Anti-Inflammatory Diet

All health care starts with diet. My recommendations for a healthy diet are here:
Anti-Inflammatory Diet and Lifestyle.
There are over 190 articles on diet, inflammation and disease on this blog
(find topics using search [upper left] or index [lower right]), and
more articles by Prof. Ayers on Suite101 .

Friday, November 28, 2008

Melamine Contaminated Formula

Baby formula is called, in the medical profession, an artificial milk substitute. It is made of highly processed food additives, and all of these additives are prone to contamination. The recent melamine scare is just the most recent example of dangerous contamination. With breast milk, the mother’s body provides another detoxification barrier to protect babies from food contaminants. Mother’s who eat melamine-contaminated food don’t pass the toxin on to their babies, but melamine-contaminated formula can kill babies.

When you look at the structure of melamine, you see a lot of nitrogen atoms, and since protein is frequently measured in food products by measuring nitrogen content, melamine mimics protein. Since protein is expensive and melamine is cheap, people can make money by diluting protein solutions, such as milk, and adding melamine to make it look as if it has the normal protein composition. In China, that little bit of subterfuge resulted in the hospitalization of thousands of children. Melamine may act like protein in simple nitrogen assays, but the body doesn’t have enzymes to react with it or transport proteins to excrete it. Melamine forms crystals, blocks kidneys and kills small people.

The newest threat is based on the report of a trace amount of melamine in formula in the US. It is hard to determine how the melamine got into the formula, because formula is made of dozens of highly processed and synthetic ingredients. Production of this artificial milk substitute from so many different sources has resulted in dozens, if not hundreds of contamination incidents.

Formula is a gut flora disrupter. In contrast to the trend toward prebiotics to support healthy anti-inflammatory probiotic bacteria in the gut, research shows that even a single feeding of formula will shift the gut flora of a newborn to an inflammatory composition. Gut inflammation, along with delayed intestinal development and absence of breast milk’s immunity enhancers, are considered to be the reasons why formula lowers intelligence (5-10 IQ pts.) and increases the incidence of allergic, autoimmune and infectious disease. Formula can be tolerated by babies in developed countries, because of the high hygiene. Formula use in developing countries is unsafe. In fact even though there is a small risk of transfer of HIV from an HIV positive mother to baby by nursing, it is safer for HIV positive mothers to breastfeed in some countries than to use formula.

The presence of melamine in formula would result in the introduction of a toxic compound into a immune compromised baby. It is very important to test formula very carefully for even seemingly innocuous contaminants. Breastfed babies would be protected from melamine even if the mother ingests melamine-contaminated food, because toxins, including most pharmaceuticals, are not passed into breast milk. Breast milk is the anti-inflammatory diet for babies and should be encouraged at least until solid food is started after the emergence of two teeth, top and bottom. The American Academy of Family Practice Physicians recommends breastfeeding for at least two years with exclusive breastfeeding (no formula or solid food) for the first six months. The worldwide average weaning age is 4 years.

Thursday, November 27, 2008

Turkey, Tryptophan & Transmitters

Does eating turkey make you stuffed and drowsy? It must the be tryptophan... or not. Sure there is tryptophan in turkey and tryptophan is the starting point for making some neurotransmitters and hormones, but turkey meat is simply protein and fat. Tryptophan (left) is just one of the twenty amino acids found in most proteins, so the drowsiness after the big Turkeyday dinner is more about the “big” and less about the turkey.

Turkey meat is muscle and muscle, as the diagram shows is made of protein molecules that use energy in the form of ATP to move past each other and contract. We chew up the turkey muscle and our stomach juices contain enzymes (these “proteases” are also proteins) that reverse the process of protein synthesis and produce protein fragments called peptides. The specificity of the proteases in the stomach, e.g. pepsin, results in peptides containing intact heparin-binding domains that are also antimicrobial. In the intestines, a new group of proteases are added by the pancreas and the peptides are further reduced in size and heparin-binding domains are degraded. [Pathogens need heparin-binding domains to bind to the intestines.] The remaining peptides bind to the microvilli of the endocytes lining the small intestines, surface bound peptidases release individual amino acids and transport proteins bring amino acids into the endocytes and on to the blood stream.

In the brain, tryptophan is converted by a series of enzymes into serotonin and the serotonin is stored in secretory vesicles adjacent to the synapse that controls signals between nerves. A nerve action potential moves down the axon from the cell body to the synapse. The change in electrical potential reaching the synapse causes the secretory vesicles to fuse with the cytoplasmic membrane and release the serotonin into the synapse. The serotonin binds to the receptors of the adjacent nerve and starts a new action potential that travels to the next nerve body to repeat the process. The synapse is reset by reuptake or degradation of the serotonin. The degradation product, 5-HIAA, is removed into the blood and excreted in urine.

Turkey tryptophan does get converted into serotonin and high serotonin could make you mellow, but turkey is just like any other meat source of tryptophan. The big meal just makes you groggy, because there is less blood to your brain when the mysenteric blood flow is enhanced for digestion. There may also be a rise in blood sugar as the starch off your plate is rapidly converted into glucose in your blood. The potentially damaging high blood sugar is controlled by a rise in insulin that lowers glucose in the blood by stimulating transport into fat cells for immediate conversion into fat. The starch from the meal is rapidly depleted, blood sugar rises and then sudden falls. The low blood sugar also leaves you groggy.

So it was the size of the meal (decreased brain blood flow) and the sweet potatoes and rolls (starch-induced hypoglycemia) that induced you to kickback on the sofa and pass out with the big game lulling you to sleep. Tryptophan from the big bird is in the background waiting for you to awaken. Before you take the first mouthful, check to make sure that your meal follows the anti-inflammation guidelines. Planning ahead can help you to enjoy a meal that won't be a pain later.

Wednesday, November 26, 2008

CIDP, Inflammation and Autoantigens

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is chronic, relapsing autoimmune disease in which the immune system attacks the insulating myelin sheaths of nerves in the limbs. The result is numbness and pain. An acute version of this myelin compromising disease is Guillain-Barre syndrome (GBS) typically initiated by Campylobacter jejuni infection. A related disease of brain tissue is multiple sclerosis (MS). In each of these cases antibodies bind to protein or glycolipid antigens unique to myelin and target the attack by lymphocytes.

Autoimmune diseases represent a disruption of the normal function of the immune system that arises from a breakdown of the self/non-self tolerance process. Immune responses by antibodies or lymphocytes is normally reserved for molecules that don’t exist in the body, i.e. self. Differentiation of lymphocytes in the thymus or bone marrow involves systematic elimination of all lymphocytes that interact with self antigens. There are, however, self antigens that are not normally encountered by the immune system, e.g. nuclear antigens, brain antigens, since these antigens are only excluded from the cytoplasm or result from specialized differentiation. Thus, you can find in mystery novels the use of letters coated with powdered brain antigen to slowly kill targets by induction of a lethal autoimmune disease.

The self antigens that are the typical targets of the CIDP, GB and MS are gangliosides, myelin glycolipid also produced by C. jejuni, and basic proteins such as peripheral myelin protein 22. The glycolipid makes sense, because the initial exposure is during a bacterial infection that also produces inflammation. The basic proteins are a different case.

I have examined numerous self or autoantigens that are the targets for antibodies produced in autoimmune diseases and allergies. In each case the same amino acid sequence or domain is present, three basic (positively charged, arginine or lysine) amino acids. This is true for the myelin autoantigens; allergens from ragweed, mites, peanut, etc.; diabetes, lupus and arthritis.

