptophan; calcium; fish oil; 5-HTP; magnesium; melatonin; passionflower; pyridoxine; SAM-e; St. John’s Wort; zinc.

To achieve a healthy nervous system, the stimulatory and inhibitory neurotransmitters should be balanced as much as possible.  Sometime this is not as easy as it sounds.  However, it is important to achieve a synergistic energy between the stimulatory and inhibitory neurotransmitters in which they work together to create balance in the nervous system.

An imbalanced neurotransmitter system can be characterized by a low level of all four neurotransmitters or a low level of a few neurotransmitters and an excess of other neurotransmitters.  Neurotransmitter imbalances can lead to a number of symptoms and pathologies.  Such imbalances are linked to:

  • ADD/ADHD
  • Addiction or dependency
  • Adrenal dysfunction
  • Anxiety
  • Compulsive behavior
  • Cravings
  • Depression
  • Fatigue
  • Insomnia
  • Loss of appetite control
  • Loss of mental focus, or cognitive fog
  • Low libido
  • Migraines
  • Obsessive Compulsive Disorder
  • Poor sleep
  • Sexual dysfunction
  • Weight Issues

The cause of neurotransmitter imbalances can be defined by many different factors, including:

  • Alcohol
  • Caffeine usage
  • Dietary deficiencies
  • Digestive imbalances
  • Drug use (prescription and recreational)
  • Food intolerances
  • Genetic predisposition
  • Medication use, including antidepressants, anti-anxiety, sleep and migraine medications
  • Neurotoxins
  • Poor eating habits
  • Sleep disturbances
  • Stress
  • Toxic burden

Stress is often times the primary contributor to neurotransmitter imbalance. The nervous system uses up large amounts of neurotransmitters in order to cope with the ongoing stress.

A number of tests have been developed that may determine what neurotransmitters are low or imbalanced:

Dr. Braverman, M.D. of Path Medical in New York City has designed two interesting tests that can be taken quickly to determine your neurotransmitter dominance and neurotransmitter deficiency:

Another test is offered by Integrative Psychiatry and is used to determine neurotransmitter deficiency:

In addition to the written tests to determine neurotransmitter deficiencies, there are also medical lab tests that can be prescribed by a health care professional.  These medical tests include:


For a more in-depth analysis of each of the four neurotransmitters and how to enhance these neurotransmitters and create a balanced nervous system, please read the following articles below:

Acetylcholine

Dopamine

GABA

Serotonin


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Maintaining the Integrity of the Blood-Brain Barrier

The blood–brain barrier (BBB) is a highly selective permeability barrier that separates the circulating blood from the brain extracellular fluid (BECF) in the central nervous system (CNS). The blood–brain barrier is formed by capillary endothelial cells, which are connected by tight junctions with an extremely high electrical resistivity.

The BBB is distinct from the quite similar blood–cerebrospinal-fluid barrier, which is a function of the choroidal cells of the choroid plexus, and from the blood–retinal barrier, which can be considered a part of the whole realm of such barriers.

The BBB has several important functions:

  • Protects the brain from “foreign substances” in the blood that may injure the brain
  • Protects the brain from hormones and neurotransmitters in the rest of the body
  • Maintains a constant environment for the brain

The general properties of the BBB include:

  • Large molecules do not pass through the BBB easily
  • Low lipid (fat) soluble molecules do not penetrate into the brain. However, lipid soluble molecules, such as barbituate drugs, rapidly cross through into the brain
  • Molecules that have a high electrical charge are slowed

The BBB can be broken down (permeated) by:

  • Hypertension (high blood pressure): high blood pressure opens the BBB.
  • Hyperosmolitity: a high concentration of a substance in the blood can open the BBB.
  • Microwaves: exposure to microwaves can open the BBB.
  • Radiation: exposure to radiation can open the BBB.
  • Infection: exposure to infectious agents can open the BBB.
  • Trauma, Ischemia, Inflammation, Pressure: injury to the brain can open the BBB.

Through extensive study, scientists have found that compounds that are very small and/or fat-soluble, including antidepressants, anti-anxiety medications, alcohol, cocaine, and many hormones are able to slip through the endothelial cells that make up the blood-brain barrier without much effort. In contrast, larger molecules, such as glucose or insulin, must be ferried across by proteins. These transporter proteins, located in the brain’s blood vessel walls, selectively snag and pull the desired molecules from the blood into the brain.

When the blood-brain barrier breaks down, as is the case in some brain cancers and brain infections or when tiny ruptures to blood vessels occur, some substances that are normally kept out of the brain gain entry and cause problems for the brain.

Mercury penetrates the blood-brain barrier around the brain, and as little as one part per million can impair this barrier, permitting entry of substances in the blood that would otherwise be excluded.  1

There are a number of natural substances that can be consumed to maintain the integrity of and enhance the blood-brain barrier.  These natural substances are listed in the Table below:

Natural Substances that Maintain the Integrity of and Enhance the Blood-Brain Barrier

CategoryNatural SubstanceReferences
Foods
Bilberry1
Herbs
Ginko Biloba2
Hormones
Progesterone3
Polyphenols
Anthocyanins (Plants rich in anthocyanins are Vaccinium species, such as blueberry, cranberry, and bilberry; Rubus berries, including black raspberry, red raspberry, and blackberry; blackcurrant, cherry, eggplant peel, black rice, Concord grape, muscadine grape, red cabbage, and violet petals. Red-fleshed peaches and apples contain anthocyanins.)4 5
Curcumin6
Vitamins
Vitamin B1 (Vitamin B1 deficiency can lead to break down of BBB)7 8


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Amino Acid Conjugation Pathway in Metabolic Detoxification: Glycine is the Main Amino Acid

Phase 1 Biotransformation Process

The primary function of the Phase I biotransformation process is to either:

  • Biotransform a toxic lipophilic compound directly to a more hydrophilic compound so it can be directly excreted in the kidneys (e.g. caffeine). Though, Phase I usually results in only a small amount of direct hydrophilicity and excretion
  • The bulk of Phase I enzymatic activity takes place in the form of altering unwanted compounds in a way as to either expose or introduce a functional group. Functional groups such as: Carboxyl group (–COOH), hydroxyl group (– OH), amino group (-NH2), or sulfhydryl group/thiol (-SH)

In the Phase 1 detoxification process a toxic chemical is converted into a less harmful chemical through various chemical reactions.  Phase 1 is essentially responsible for breaking fat-soluble toxins down and then sending the raw materials to Phase 2 detoxification process.  Phase 2 is the addition or conjugation phase where new substances are added/conjugated to the toxic metabolites produced in Phase 1 in order to make them easier to transport, more stable and/or more functional for the body.

Phase 2 Conjugation Pathways

There are 6 Conjugation Pathways in the human body and they include:

  • Sulphation (sulfation) pathway
  • Glucoronidation pathway
  • Glutathione conjugation pathway
  • Acetylation pathway
  • Methylation (& Sulfoxidation) pathway
  • Amino Acid conjugation pathway (glycine, cysteine, glutamine, methionine, taurine, glutamic acid and aspartic acid)

These 6 conjugation pathways occur in different organs of the body.  The locations of the Phase 2 conjugation pathways are listed in Table 1.

  Table 1 Locations of Phase 2 Conjugation Systems

Conjugation System

Location in Body

Glycine conjugation

liver, kidney

Glutathione conjugation

liver, kidney

Glucuronidation

liver, kidney, intestine, lung, skin, prostate, brain

Acetylation

liver, lung, spleen, gastric mucosa, RBCs, lymphocytes

Sulphation

liver, kidney, intestine

Methylation

liver, kidney, lung, CNS

(Source:   Liston HL, Markowitz JS, DeVane CL (October 2001). “Drug glucuronidation in clinical psychopharmacology”. J Clin Psychopharmacol 21 (5): 500–15.)