Here is the example of the CIDP autoantigen, peripheral myelin protein 22:

The three basic amino acids, RKR, are at the end of the protein amino acid sequence.

A dramatic instance of tissue damage caused by physical injury or infection, is superimposed on chronic dietary inflammation to provide the environment for an inappropriate response of the immune system to a self or identical foreign antigen. The only proteins that seem to be presented in this way to the immune system are those with the strong heparin-binding domain, BBB (B = basic amino acid). This indicates that perhaps the reduction in heparin production that accompanies inflammation, may be responsible for the aberrant immune response. It is also noteworthy that heparin and anti-inflammatory agents can reduce the symptoms of many autoimmune diseases.

There are many complex therapies to deal with the symptoms of these autoimmune diseases. In all of these cases, one of the most effective approaches is an anti-inflammatory diet and lifestyle. A novel additional approach is helminth therapy, infection with parasites to suppress the T-lymphocyte autoimmune attack. This approach is effective with MS, and I think would be an excellent, relatively safe approach to be examined for the other myelin autoimmune diseases.

Tuesday, November 25, 2008

Hazards of Air Travel: DVT

Deep Vein Thrombosis (DVT) -- clots in your veins

Air travel during the holidays means sitting quietly for hours while the blood pools in the major veins of your legs. This is a test. How have you been eating lately? If you stuck to an anti-inflammatory diet and got your exercise, just fidgeting a little and flexing your legs ever once in a while should avoid clots. If you are the typical sedentary American with an inflammatory diet, then worry. One tenth of you will typically have clots in your leg veins after a long flight.

Rolling stones gather no moss, and the same is true for rapidly moving red blood cells (RBCs). Keep them moving and they don’t stick together. Slow down RBCs traveling along sticky vessel walls and you have problems. RBCs have no nuclei and since the intracellular secretory system originates from the outer membrane of the nucleus, red blood cells don’t secrete anything. RBCs just age until they are removed by the spleen. So RBCs just move passively with the rest of the blood.

Another player in clot formation is the platelet. Platelets are cell fragments. They are formed by extrusion and shearing. The process is like bubbles forming as you blow air through a child’s bubble wand. Cells in the bone marrow are squeezed through a grid and the extruded fingers of the cells are blown away in the blood flow as platelets. The electron micrograph shows a platelet between and RBC and a white blood cell. Platelets don’t have any active cell machinery, so they are just little bags containing secretory vesicles that can be released by triggering of receptors on their surface. Platelets are only good for one shot of release.

Platelet release of secretory contents is triggered by norepinephrin, ADP and PGI2, an inflammatory prostaglandin produced from the omega-6 arachidonic acid. Norepinephrin is one of the fight-or-flight hormones that prepares the vascular system for damage control. ADP is released from other activated platelets and insures that isolated platelets are not randomly activated.

One of the proteins released is platelet factor 4. I have illustrated PF4 and the strip of basic amino acids (blue) that girdles the protein are readily apparent. PF4 binds strongly to heparin. Since the clotting process is normally under heparin inhibition, PF4 release from platelets removes the heparin inhibition and promotes clotting. ADP is also released and promotes further activation of other platelets.

Clot formation occurs in response to stress (norepinephrin), damage (vascular inflammation) and a consensus of platelets (ADP). Chronic inflammation can mimic this combination of signals through its impact on heparin metabolism. My research suggests that inflammation lowers heparin synthesis. An example of this effect is kidney damage caused by diabetes. High blood sugar causes inflammation of the kidney blood vessels, this reduces heparin production and since heparin lining the vessels is needed to retain proteins as blood is filtered in the kidney, protein is lost into the urine, i.e. proteinuria. Similarly, chronic inflammation can disrupt the blood brain barrier that is also made up of heparin.

A major source of chronic inflammation is an inflammatory diet. A recent research study indicated that a typical inflammatory American diet leads to elevated risk for deep vein thrombosis. Alternatively, an anti-inflammatory diet rich in B vitamins and omega-3 oils minimized DVT. Saturated fats had no impact, consistent with the lack of evidence supporting the shift from saturated fats to toxic omega-6-rich polyunsaturated vegetable oils.

So, the best thing that you can do to protect yourself from clots when you travel over the holidays, is to eat right and get your exercise, before you travel. Avoid starch (in large amounts) and polyunsaturated vegetable oils (except olive oil.) Corn oil, soy oil, cottonseed oil and safflower oil are particularly inflammatory. Eat plenty of veggies and fruits and enjoy the turkey and cranberries. Make sure that the only sweeteners used are sugar and honey (avoid high fructose corn syrup.) Light corn syrup is the stealth form of HFCS -- it may be lower in calories, since fructose is sweeter than sugar, but it is highly inflammatory! (Research also indicates that fructose causes premature wrinkling and skin aging, by enhancing the crosslinking of collagen. HFCS also causes type II diabetes in lab animals.)

Monday, November 24, 2008

Crohn’s Disease and Cryptidins

The intestines produce enzymes to digest food, antimicrobial peptides to kill pathogens and have lots of surface area to absorb nutrient molecules released from the food macromolecules (protein, polysaccharides, fats). The epithelial cells that line the intestines, enterocytes, must communicate with bacteria in the gut, the gut flora, to maintain bacteria helpful in food digestion, i.e. probiotic bacteria, and trigger an immune response to eliminate pathogens. Probiotic bacteria are tolerated and pathogens are identified and attacked.

Enterocytes are produced by division of stem cells at the bottom of the crypts that are in the valleys between the villi that project into the lumen where the digesting food is. New enterocytes are added at the base of the villi and old enterocytes are sloughed off at the top of the villi. As the new enterocytes move up the villi, they differentiate to produce the dramatic surface of microvilli, the furry brush border that further expands their surface area. The mature enterocytes produce transport proteins on their microvilli to take up sugars, amino acids and fats. The small nutrient molecules pass through the base of the enterocytes and bath the cells below, the lamina propia. The nutrients enter the capillaries of the villi and travel to the liver. Fats are transported through the lymphatic system.

Bacteria that slip through the enterocyte layer encounter macrophages and other types of white blood cells of the lamina propia. Among these cells are the Paneth cells. Fragments of the cell walls of bacteria bind to the NOD proteins of the Paneth cells and trigger the secretion of antimicrobial peptides, the cryptidins. Cryptidins are antimicrobial because of their array of basic amino acids surrounded by hydrophobic amino acids. These short proteins are able to disrupt the membrane function of most bacteria. I think they work on bacteria the same way that amyloid proteins, e.g. amyloid plaque proteins of Alzheimer’s disease, kill human cells. In fact, amyloid fibers bind to heparin and so do antibiotic peptides.

Here is an example of an antibiotic peptide, cryptidin 4,


Note the pairs of basic amino acids (blue). These amino acids are necessary for toxicity to bacteria. Heparin binding domains from proteins are produced naturally as proteins are digested to peptides in the stomach by pepsin. Pepsin hydrolyzes proteins next to the basic amino acids and leaves antimicrobial peptides that sterilize incoming food. I have illustrated the cryptidin protein to show how the basic amino acids (blue) are displayed on its surface.

With each meal, the fat content normally stimulates the production of a hormone, cholecystokinin, that binds to a receptor and causes an anti-inflammatory release of cytokines from the vagus nerves that reach the villi. Thus, food normally makes the intestines more tolerant of food antigens.