Amino Acid Conjugation Pathway

The Amino Acid conjugation pathway is less utilized by the body, yet is still a very important conjugation pathway. 

The conjugation of toxins with amino acids occurs in this pathway. The amino acids commonly used in this pathway include:

  • Glycine
  • Taurine
  • Glutamine

but arginine, and ornithine are also used.

image

Figure 1:  Amino acid conjugation pathways

(Source:  Wikipathways)

The Amino Acid Conjugation Pathway often includes the Acylation Pathway.  Acylation uses acyl CO-A with the amino acids glycine, glutamine and taurine. Conjugation of bile acids in the liver with glycine or taurine is essential for the efficient removal of these potentially toxic compounds.  

The main amino acid in the Amino Acid Conjugation Pathway is glycine.  Glycine is the smallest of the 20 amino acids commonly found in proteins.  Glycine is a colorless, sweet-tasting crystalline solid. It is unique among the proteinogenic amino acids in that it is achiral. It can fit into hydrophilic or hydrophobic environments, due to its minimal side chain of only one hydrogen atom.

Since it plays such an important role in the Amino Acid Conjugation Pathway, it is also known as the Glycination Pathway.  Salicylates and benzoate are detoxified primarily through glycination. Benzoate is present in many food substances and is widely used as a food preservative.

In humans, there is a wide variation that exist in the activity of the glycine conjugation, which is primarily due not only to genetic variations, but also to the availability of glycine in the diet.

High-protein rich foods should be consumed in the diet to ensure that the amino acid conjugation is functioning properly.  There are a number of natural substances that induce the

Amino Acid Conjugation Pathway and act as co-factors in the conjugation process.  These substances are listed in Table 2. 

Table 2 Natural Substances that Induce the Amino Acid Conjugation Pathway

 

Category

Food

Minerals

 

 

Magnesium

 

Iron

Vitamin

 

 

B Complex Vitamins (particularly

Vitamin B3 and Vitamin B6)

Amino Acids

 

 

Glycine

 

Methionine

 

Taurine

 

Cysteine

 

Glutamine


Resources:

Life Extension – Glycine (Capsules)

NOW – Glycine (Powder)


Cover Photo Source:  Perfect Health Diet


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Vitamin D Deficiency is Associated with a Substantially Increased Risk of All-Cause Dementia and Alzheimer Disease

Vitamin D refers to a group of fat-soluble secosteroids (pro-hormones) responsible for increasing intestinal absorption of calcium, iron, magnesium, phosphate, and zinc, among other multiple functions.

For human therapeutic purposes, there are two important compounds in the vitamin D group:

  • Vitamin D2 (also known as ergocalciferol)
  • Vitamin D3 (also known as cholecalciferol)
Image result for cholecalciferol ergocalciferol

Vitamin D deficiency is associated with a substantially increased risk of all-cause dementia and Alzheimer disease

A  number of research studies have indicated that low levels of 25-hydroxyvitamin D is associated with the development of dementia and ultimately Alzheimer’s disease.

In a study from October 2014, epidemiological evidence strongly suggests that circulatory levels of 25-hydroxyvitamin D below 50 nmol/l are associated with cognitive impairment and the development of dementia.  1    

Image result for vitamin d alzheimers

Figure 1. Circulatory levels of 25-hydroxyvitamin D below 50 nmol/l are associated with cognitive impairment and the development of dementia   (Source)

In another study from August 2014, researchers sought to determine whether low vitamin D concentrations are associated with an increased risk of incident all-cause dementia and Alzheimer disease. 

One thousand six hundred fifty-eight elderly ambulatory adults free from dementia, cardiovascular disease, and stroke who participated in the US population–based Cardiovascular Health Study between 1992–1993 and 1999 were included. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected in 1992–1993.

During a mean follow-up of 5.6 years, 171 participants developed all-cause dementia, including 102 cases of Alzheimer disease.

Using Cox proportional hazards models, the multivariate adjusted hazard ratios (95% confidence interval [CI]) for incident all-cause dementia in participants who were severely 25(OH)D deficient (<25 nmol/L) and deficient (≥25 to <50 nmol/L) were 2.25 (95% CI: 1.23–4.13) and 1.53 (95% CI: 1.06–2.21) compared to participants with sufficient concentrations (≥50 nmol/L).

The multivariate adjusted hazard ratios for incident Alzheimer disease in participants who were severely 25(OH)D deficient and deficient compared to participants with sufficient concentrations were 2.22 (95% CI: 1.02–4.83) and 1.69 (95% CI: 1.06–2.69). In multivariate adjusted penalized smoothing spline plots, the risk of all-cause dementia and Alzheimer disease markedly increased below a threshold of 50 nmol/L.

Researchers confirmed that vitamin D deficiency is associated with a substantially increased risk of all-cause dementia and Alzheimer disease. This adds to the ongoing debate about the role of vitamin D in nonskeletal conditions.  2

171 participants developed all-cause dementia

102 participants developed Alzheimer disease

The risk of all-cause dementia and Alzheimer disease markedly increased below a threshold of 50 nmol/L.

In a study from May 2014, researchers hypothesized that reduced plasma 25-hydroxyvitamin D (25[OH]D) is associated with increased risk of Alzheimer’s disease (AD) and vascular dementia in the general population.  They measured baseline plasma 25(OH)D in 10,186 white individuals from the Danish general population.

During 30 years of follow-up, 418 participants developed AD and 92 developed vascular dementia. Multivariable adjusted hazard ratios for AD were 1.25 (95% confidence interval [CI], 0.95-1.64) for 25(OH)D less than 25 nmol/L vs. greater than or equal to 50 nmol/L, and 1.29 (95% CI, 1.01-1.66) for less than the 25th seasonally adjusted 25(OH)D percentile vs. more than the 50th seasonally adjusted 25(OH)D percentile. Multivariable adjusted hazard ratios for vascular dementia were 1.22 (95% CI, 0.77-1.91) for 25(OH)D less than 50 nmol/L vs. greater than or equal to 50 nmol/L, and 1.22 (95% CI, 0.79-1.87) for less than or equal to the 50th vs. more than the 50th seasonally adjusted 25(OH)D percentile.

Researchers observed an association of reduced plasma 25(OH)D with increased risk of the combined end point of AD and vascular dementia in this prospective cohort study of the general population.  3

418 participants developed Alzheimer disease

92 participants developed vascular dementia

The risk of vascular dementia and Alzheimer disease markedly increased below a threshold of 50 nmol/L.

Testing for Vitamin D levels in Blood Serum

Vitamin D levels in the blood serum can be tested with a blood draw test.  Both forms of vitamin D can be tested.  The names of the tests are:

  • 25-hydroxyvitamin D3 (cholecalciferol)
  • 25-hydroxyvitamin D2 (ergocalciferol)

The Vitamin D Council has written about the various levels of 25(OH)D and their recommendations of how much vitamin D3 to supplement to raise it to safe levels.

Image result for vitamin d council vitamin d levels

The Vitamin D Council suggests that a level above 50 ng/ml and below 80 ng/ml is the ideal level to aim for. This is why the Council recommends that adults take 5,000 IU/day of vitamin D supplement in order to reach and stay at this level.

Foods that Contain Vitamin D2 and Vitamin D3

There are a limited number of foods that contain vitamin D2 and vitamin D3.  There are more of a variety of foods that contain vitamin D3 than vitamin D2.  Of all the foods that contain vitamin D2 and D3, none of them have high quantities, with maybe cod liver oil as the exception.

Because there are limited amounts of foods that contain vitamins D2 and D3, it is necessary to supplement with vitamin D3 to reach the acceptable levels of 25-OH-D.