If the intestines become chronically inflamed, then exposure to normal probiotic bacteria can lead to cycles of inflammation that damage the integrity of the intestines. The intestines lose the ability to discriminate between probiotic and pathogen.

Crohn’s disease is an inflammatory, autoimmune disease of the bowel. The chronic inflammation of the lamina propia eliminate the ability of the Paneth cells to produce cryptidins and bacteria set up residence in the crypts and cause continual inflammation. This disease is typically treated by suppressing inflammation and treating with antibiotics.

Other treatment approaches that have been found effective are omega-3 oils to stimulate production of anti-inflammatory prostaglandins, pre- and probiotics, heparin and helminth eggs, e.g. wireworm.

Crohn’s disease would seem to benefit from the standard recommendation of an anti-inflammatory diet and lifestyle.

Friday, November 21, 2008

Fecal Transplants

Grey’s Anatomy, “In the Midnight Hour,” episode 8 of season 5 includes a fecal transplant from a recalcitrant husband to his anxious, antibiotic-compromised wife. Drama aside, fecal transplants, the introduction of gut bacteria from a healthy donor into a patient for treatment, represent a powerful potential therapy. Your gut flora may be your health destiny.

Here is a smattering of the recent biomedical research literature that is an indication of the influence of gut flora on health:

  • The appendix has been identified as a bacterial reservoir to reestablish gut flora after diarrhea clears the gut.
  • Fecal transplants between obese and lean patients reverses weight gain patterns.
  • Hospital-acquired Clostridium infections can be treated with fecal transplants.
  • Success of total gut transplants is improved by retaining the gut flora of the donor.
  • Formula disrupts the gut flora of newborns leading to lower intelligence and increased morbidity.
  • Prebiotics change gut flora and enhance beneficial bacteria, probiotics, that reduce inflammation and promote health.
  • The National Institutes of Health have launched a major initiative to identify the bacteria that live in and on the human body.

Most of the migratory cells of the immune system are in residence in intestinal tissues that communicate with gut flora and ingested contents. What we eat determines our gut flora, but our gut bacteria also communicate with the intestines and alter our inflammatory/immune status. This gut/bacteria communication controls the shift of the gut from tolerant suppression of immunological responses to mundane food molecules, to alarmed defense against pathogens. Mistakes in communication can lead to susceptibility to pathogens or autoimmune diseases of the gut, joints, brain, etc.

The dawning recognition of the importance of the symbiotic relationship between gut and bacteria on health and disease, is also spawning numerous interventions that involve injecting donor bacteria into patient intestines. This type of procedure may be the next fad. Imagine going to a health spa for a gut flora replacement. It may soon be possible to pick your donor from a catalogue. The possibilities for celebrity gut flora are mind boggling. There may even be an upsurge in nerd transplants in preparation for college finals. You are what you eat is still true, but the potty is proving to be a measure of more than passing performance.

Thursday, November 20, 2008

Brain Arachidonic Acid: Alzheimer’s, Bipolar, Parkinson’s

A recent review article on brain lipid metabolism discussed the results obtained by looking at how the major omega-6 fatty acid, arachidonic acid is imported and used in brain tissue. Arachidonic acid conversion to inflammatory prostaglandins was monitored by extracting lipids from rat brains after a variety of treatments. Similarly, isotopes (13C) of fatty acids were imaged by PET scans in patients treated for Alzheimer’s, bipolar disorder and Parkinson’s disease.

The major findings on brain arachidonic acid (AA, omega-6) and docosahexaenoic acid (DHA, omega-3) are:

  • Ca. 5% of daily dietary AA and DHA are converted to make prostaglandins in the brain. Converted AA and DHA are rapidly replaced by serum AA and DHA.
  • Brain DHA and AA metabolisms are independent.
  • AA and DHA are rapidly circulated into phospholipids (R2 on the diagram) on the endoplasmic reticulum, move to the cytoplasmic membrane (see diagram, gray and white strands) removed by phospholipase A2 in synapses, converted to prostaglandins, leukotrienes, etc., or recycled to phospholipids. Enzymes that catalyze these reactions are usually different for DHA and for AA.
  • Drugs used to treat bipolar disorder (lithium, carbamazepine, valproic acid, lamotrigine) lower AA conversion in rats, but do not affect DHA conversion.
  • Experimentally induced brain inflammation or neurotoxicity increases AA conversion, but not DHA conversion to prostaglandins.
  • An omega-3 fatty acid deficient diet also increases AA, but not DHA conversion.
  • More AA is converted in Alzheimer’s patients. This is consistent with increased inflammation and neurotoxicity in postmortem examinations.
  • Mice that have been genetically manipulated to eliminate alpha-synuclein, a protein implicated in Parkinson’s disease, also show an increase in AA conversion and a decrease in DHA conversion.

Interpretation: Inflammation in the brain is separate from the rest of the body, but is the foundation of many brain disorders, including Alzheimer’s disease, bipolar disorder and Parkinson’s disease. In these disorders, arachidonic acid is rapidly converted into inflammatory prostaglandins and leukotrienes. Drugs that reduce symptoms, reduce AA conversion.

A diet rich in omega-3 DHA and reduced omega-6 arachidonic acid reduces the symptoms of these diseases -- an anti-inflammatory diet and lifestyle should be the first line of defense against brain/mental disorders.

Rapoport SI. 2008. Brain arachidonic and docosahexaenoic acid cascades are selectively altered by drugs, diet and disease. Prostaglandins Leukot Essent Fatty Acids. Oct 28. [Epub ahead of print]

Wednesday, November 19, 2008

Inflammation Causes Disease

Human diets have changed dramatically over the last few hundred years, and as a consequence so have our diseases. The most recent shift in diet over the last hundred years has resulted in a shift from infectious diseases to degenerative diseases. This trend is summarized in the following Wikipedia entry.

Lifestyle diseases, from Wikipedia:

"Lifestyle diseases (also called diseases of longevity or diseases of civilization) are diseases that appear to increase in frequency as countries become more industrialized and people live longer. They include Alzheimer's disease, atherosclerosis, asthma, cancer, chronic liver disease or cirrhosis, Chronic Obstructive Pulmonary Disease, Type 2 diabetes, heart disease, nephritis or chronic renal failure, osteoporosis, acne, stroke, depression and obesity.

Death statistics in the United States
In 1900, the top three causes of death in the United States were pneumonia/influenza, tuberculosis, and diarrhea/enteritis. Communicable diseases accounted for about 60 percent of all deaths. In 1900, heart disease and cancer were ranked number four and eight respectively. Since the 1940s, the majority of deaths in the United States have resulted from heart disease, cancer, and other degenerative diseases. And, by the late 1990s, degenerative diseases accounted for more than 60 percent of all deaths.
National Center for Health Statistics, National Office of Vital Statistics, 1947 for the year 1900 (page 67), for the year 1938 (page 55)."

My point here is that all of the so-called lifestyle diseases are also based on inflammation. I checked the research literature for studies of the response of each of these diseases to diets supplemented with omega-3 fish oils. Studies had been performed in each case. Reduction of inflammation by fish oil treatment was uniformly effective in reducing symptoms of all of the degenerative diseases. Other diseases that can be added to the inflammatory list are spinal disc problems and hypertension. It is interesting that disc dislocations are associated with coeliac, an inflammatory/autoimmune disease. It is also interesting that acne and depression are listed. Acne is indirectly associated with diet, but if sufferers shift to an anti-inflammatory diet, acne symptoms disappear. Depression associated with childbirth is particularly responsive to anti-inflammatory drugs, diet and exercise. Most of the symptoms associated with aging are just due to inflammation and are similarly responsive to anti-inflammatory lifestyle changes

To summarize:
  • Modern degenerative diseases are caused by modern inflammatory diets (and insufficient exercise.)
  • Anti-inflammatory diet and lifestyle reduce degenerative diseases.
  • Aging is predominantly mismanaged inflammation.