Vitamin D2

Very few foods contain Vitamin D2:

All of the above listed foods contain less than 600 IU’s per 100 grams.

Vitamin D3

Most vitamin D3 found in food is from animal sources (fish, eggs, beef):

  • Lichen (Cladina arbuscula)
  • Cod liver oil (4.5 g (1 teaspoon) provides 450 IU (100 IU/g))
  • Salmon
  • Mackerel
  • Tuna
  • Sardines  (canned in oil)
  • Egg yolk  (cooked)
  • Beef liver  (cooked, braised)

Other than cod liver oil, all other foods that contain vitamin D3 contain less than 600 IU’s per 100 grams.

Very few foods contain vitamin D so the synthesis of vitamin D (specifically cholecalciferol) is through the skin. Dermal synthesis of vitamin D from cholesterol is dependent on sun exposure (specifically UVB radiation).  

Informational References:

Vitamin D Council

Vitamin D Day  

Detoxifying Heterocyclic aromatic amines (HCAs) and Polycyclic aromatic hydrocarbons (PAHs) with Chlorella vulgaris

Heterocyclic aromatic amines (HAAs) and polycyclic aromatic hydrocarbons (PAHs) have been identified by scientific research as carcinogenic chemicals in the diet. 

Heterocyclic aromatic amines (HAAs)

Heterocyclic aromatic amines are a group of 20 chemical compounds formed during cooking. They are found in meats that are cooked to the well done stage, in pan drippings, and in meat surfaces that show a crispy brown crust.

Related image

Epidemiological studies show associations between intakes of heterocyclic aromatic amines and cancers of the:

  • colon
  • rectum
  • breast
  • prostate
  • pancreas
  • lung
  • stomach
  • esophagus

The U.S. Department of Health and Human Services Public Health Service labeled several heterocyclic aromatic amines as likely to be carcinogenic to humans in its most recent Report on Carcinogens.  1 

The most common types of Heterocyclic Aromatic Amines (HAAs) include:

  • 4,8-DiMelQx 2-Amino-3,4,8-Trimethylimidazo [4,5-f]Quinoxaline
  • 8-MelQx 2-Amino-3,8-Dimethylimidazo [4,5-f]Quinoxaline
  • IQ 2-Amino-3-Methylimidazo [4,5-f]Quinoline
  • MelQ 2-Amino-3,4-Dimethylimidazo [4,5-f]Quinoline
  • PhIP 2-Amino-1-Methyl-6-Phenylimidazo [4,5,b]Pyridine
  • TMIP 2-Amino-N,N,N-Trimethylimidazopyridine

HAAs form when Amino Acids and Creatine present in muscle Meats react at high temperatures (above 100° C). Temperature is the most important factor in formation of HAAs. Frying, Grilling, and Barbecuing produce the largest amounts of HAAs because the Meats are cooked at very high temperatures. Roasting and Baking are done at lower temperatures, so lower levels of HAAs are likely. Microwaving, Stewing, Boiling, or Poaching are done at or below 100° and cooking at this low temperature creates negligible amounts of HAAs.

Polycyclic aromatic hydrocarbons (PAHs)

Polynuclear aromatic hydrocarbons (PAH) are potent atmospheric pollutants. Some compounds have been identified as carcinogenic, mutagenic, and teratogenic.

Image result for polycyclic aromatic hydrocarbons

The EPA has classified seven PAH compounds as probable human carcinogens:

  • benz[a]anthracene,
  • benzo[a]pyrene,
  • benzo[b]fluoranthene,
  • benzo[k]fluoranthene,
  • chrysene,
  • dibenz(a,h)anthracene, and
  • indeno(1,2,3-cd)pyrene

The source of PAH’s include:

  • Car exhaust
  • The smoke generated by various cooking methods
    • High heat grilling
    • Barbequing
    • Smoked foods (meats, fish,etc.)
  • Tobacco smoke

Detoxifying Heterocyclic aromatic amines (HAAs) and Polycyclic aromatic hydrocarbons (PAHs) with Chlorella vulgaris

A randomized, double blind, placebo-controlled crossover study from January 2015 assessed the ability of Chlorella vulgaris to detoxify carcinogenic HAAs and PAHs.   Researchers analyzed urine specimens of 6 females with ages around 27 years for 2 weeks.  Urine specimens showed high levels of three HAAs, specifically:  2

  • MeIQx                 323.36±220.11ng/L
  • PhIP                    351.59±254.93ng/L
  • IQx-8-COOH       130.85±83.22ng/L

Consumption of Chlorella vulgaris significantly reduced urinary levels of MeIQx:

  • Before    430±226.86pg/mL
  • After       174.45±101.65pg/mL

Urinary levels of PhIP or IQx-8-COOH, a major metabolite of MeIQx, were not changed by chlorella supplementation.  

Natural Anticoagulant Regimen from Dr. Phillip Lee Miller

Dr. Philip Lee Miller, MD is the Founder, Medical Director and CEO of California Age Management Institute.  He has been in medical practice for over 43 years.

He graduated from UC Berkeley in 1968 (Centennial ) with a degree in Biochemistry.  In 1972 he graduated from the School of Medicine at UC San Diego with an MD degree.  This was the school’s first (charter) graduating class.  There was further training in Neurology at UC Davis.  He was ABEM Board Certified in Emergency and is currently a Diplomat of the ABAAM Board.

Dr. Miller has become a recognized leader in anti aging and integrative medicine.

Dr. Miller has written a very interesting four-part series on a natural anticoagulant regimen on his antiaging blog.

The four articles include:

Coagulation Stroke Heart Attack Part 1

Coagulation Heart Attack and Stroke – Part 2

AntiPlatelet AntiCoagulant Drugs

Anticoagulant Natural Alternative

Dr. Miller’s has identified five powerful natural anticoagulants.  They include the following:

  • Nattokinase — 100 mg (2000 FU) twice daily
  • Ginkgo biloba — 120 mg daily
  • High-dose fish oils — 1 tablespoon (10 grams) daily
  • Vitamin E — 400-800 units of mixed tocopherols daily
  • Adequate hydration — many glasses of pure water daily  

Natural Substances that May Potentially Detoxify Certain Environmental Toxins

Environmental toxins or toxicants are universal and are virtually impossible to avoid anywhere in the world.  There are, of course, more pristine areas of the world than others, but in this day and age your exposure to environmental toxins, to a certain extent, are inevitable.

Having a good understanding of the most prevalent and health damaging environmental toxins is important to maintaining overall health and avoiding possible disease pathologies, especially cancer and neurological disorders. 

There are a number of online resources that can educate you on these environmental toxins.  Four important resources are listed below:

Toxicology and Environmental Health Information Program (TEHIP)

The National Library of Medicine (NLM) Toxicology and Environmental Health Information Program (TEHIP) evolved from the Toxicology Information Program (TIP) that was established in 1967 at the (NLM) in response to recommendations made in the 1966 report “Handling of Toxicological Information,” prepared by the President’s Science Advisory Committee.

TEHIP maintains a comprehensive web site that provides access to resources produced by it and by other government agencies and organizations. This web site includes links to databases, bibliographies, tutorials, and other scientific and consumer-oriented resources. TEHIP also is responsible for the Toxicology Data Network (TOXNET®), an integrated system of toxicology and environmental health databases that are available free of charge on the web.

The Agency for Toxic Substances and Disease Registry (ATSDR)

The Agency for Toxic Substances and Disease Registry (ATSDR), based in Atlanta, Georgia, is a federal public health agency of the U.S. Department of Health and Human Services. ATSDR serves the public by using the best science, taking responsive public health actions, and providing trusted health information to prevent harmful exposures and diseases related to toxic substances.