Gulf War Syndrome

Gulf war syndrome (GWS)is now officially a disease. It shares many of the symptoms of chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivity and post traumatic shock syndrome. In other words, GWS is the body’s response to neurotoxins (acetylcholinesterase inhibitors) under inflammatory conditions.

The nervous system has to detect external signals, transmit the sensory information to the brain, process the information, transmit signals to peripheral organs/muscles, and stimulate responses in peripheral organs/muscles. At the molecular level, all of this detection and transmission of signals is accomplished by small molecules binding to and changing the shape/function of proteins. Disrupting the interaction between the small signal molecules (neurotransmitters) and their protein receptors is used throughout nature as an attack on the most vulnerable animal characteristic, the nervous system. Examples of nerve system attackers include mushroom toxins, plant alkaloids (atropine), spider/insect/frog/snake venoms, organophosphate/chloride pesticides, and mustard/nerve gas.

During the Gulf War, several chemicals that mimic neurotransmitters were used with the intent to protect soldiers. The neurotransmitter mimicked was acetylcholine, which is the signal used between peripheral nerves and muscles. Nerve gas targets acetylcholine signaling by blocking the enzyme, acetylcholinesterase, that sits in the space between the nerve and muscle and destroys the acetylcholine in preparation for the next signal. I have illustrated a model of the acetylcholine enzyme and have an inhibitor (grey and red) bound in the cavity of the active site of the enzyme. The active site is lined with hydrophobic tryptophan (yellow) and tyrosine (orange) amino acids.

The pesticides used by the soldiers were designed to kill or repel insects, but they also act as acetylcholine mimetics and bind to acetylcholinesterase. These include Lindane (left), Permethrin (right) and DEET (lower left).

The American soldiers were also forced to take a chemical to protect them from nerve gas. This compound, pyridostigmine (lower right) bind reversibly to acetylcholinesterase and since nerve gas is very reactive, presumably the pyridostigmine will protect some of the acetylcholinesterase until the nerve gas is depleted.

Unfortunately it appears that both the insecticides and the pyridostigmine had a permanent impact on the nervous systems of many of the Gulf War soldiers. Soldiers from other countries did not use the same chemicals on their soldiers, so they were not similarly affected.

It is now fairly well established that pesticides and pyridostigmine were involved in causing Gulf War Syndrome, but very little research has been performed to explain how these chemicals cause the damage or what therapy can reverse the damage.

It appears to me that GWS occurs in similar manner to related illnesses, e.g. chronic fatigue syndrome, multiple chemical sensitivity, fibromyalgia, which can also be induced by organophosphate pesticide exposure. Two insults to the body appear to be needed: acetylcholine signal disruption and inflammation. The acetylcholine mimetics (pesticides, pyridostigmine) disrupted the nervous system and numerous immunological, infectious, chemical and emotional stresses generated a high level of chronic inflammation. The vaccine against anthrax and exposure to burning oil wells may have contributed to inflammation.

Sunday, November 16, 2008

Topoisomerase Inhibitors

Inhibiting enzymes involved in DNA synthesis should stop cancer cells, because cancer is uncontrolled cell division. Topoisomerases are enzymes that help to relieve the twists on double helical DNA as it unwinds preparatory to replication. It appears logical that topoisomerase inhibitors should be cancer inhibitors. Unfortunately targeting DNA-binding proteins also targets most of the signal receptors that are the targets for the evolution of plant alkaloids.

Drugs are designed to be specific in their interactions with a particular target protein, but they are too small to be specific and end up binding to many other related proteins. Hence, drugs have side reactions that are to some extent unpredictable, because the interacting proteins are not known.

Aspirin, for example, is supposed to bind to and inhibit COX-2, the enzyme that converts omega-3 and omega-6, long-chain fatty acids into corresponding anti-inflammatory and inflammatory prostaglandins, resp. Aspirin also binds to proteins that inhibit NFkB, the transcription factor that controls expression of inflammatory genes. Aspirin binds to dozens of other proteins. Aspirin does lots of other things than just blunt inflammation, but those side reactions are usually not significant enough to get our attention.

Heparin is one of the most commonly used drugs. It binds to and activates an inhibitor of thrombin, an enzyme that activates fibrin and mediates clotting. Heparin also binds to other components of the clotting system, as well as a dozen components of the complement system, and most of the cytokines that control communications throughout the body. When patients are given heparin injections, heparin binds continually to all of these components and must be constantly supplemented and monitored. Inflammation depletes the heparin components throughout the body, so it is not known prior to injection, how much heparin will be needed to saturate other serum proteins before the desired level of clotting inhibition is achieved. This illustrates rather dramatically that most drugs have only limited specificity.

One of my students provided another example of the minimal specificity of small molecules, especially the alkaloids and phenolics produced by plants. He brought to me a research article espousing the use of phenolics from yerba mate, which serves as a coffee-like stimulant in Argentina, as a topoisomerase inhibitor and potential anti-tumor treatment. Sure enough, phenolics extracted from this plant inhibit topoisomerase, and they may well be able to inhibit the growth of tumors, but it is doubtful that the binding of the phenolics to topoisomerase in the tumor nuclei has anything to do with inhibition of tumor growth.

Topoisomerase binds to nuclear DNA as the DNA unwinds during replication to produce two new double helical DNA molecules. Topoisomerase is a DNA-binding protein, i.e. a protein that binds to a negatively charged polymer of small deoxyribose sugars and flat purine and pyrimidine bases. Proteins bind to DNA in two ways. Amino acids of the protein either bind along the edges of the hydrophobic stack of base pairs, e.g. sequence-specific transcription factors, or they provide hydrophobic, flat surfaces that bind to the hydrophobic faces of the separated bases. Topoisomerase does both, because it deals with single-stranded regions of DNA and therefore binds to both the phosphates, as well as the bases. The important point here is that both aromatic amino acids, with flat hydrophobic rings, and the hydrophobic tails of basic amino acids, i.e. lysine and arginine, bind to the hydrophobic faces of nucleic acid bases.

I have illustrated the binding of a “topoisomerase inhibitor” to show the arginine (blue) in the active site cleft of the topoisomerase that binds across the hydrophobic face of the inhibitor (grey and red). Many plant phenolics and alkaloids would be expected to similarly bind and act as inhibitors of topoisomerase. This observation and the ease by which alkaloids enter cells (attached to circulating heparan sulfate?) suggests that a major function of the nuclear envelope may be to minimize access of alkaloid and related molecules to the nucleic acid binding proteins of the nucleus.

The binding promiscuity of secondary plant products is further exemplified by berberine. Berberine is an alkaloid found in goldenseal and is an herbal remedy used to treat a variety of inflammatory diseases. It also binds to heparin (and nucleic acids) to produce a fluorescent complex. Thus, mast cells that store and secrete histamine and heparin to produce the symptoms of allergy, can be vividly stained with berberine.

I could not resist the temptation to check to see if berberine also binds to topoisomerase. A quick search of the research literature showed that berberine is in fact a topoisomerase inhibitor.

The numerous cross reactions of drugs are further illustrated by metformin, the common drug used in the treatment of type II diabetes. Metformin is approximately planar and provides a surface that cannot hydrogen bond, i.e. it is hydrophobic. I expected that metformin would bind to tryptophans that I observed as common substrate-binding amino acids in the active sites of proteins that bound to polysaccharides, e.g. lectins, glycosidases and glycanases. To test this, I had students in one of my courses examine the inhibitory activity of metformin on E. coli beta-galactosidase. They found measurable inhibition and support for competitive binding to the active site that contains a pair of the predicted tryptophans.

My protein modeling and structural studies show the basis for numerous interactions between plant secondary compounds, drugs, nucleic acids, polysaccharides (glycosaminoglycans, e.g. heparin) and proteins. Unpredicted cross reactions abound and every drug can be expected to interact with multiple proteins. This provides a note of caution to the use of any drug and encourages minimal exposure, since many unobserved and unanticipated side effects are occurring. These observations also question routine ingestion of herbal remedies, after all, plants use their secondary products as potent defenses against being eaten. Alkaloids disrupt nervous systems and cellular signaling. Plants are not naturally safe.

Friday, November 14, 2008

Fiber Phytate

Some polysaccharides are only digested by the action of colon bacteria. Some of these fiberous plant polysaccharides (and associated macromolecules, such as lignan) are insoluble, whereas the soluble fiber is made of beta-glucans. Insoluble fiber also contains the active ingredient, phytic acid (inositol hexasulfate).

Fiber stimulates the passage of ingested material through the colon, i.e. it has a laxative effect. Growth of beneficial (probiotic) bacteria are enhanced by fiber. Beta-glucans also enhance immune function and have been reported to inhibit tumor expansion and enhance resistance to some bacterial infections, e.g. anthrax.

My personal experience with fiber components began with my graduate research. I ended up determining the structure of the beta-glucans from fungi that trigger the disease resistance of plants. Other researchers soon found that the beta-glucans also triggered the immune system of crayfish and it wasn’t long before beta-glucans were recognized as the active ingredients of a number of foods associated with reduction in diseases.

More recently, I began using yeast beta-glucan to stimulate inflammation in my study of rat chondrocyte cultures. It appears that these glucans are recognized by a cell surface receptor and trigger NFkB-mediated expression of typical inflammatory genes, COX-2, iNOS, IL-1, IL-6, TNF, etc. This form of inflammation also reduces the expression of heparan sulfate proteoglycans.

Beta-glucan-stimulated inflammation may also enhance infiltration of tissue with neutrophils and other leukocytes that provide cellular immunity against some tumors.

Immunity may also be altered by the impact of soluble and insoluble fiber on the bacteria of the gut. Fructose oligosaccharide, such as those in milk, enhance the growth of lactobacilli that are anti-inflammatory. Soluble and insoluble beta-glucans are also prebiotic. The prebiotic effects on the gut flora may be partially responsible for the enhanced resistance to infectious bacteria resulting from ingestion of soluble beta-glucans.

I encountered another activity of fiber in my work on heparin and inflammation. Heparin is derived from a polysaccharide made from glucose and glucosamine. Several enzymes add sulfates and the heavily sulfated, negatively charged fragments, oligosaccharides are secreted from mast cells as heparin.

Other negatively charged polysaccharides, e.g. nucleic acids and sugars also have some of the properties of heparin. One of these molecules that mimics heparin is inositol hexaphospate, phytate. As I pursued the binding of tryptophan and related structures to proteins, I remembered a similar molecule, auxin or indole-acetic acid, from my plant work and examined an auxin receptor. I was pleasantly shocked when I looked at the auxin receptor sequence. I expected to find that a heparin-binding domain was used to bind auxin to this protein receptor. That proved to be the case and substantiated the generalized observation that tryptophan and similar molecules bind to basic amino acids, and that sugars also bind to both aromatic and basic amino acids. What was amazing about the auxin receptor was that the purified and crystalized protein had a phytate bound to an assortment of basic amino acids in the center of its structure.

I have illustrated the structure of the auxin receptor here to show how the blue arginines extend as inward pointing spokes from a wheel of alpha-helices, and the orange/red sulfates of the phytate attach to the arginines. Only the lower right quarter of the image is shown in the closeup, with the whole molecule shown in the smaller picture.

Phytate is important, because it holds much of the phosphate content of the fiber, and the binding of divalent cations, e.g. calcium, magnesium, to the phytate may prevent these minerals from being absorbed. In ruminants, e.g. cattle, the gut bacteria produce and enzyme, phytase, that removes the phosphates and solves the absorption problem. This is frequently not the case in humans.

Inositol with two or more phosphates is attached to the lipids of membranes to make phospholipids. Signal cascades may activate enzymes that release the inositol phosphates (IP3) into the cytoplasm where they can cause the elevation of cytoplasmic calcium and the release of secretory granule contents, e.g. neurotransmitters.

Phytate is considered to be responsible for the reduction in colon cancer attributed to fiber from grains and legumes. The heparin-mimicking actions are probably the basis for its activity, since phytate can partially replace or inhibit surface receptor interactions that normally involve heparan sulfate proteoglycans. Phytate can also be internalized along with heparin and it should be very aggressive if released into the cytoplasm.

Phytate has been found to be very safe, but may be more effective if ingested in the soluble form, since it is frequently not released from fiber. Extensive cooking is required to release phytate from insoluble fiber. Soybeans are one of the best sources of phytate, so maybe it would be wise to cook some for hours just to release the phytate.

Wednesday, November 12, 2008

More Inconvenient Truths

I am writing this shouting summary of bottom lines in response to recent good news and bad news. The good news is that Michael Pollan is speaking in Boise, near my home town. The bad news is the recent press coverage of the JUPITER study on statins.

Michael Pollan is one of my heros. He speaks simply and clearly about the role of national agriculture policy in promotion of hazardous foods that lead to profits in the healthcare industry, but death and disease for the US population. Pollan also provides wise advice to solve our problems.

A new statin, Crestor, was shown in the JUPITER study to significantly reduce the risk of cardiovascular events, e.g. heart attacks, stroke, death, in a study population with normal LDL and elevated C-reactive protein, an indicator of inflammation. The press supported the drug maker’s interpretation that the statin provided benefit by lowering LDL in a population with chronic inflammation. What is missing is the clarification that lowering LDL is unimportant in reducing cardiovascular risk. Lowering inflammation lowers cardiovascular risk and there are more appropriate ways of lowering inflammation than using very expensive drugs. It is much cheaper, healthier and effective to switch to an anti-inflammatory diet and lifestyle!

After reading thousands of articles in the biomedical research literature, here are a few of my obvious bottom lines. Diet affects your health and the most fragile stages of development and most fragile organs, are the most sensitive to abuse. Therefore, damaging diets are most harmful to fetuses, newborns, brains, the cardiovascular system and reproductive systems.