U.S. Environmental Protection Agency’s Toxics Release Inventory (TRI) Program

TRI is a resource for learning about toxic chemical releases and pollution prevention activities reported by industrial and federal facilities. TRI data support informed decision-making by communities, government agencies, companies, and others.

The Environmental Working Group

The Environmental Working Group’s mission is to empower people to live healthier lives in a healthier environment. With breakthrough research and education, we drive consumer choice and civic action. We are a non-profit, non-partisan organization dedicated to protecting human health and the environment. 


Despite the fact that there have been hundreds of environmental toxins identified and categorized, this article will only focus on eleven (11) common environmental toxins and examine their various sources and possible disease pathologies that may develop as a result of exposure.  These eleven environmental toxins include:

  • Aluminum
  • Asbestos
  • Benzo[a]pyrene (Polycyclic aromatic hydrocarbon)
  • Bisphenol A (BPA)
  • Chloroform
  • Cyanide
  • Dioxins
  • Formaldehyde
  • Heterocyclic amines
  • Perchlorate
  • Polycyclic aromatic hydrocarbons

The Table below lists the eleven environmental toxins and their sources and possible disease states based on ongoing exposure:

List of Certain Environmental Toxins

ToxinSourcesPotential Diseases
AluminumAluminum is used for beverage cans, pots and pans, airplanes, siding and roofing, and foil. Aluminum is often mixed with small amounts of other metals to form aluminum alloys, which are stronger and harder. Aluminum compounds have many different uses, for example, as alums in water-treatment and alumina in abrasives and furnace linings. They are also found in consumer products such as antacids, astringents, buffered aspirin, food additives, and antiperspirants.Musculoskeletal (Muscles and Skeleton), Neurological (Nervous System), Respiratory (From the Nose to the Lungs)
AsbestosInsulation on floors, ceilings, water pipes and heating ducts from the 1950s to 1970sAsbestos is linked to increased risk of lung cancer, and development of mesothelioma (cancer of the thin lining surrounding the lung (pleural membrane) or abdominal cavity (the peritoneum)) and laryngeal cancer. Cancer may appear 30 to 50 years after exposure.
Bisphenol A (BPA)It is used in making all kinds of plastics and resins, including water bottles and food containers. It is used in hard plastics, food cans, drink cans, receipts, and dental sealants.BPA is an endocrine disruptor linked to breast and prostate cancer.
ChloroformAir, drinking water and food can contain chloroform. Other names for chloroform are trichloromethane and methyl trichloride.Cardiovascular (Heart and Blood Vessels), Developmental (effects during periods when organs are developing) , Hepatic (Liver), Neurological (Nervous System), Renal (Urinary System or Kidneys), Reproductive (Producing Children)
DioxinsDioxins are a group of chemicals formed as unintentional byproducts of industrial processes involving chlorine, such as waste incineration, chemical manufacturing, and pulp and paper bleaching. Dioxins include polychlorinated dibenzo dioxins (PCDDs), polychlorinated dibenzo furans (PCDFs), and the polychlorinated biphenyls (PCBs). Exposure is through the ingestion of contaminated foods and, to a lesser extent, dermal contact. Farm-raised salmon. Most farm-raised salmon, which accounts for most of the supply in the United States, are fed meals of ground-up fish that have absorbed PCBs in the environment. Polychlorinated biphenyls (PCBs) are commonly found in foods of animal origin (meat, dairy, and fish, depending on the country of origin)cancer classification depends on the dioxin: 2,3,7,8-TCDD (Agent Orange) is a known human carcinogen; some other dioxins are probable or possible human carcinogens.
FormaldehydeFormaldehyde can be found in a variety of building and home decoration products (as urea-formaldehyde resins and phenol-formaldehyde resin). It is also used as a preservative and disinfectant.Exposure is through inhalation and dermal contact. Automobile exhaust is the greatest contributor to formaldehyde concentrations in ambient air. Construction materials, furnishings, and cigarettes account for most formaldehyde in indoor air.Formaldehyde has caused nasal cancer in rats after long term exposure; it is linked to leukemia and nasopharygeal cancer in humans. It is a known human carcinogen.
Heterocyclic aminesChemicals that form when meat is cooked at high temperatures (e.g., grilled or broiled)Some heterocyclic amines (HCAs) found in cooked and especially burned meat are known carcinogens. Harmane, a β-carboline alkaloid found in meats, has been shown to have strong neurotoxic characteristics, and in particular, is "highly tremorogenic" (tremor inducing).
PerchlorateThe dominant use of perchlorates are for propellants in rockets. Of specific value is Ammonium perchlorate composite propellant as a component of solid rocket fuel. Low levels of perchlorate have been detected in both drinking water and groundwater in 26 states in the U.S., according to the Environmental Protection Agency.Perchlorate is a potent competitive inhibitor of the thyroid sodium-iodide symporter. Some studies suggest that perchlorate has pulmonary toxic effects as well.
Polycyclic aromatic hydrocarbonsThey are products of fossil fuel combustion, particularly petrochemicals, and are a major source of cancer-causing chemicals in polluted air. Polycyclic aromatic hydrocarbons (PAHs) form as a result of incomplete combustion of organic compounds: combustion from wood and fuel in residential heating, coal burners, automobiles, diesel-fueled engines, refuse fires, and grilled meats. They are found in coal tar and coal tar pitch, used for roofing and surface coatings. Exposure to these lipophilic substances results from inhalation of polluted air, wood smoke, and tobacco smoke, and ingestion of contaminated food and water. PAHs are reasonably anticipated to be a human carcinogen. PAHs have been linked to skin, lung, bladder, liver, and stomach cancers in well-established animal model studies. 1