  • Formula promotes inflammatory bacteria in newborn guts resulting in lower intelligence, disrupted immunity, infections, allergies, obesity, degenerative diseases and autoimmune diseases. Breastfeeding is the only anti-inflammatory answer for infants.
  • The US diet (hyperglycemic starch/sugar, high omega-6 to omega-3 fatty acid ratio, HFCS, low vegetable anti-oxidants, low vitamin D/sun exposure, low vitamin C, grain-fed meat instead of fish) is inflammatory.
  • The Mediterranean Diet (small portions of starch, low omega-6 oils, no HFCS, high vegetable anti-oxidants, routine sun exposure, adequate vitamin C, fish and grass-fed meat) is anti-inflammatory.
  • Inflammatory diets lead to infertility (female and male), problems during pregnancy (e.g. preeclampsia is an omega-3 fatty acid deficiency) and prematurity/low birth weight.
  • Mental illnesses of many different types benefit from anti-inflammatory diet and lifestyle. Diet-based brain inflammation may be a major predisposing factor.
  • All of the prevailing drug therapies for cardiovascular disease benefit from anti-inflammatory diet and lifestyle. Most of the drugs that reduce cardiovascular events rely on anti-inflammatory activities. Inflammation is the primary cause of cardiovascular disease, not elevated blood lipids/cholesterol.
  • Vegetable oils (corn, soy, cottonseed, safflower) are rich in omega-6 fatty acids and are dangerously inflammatory. These polyunsaturated oils are less healthy than saturated fats. Olive oil is the most healthy.
  • Reasonable routine exposure to the sun could eliminate inflammatory vitamin D deficiencies.
  • Obesity is inflammatory, but diet-based inflammation may also be a major contributor to obesity.
  • Genetic predisposition to specific diseases is triggered by diet-based chronic inflammation.
  • Diseases and disabilities associated with aging are symptoms of mismanaged chronic inflammation typically resulting from decreasing muscle mass and increasing fat.
  • Sensible diet and lifestyles could dramatically improve quality of life and reduce healthcare expenditures in the US.

Prescription: eliminate vegetable oils, eliminate HFCS, eliminate trans fats, use olive oil, reduce starch, eat vegetables, eat more fish and less meat, get daily sun, use fish oil supplements, get frequent muscle-building exercise, and stay lean.

Tuesday, November 11, 2008

Bee Sting Allergy

Typical. I started to write an article on leukotrienes, the inflammatory derivatives of the omega-6 fatty acid, arachidonic acid, but ran across another powerful example to test my hypothesis to explain the cause of allergies. The leukotriene article will have to wait till another day.

Wikipedia is my source of choice for up-to-date summaries of biomedical information. I queried “leukotrienes” and immediately ran across the original name for these inflammatory compounds, “slow reacting substance of anaphylaxis”. I was initially distracted by the classic experimental use of snake venom and histamine to induce leukotriene production. Snake venom has the same enzyme, PLA2, as brown recluse spider venom (subject of a previous article) and honey bee venom, that releases arachidonic acid (ADA). ADA is an omega-6 fatty acid that is the starting material for inflammatory prostaglandins and leukotrienes.

The mention of honey bee venom in the Wikipedia article on anaphylaxis sent me on a quick check of the structure and sequence of the honey bee allergen. I initially found that the major allergen is a hyaluronidase. I quickly searched for a three amino acid sequence that I predicted would make it an allergen. It was just where I expected to find it. About two thirds of the way along the amino acid sequence I found, -TTSRKKVLP-. Three basic amino acids together, in this case -RKK-, argininine-lysine-lysine, form a strong heparin-binding domain, that I believe takes proteins into cells and during inflammation primes the immune system for allergic responses.

I have found the same strong heparin-binding domain associated with allergens of ragweed, dust mites and peanuts. The principal autoantigens of autoimmune diseases, such as lupus, celiac, etc. also display the same unusual sequences. In lupus, or example, nuclear proteins with the internalization signal provided by nucleic acid-binding domains (and nuclear localization signas) are autoantigens. This pattern is found with all allergens that I have examined. There are a few apparent exceptions, but in all of these cases, there is a closely related allergen from a related source that has the expected strong heparin-binding domain. It appears that in these cases, the less common allergen provides the initial exposure during the presentation phase of high inflammation, and the allergy is maintained by subsequent exposure to the more common allergen. After the establishment of the allergy, the strong heparin-binding domain is no longer needed, because antibodies bind to other parts of homologous allergenic proteins for internalization.

Just for fun, I have illustrated the honey bee allergen, hyaluronidase, to show both its strong heparin-binding domain (blue) along with its substrate hyaluronan (grey and red). Note that the substrate sugars are in the slot of the active site, which is lined with orange and yellow aromatic amino acids that provide flat, hydrophobic binding platforms for each sugar.

After this little distraction to provide further support for my explanation of the cause of allergies, I have to get back to looking at the role of leukotrienes in anaphylaxis, COPD, asthma and other inflammatory diseases.

Monday, November 10, 2008

Statins and Atherosclerosis

A recent study (JUPITER) on the statin Crestor was ended prematurely when the drug was shown to dramatically reduce vascular events. The statin was tested on patients with chronic inflammation as judged by elevated C-reactive protein, but with low LDL. These patients would not normally be treated with statins and therefore represent an immense new market for statins.

Statins are supposed to act by interfering with the synthesis of cholesterol and thereby lowering the serum concentration of the lipid carrier LDL. Lowered LDL is supposed to decrease vascular disease that is aggravated by accumulation of cholesterol at sites of inflammation on the surface of blood vessels.

Unfortunately the data linking cholesterol production, LDL levels and vascular disease is weak. Thus, it is possible to lower LDL and have no impact on cardiovacular disease statistics. The recent study on Crestor was interpreted as being support for the link between LDL levels and vascular disease, but I think it shows something very different.

There is increasing evidence that vascular disease is based on diet-based chronic inflammation and that statins have a mild impact on reducing inflammation. It follows then that statins will reduce inflammation enough to have an impact on vascular disease, independent of effects on LDL levels. The Crestor study actually showed that patients with low levels of LDL but chronic inflammation benefited from lowering of inflammation. The LDL levels were unimportant. Reducing inflammation was the point and using statins to reduce inflammation is unnecessarily expensive and ineffective. Adjusting diet makes a lot more sense.

Drug companies are already pushing for increased use of statins on larger segments of the US population to provide prevention from atherosclerosis, stroke and heart disease. This would be immensely expensive with marginal returns. It is also just treating the symptoms without addressing the cause.

The solution to cardiovascular disease is dietary. Omega-6 oils and low availability of omega-3 fish oils is the major cause of the chronic inflammation that is the major risk factor for cardiovascular disease. The major US vegetable oils, corn, soybean, cottonseed, safflower, need to be drastically restricted and olive oil needs to be encouraged. We need to recognize that saturated fats are safer than the omega-6 polyunsaturated fats that have replaced them. Elimination of omega-6 vegetable oils and use of fish oil supplements are cheap and effective ways of lowering chronic inflammation.

Cardiovascular disease is also based on decreasing muscle mass, sarcopenia, which is also the basis for increasing chronic inflammation inappropriately attributed to aging. People get less physical exercise as couch potatoes or with decreasing activity as they age. The result is replacement of muscle by fat, and fat is inflammatory. Obesity is an extreme of this trend that leads to high chronic inflammation identified as metabolic syndrome, the prelude to a suite of nasty degenerative diseases: diabetes, atherosclerosis, allergies, cancer, Alzheimer’s, etc.

The obvious bottom line is to avoid all of these problems with an anti-inflammatory diet and lifestyle.

Saturday, November 8, 2008


Bones like stones, that is osteo-petrosis. It is the opposite of osteoporosis, porous bones. Osteopetrosis is a disruption of bone metabolism so that mineralization by osteoblasts predominates over demineralization by osteoclasts.

Mice lacking almost all genes, i.e. knockout mice, are now available. To determine which body tissues require the inflammatory transcription factor, NFkB, NFkB knockout mice were engineered and their characteristics were carefully analyzed. Their bones kept mineralizing and mineralizing and mineralizing. NFkB function was required for the development and function of osteoclasts, the macrophage-derived cells that remove bone.

Inactivation of osteoclasts or inhibition of osteoclast development by bisphenols, such as Boniva, leads to a minor version of osteopetrosis. Killing osteoclasts leads to a reversal of osteoperosis. An omega-3 fatty acid deficient diet leads to osteoporosis in mice.

Omega-3 fish oil has been used to reduce inflammation induced bone loss associated with many diseases, e.g. arthritis, periodontitis and osteoporosis. In a recent study (below) the fish oils, DHA and EPA were added to mouse macrophages in culture and the impact on differentiation into osteoclasts was analyzed. DHA was more effective than EPA in reducing NFkB activation and TFA response leading to macrophage differentiation. The omega-6 fatty acid, ALA, enhanced osteoclast differentiation, consistent with many animal and human studies that show that the high omega-6 fatty acid content of such common vegetable oils as corn, soybean and safflower, are inflammatory and presumably encourage osteoporosis.

Osteoporosis increase in our population has paralleled the increase in use of omega-6 vegetable oils, and the increase in chronic inflammation. The first step in treating osteoporosis should be a shift to an anti-inflammatory diet lacking these vegetable oils. Olive oil is much safer.

Rahman MM, Bhattacharya A, Fernandes G. 2008. Docosahexaenoic acid is more potent inhibitor of osteoclast differentiation in RAW 264.7 cells than eicosapentaenoic acid. J Cell Physiol. 214:201-9.

Friday, November 7, 2008

Oxygen Starved

Hypoxia is the low oxygen environment of tissue lacking blood vessels. Oxygen is needed as the final, low energy electron acceptor of the aerobic metabolism of mitochondria, but it is also needed to make hydroxyproline, the special amino acid of collagen. Expression of genes in response to the oxygen available is controlled by a transcription factor, HIF.

The oxygen that we breathe is used as a place to dump the low energy electrons produced by mitochondria as ATP is using energy from high energy electrons of carbon and hydrogen present initially in glucose. In the absence of oxygen, fermentation can use glycolysis and dispose of the low energy electrons in the form of products such as lactic acid or ethanol. Aerobic metabolism, in the presence of oxygen, is much more efficient (more ATP per glucose), so fermentation is only used when oxygen is depleted, as in the case of exhausted muscles.

Low oxygen, hypoxia, is also encountered in tissues isolated from the oxygen-distributing vascular system. Cells that constantly secrete new cartilage, chondrocytes, are prevented from ready access to oxygen, because the tensile strength of cartilage would be sacrificed by mechanically weak blood vessels. This is paradoxical, because cartilage also contains large amounts of reinforcing collagen fibers, that require oxygen. Consumption of oxygen by aerobic metabolism must be restricted in chondrocytes to reserve diffusing oxygen for collagen synthesis. This also predicts that energy metabolism in chondrocytes exposed to ample oxygen, as in developing bone or wounds, must be drastically different from metabolism in mature chondrocytes that may be centimeters away from the nearest blood vessel.

Oxygen is used in collagen production to produce the hydroxyproline of the repeated triplets of amino acids that form the spiral threads of collagen. Every third amino acid is glycine and prolines that precede a glycine are converted to hydroxyproline by an enzyme that uses vitamin C. Thus, scurvy, a vitamin C deficiency, is characterized by weakened cartilage, e.g. loose teeth. The high hydroxyproline content of collagen also explains the low nutrition of gelatin, which is denatured collagen.

The trigger for shifting a cell to a low oxygen metabolism, is production of hydroxyproline in the transcription factor called, hypoxia-inducible factor, HIF. If oxygen is abundant, a particular proline in HIF is converted to hydroxyproline, and this modified HIF is quickly degraded in proteosomes. Lack of oxygen prevents modification of hydroxyproline and HIF successfully migrates to the nucleus, binds to the promoter sites of specific genes and changes the pattern of proteins in the cell.

HIF is important in all diseases that result in damage to blood supply. Tumors, for example stop growing when they reach a size that limits the oxygen that can diffuse from surrounding blood vessels to the center of the tumor. Hypoxia in a tumor causes release of angiogenic, blood vessel proliferating, cytokines from the tumor. HIF induces the production of angiogenic molecules. In the opposite direction, damage to cartilage that results in increased oxygen, will turn off HIF and prevent the secretion of mature cartilage by chondrocytes. Chondrocytes also secrete proteins that actively block the formation of blood vessels, e.g. endostatin, the end of one of the collagen.

Several drugs are now being developed to block HIF activity and starve cancers. These drugs will also modify the metabolism of many other cells that use HIF. It is worth noting that mice with the HIF gene knocked out do not survive long after birth.

Thursday, November 6, 2008

Arthritis Antibodies

Antibodies can be used to attack the signaling (TNF) molecule that mediates the autoimmune attack on arthritic joint tissues. These anti-TNF antibodies minimize inflammatory signaling, reduce joint inflammation and also reduce bone attrition.

Inflammation is an activated state of a tissue in which inflammatory cytokines, TNF, IL-1, IL-6 are secreted by T-cells and the tissue responds by expressing genes that cause characteristic vascular dilation and accumulation of migrating cells of the immune system. One particular type of blood cell, a macrophage, can also migrate to the site of inflammation and develop, in response to signals from the inflamed tissue and resident bone secreting cells, osteoblasts, into osteoclasts that degrade bone. Thus, inflammation of joints can result in bone destruction and increase in serum calcium.

TNF is particularly pivotal in the development of osteoclasts and bone destruction. Thus, drugs, such as thalidomide, that block TNF production, also block the symptoms of arthritis. Antibodies can also be developed that bind to TNF and some of these antibodies have been chemically and genetically modified to make them useful as drugs. Examples are Infliximab and Andalimumab. These are proteins that bind to and inactivate TNF. In a similar alternative strategy, a portion of the TNF receptor was engineer to serving as a neutralizing molecule to bind TNF in inflamed tissue. All of these TNF inactivators can reduce symptoms and provide effective therapy for arthritic joints.

The unanswered question in the use of TNF inactivators is, “What caused the inflammation of the joint in the first place?” Inactivation of TNF can provide a temporary return to approximately normal tissue function, but the symptoms are expected to return.

Thus, we come to the unifying question of what causes inflammatory disease mediated by the immune system and directed at normal tissue components. Two obvious candidates are diet and infectious agents.

Food ingredients can exacerbate or ameliorate the symptoms of inflammatory disease, and particular diets determine the risk of acquiring these diseases. Diet is a major factor in inflammation of any source. Bacterial or viral infections frequently precede inflammatory conditions.

The association of infection with inflammation remains controversial, but there is growing evidence that bacteria in particular reside in almost all inflamed tissues. Moreover, there is abundant anecdotal evidence of effective use of antibiotics in numerous inflammatory diseases, including arthritis, inflammatory bowel disease, atherosclerosis and cancers of various types.

I expect that elucidation of the link between chronic inflammation, diet and bacterial infection will provide increasingly effective and simple therapies for most diseases in the near future.