In addition to the conscious avoidance and non-exposure to these eleven environmental toxins, (e.g., non-exposure to polycyclic aromatic hydrocarbons can be avoiding or minimized by not consuming grilled, barbequed or fried meats), there are a number of natural substances that have been researched for their ability to counteract the environmental toxin and/or assist the body in detoxifying the toxin from the body by stimulating the Phase I or II metabolic detoxification system.

The Table below lists those natural substances that may potentially assist in the detoxification of the eleven environmental toxins:

Natural Substance that Detoxify Certain Environmental Substances

ToxinPotential Substances that DetoxifyReference
Aluminum
N-acetylcysteine (NAC)1
Ethylene-Diamine-Tetra-Acetate (EDTA)2
Melatonin3
Selenium4
Silicon5
Malic acid6
Citric acid7
Folic acid (folate)8
Vitamin C9
Vitamin E10
Ginko Biloba11
Propolis12  13
Magnesium14
Centrophenoxine15  16  17
Bacopa monniera18
Cnidium monnieri19
Asbestos
Green Tea20
Garlic21
Benzo[a]pyrene (Polycyclic aromatic hydrocarbon)
Calcium D-Glucaric Acid22
Quercetin23
Vitamin C24
Vitamin E25
Blueberries, raspberries, strawberries26
Bisphenol A (BPA)
Sage (Salvia)27
ChloroformN-acetylcysteine (NAC)28
Dioxins
Chitosan31
Curcumin32
Resveratrol33
Chlorophyllin34
Vitamin A35
Vitamin E36
Chlorella38 39  
Green Tea40
Korean Ginseng41
Wakame seaweed42
Formaldehyde
Melatonin43
Vitamin C44
Vitamin E45
Heterocyclic amines
Indole-3-Carbinol46
Caffeic Acid47
Curcumin48
Epigallo-Catechin-Gallate (EGCG)49
Luteolin50
Quercetin51
Chlorophyllin52 53  
Natto54
Rosemary55
Broccoli56
Brussels Sprouts57
Perchlorate
Iodine58
Polycyclic aromatic hydrocarbons
Lycopene59
Resveratrol60
Chlorophyllin61
Green Tea62
Vitamin C63
Vitamin E64


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