Wednesday, November 5, 2008

Bacterial Sex

A new study finds that women have more species of bacteria on their hands than do men. I don’t know what this means, but this brings up a question about the use of the term species in reference to bacteria.

Bacteria are bags of DNA and the proteins (and RNAs) that are coded by the genes that make up the DNA. Thus, excluding mutations, all of the progeny of a bacterium will have the same DNA sequence and proteins. Hereditary and evolutionary relationships between bacteria can be seen in their DNA sequences.

Problems arise in the definition of species, because of the promiscuous exchange of DNA between bacteria (and other organisms). Bacteria exchange genetic information on a prodigious scale. Viruses, for example, can infect one bacterium and transfer some of that bacterium’s DNA to a totally unrelated bacterium. Bacteria can also take up the DNA remains of ruptured bacteria. There is also a form of sexual, conjugal transfer of DNA between bacteria via proteinaceous bridges called sex pili.

These DNA exchanges are very wide spread in nature and some bacteria actively transmit their genes to plants, e.g. crown gall producing bacteria. Rotifers actively reconstruct their chromosomes after dehydration and will incorporate any plant or animals DNA that is present into their chromosomes as well. Humans also incorporate DNA from other species at a relatively modest pace. For example, the HIV or herpes viruses insert their genes into the chromosomes of infected human cells. As a consequence of similar historical events, human chromosomes are littered with DNA remnants from other species.

The upshot of all of this genetic exchange is the blurring of species boundaries, particularly in bacteria. Higher densities of bacteria mean more transfer, so the gut, for example, consists of bacteria defined by the cohort of genes necessary to occupy a particular biochemical niche. If bacteria identified by their biochemistry as E. coli in Boise, Idaho, are compared with E. coli identified the same way in Paris, their DNA sequences will be less similar than cats and dogs.

When I hear that women have more bacterial species on their hands than do men, I am perplexed. What do the numbers mean? How are the researchers defining the 4,700 different bacterial species that they found? I would have to say that, if the differences are real, then women have more biochemical niches on their skin than do men. The report also indicates that the one to two hundred different species on each hand of an individual also differ. This could reflect the unique colonization of each square centimeter of skin and the microstructure of bacterial populations. It does bring into question the use of the term species as applied to bacteria.

It would be interesting to see detailed DNA sequencing of bacterial populations applied to simulations of gut bacteria. I would expect that the biochemistry displayed by defined regions of the synthetic gut would become stable. This would indicate that particular species became established. But I would also expect that the DNA sequences of those “species” would continue to change, reflecting the exchange of DNA between the species. Introduction of new DNA into the system should result in a general drift of DNA sequences through the species even though the biochemical characteristics remain constant.

This discussion also applies to the inflammatory state of an individual as determined by diet and the corresponding gut flora that develops. Since there would be no advantage to bacteria to produce gut altering compounds that did not improve the reproduction of the bacteria, then the gut must initiate the exchange of molecules/nutrients and benefit from the communication. This biochemical communication is not understood, but is vitally important for health.

Tuesday, November 4, 2008

Inflammation Score

Most people need some feedback to monitor the impact of their diet and exercise on their health. I tried to point out some of the major contributors to chronic inflammation with a little check list. See how you score (choose one of the list for each category) and give me your feedback on the how you think each part contributes to inflammatory diseases.

Fat Content ____
lean 0
extra abdominal fat 4
obese 8

Carbs ____
small meals, no cereal for breakfast 0
fistful of starch with each meal 2
pasta/rice/potato as a meal 4

HFCS ____
high fructose corn syrup banned from your diet 0
don’t avoid HFCS, but avoid soft drinks 2
have replaced sucrose with HFCS, enjoy soft drinks 4

Unsaturated Fats ____
have removed vegetable oils (except olive oil) from your kitchen 0
use canola oil 2
have replaced saturated fats with corn oil 4

Trans fats ____
eat no trans fats 0
avoid trans fats on your chips 2
don’t know what trans fats are 4

Fish oil ____
supplement with two or more fish oil (DHA/EPA) capsules per day 0
eat at least two helpings of oily fish per week 2
avoid all fish products 4

Antioxidants ____
know that coffee, tea and chocolate are good sources of vegetable antioxidants 0
eat five servings of fruits and veggies 0
take vitamin C supplement, because you avoid veggies 2
avoid veggies; meat and potatoes type 4

Exercise ____
take a stroll after meals and maintain your muscle mass 0
run when you feel guilty 2
couch potato 4

If you smoke, add an extra 15 points

Add ‘em up. How much are you stoking the inflammation furnace?
0-5 Cool! You will never look your age.
6-10 You are getting warm. Hope that you don't have any genetic predispositions to disease.
11-15 You may postpone inflammatory illness until middle age. The flame is lit. Pick your disease.
16-25 If you aren’t showing a chronic disease, you will soon.
26+ You can reverse your disease symptoms with the inflammatory diet and exercise.

Monday, November 3, 2008

Thalidomide Waste

Thalidomide suppresses TNF production and alleviates cachexia and anorexia of terminal cancer. Suppression of TNF is also effective in the control of numerous inflammatory diseases.

I have often wondered how cancer actually kills. By infiltrating and displacing cells of essential organs, a metastasizing cancer can kill by starvation, suffocation, etc. Brain cancers can build up pressure in the skull and cut off neural function needed to sustain life. But what about the loss of appetite and general wasting, anorexia and cachexia, associated with the terminal stages of cancer? As more people live longer with cancer, it seems to me that avoiding the wasting of the last stage is becoming more important. So what is wasting?

It seems to me that wasting is high level chronic inflammation. Inflammatory cytokines, particularly TNF (tumor necrosis factor) reach high levels and are characteristic of acute inflammation. TNF was initially called “cachexin” based on its association with wasting. Cytokine signaling is usually balanced and local, so chronic high level TNF marks a system out of control.

Inflammation suffers from stereotyping. We spend so much time trying to block inflammation that we sometimes lose sight of the essential requirement for inflammatory processes in normal immune function, wound repair and development. We notice this need for example in the disruption of the gut by aspirin, since inflammatory prostaglandins are needed for ongoing maintenance of the gastric and intestinal epithelium. Aspirin blocks COX2, the enzyme that produces inflammatory prostaglandins from omega-6 fatty acids, and that is how it leads to problems with causing bleeding.

A potent inhibitor of TNF, thalidomide, was initially banned, because it caused horrible birth defects when taken by pregnant women. We must be vigilant when using potent drugs to selectively eliminate problematic protein functions, because proteins always have multiple functions and multiple proteins have similar structures. Thus testing for the effectiveness of a drug, does not protect us from numerous underlying unintended consequences. All drugs interact and alter numerous, and in most cases unknown, functions within a cell.

Thalidomide was found to reduce TNF and was effective in the treatment of nausea and sleeping problems of pregnancy. Its teratogenicity gave it a terrible reputation for many years, so it was a long time before its potential was appreciated. Suppression of high chronic inflammation is very useful in extreme cases of arthritis, leprosy, multiple myeloma and many other diseases currently being examined. So, thalidomide is now being vindicated.

Upon seeing these observations of the effectiveness of thalidomide, I immediately thought about the possibility of alleviating cancer cachexia and perhaps even the physiological reinforcement of anorexia nervosa. A quick check of the biomedical literature confirmed that thalidomide is a very useful new tool in the treatment of terminal cancer. Thalidomide that can be tragic to embryos can provide comfort and improve the quality of life in its final stage.