Where’s the Aspirin?

Aspirin is the traditional anti-inflammatory agent. Many of us grew up with the quintessential doctoring phrase, “Take two aspirin and call me in the morning.” Aspirin stops inflammation in several ways. Like all drugs, it interacts with many different proteins/enzymes. In fact it interacts so intimately with the inflammatory system that it suggests that the process of inflammation may require an aspirin-like molecule to function normally.

Aspirin Binds to Multiple Enzymes of Inflammation

Aspirin is observed to reduce inflammation. That means that ingested aspirin tablet dissolve in the stomach and pass through the intestines into the blood stream and subsequently bath cells of the blood and the endothelium that lines the blood vessels. In order to reach the blood stream, the aspirin must pass through the intestinal cells. That passage requires binding to a protein transport molecule.

Cells responding to an inflammatory signal (NFkB, transcription factor is activated) synthesize enzymes that release unsaturated fatty acids (ARA, EPA, DHA) from membrane phospholipids (PLA2, phospholipase A2), form a cyclic epoxide from the fatty acid (prostaglandin H2 synthase 2, also called cyclooxygenase 2, COX-2).

Aspirin binds to the inhibitor that normally inactivates NFkB and prevents NFkB activation that is required for inflammation. Aspirin also binds to PLA2 and prevents fatty acid release and thereby blocks activation of inflammation. Aspirin also binds to COX-2 and blocks the production of inflammatory prostaglandins from ARA. But that is not all that aspirin does.

Inflammation Resolution Uses Aspirin-COX-2 Interaction

The strange interaction that makes aspirin suspicious is that aspirin doesn’t just interfere with the action of enzymes, it subtly changes their specificity. Thus aspirin chemically transfers its acetyl group (CH3-COOH-) to an amino acid in the active site of COX-2 to produce a new group of anti-inflammatory lipoxins from ARA, EPA and DHA.

This raises the question of whether aspirin is a natural dietary modulator of inflammation. Recall that aspirin was initially obtained from willow (Salix) bark. Unfortunately, the data are conflicting. Initial research indicated that grains (naturally inflammatory) lacked aspirin, but many herbs, spices and leafy vegetables (naturally anti-inflammatory) contained aspirin. Subsequent tests refuted this work. It would be consistent with observations that some dietary components are anti-inflammatory, but candidate acetyl donors have not been identified.

Speculative acetyl candidates may include the menthol relatives, such as menthyl acetate (figure). Peppermint oil, which contains mostly menthol with some menthyl acetate, is more effective in the treatment of inflammatory bowel disease than most pharmaceuticals prescribed to treat the condition. This anti-inflammatory activity may be due in part to the aspirin-like chemical structure and function of the menthyl acetate. Also note that acetic acid/vinegar is sometimes suggested as a cure-all. This activity may be a consequence of its formation of ester linkages with alcohols that have structures similar to menthol.

Large Dose Aspirin as Cancer Treatment

The potent anti-inflammatory effects of aspirin have been compromised, because inflammation is an essential developmental activity. Thus, the integrity of the gut, for example, requires modest production of inflammatory prostaglandins and a pill of aspirin can disrupt gut tissue. Large doses of aspirin cannot be given orally. Intravenous administration of large doses of aspirin, however, is possible and the impact on process that require inflammation is dramatic.

Anecdotal evidence indicates that large dose aspirin is able to disrupt cancers, because proliferation of cancer cells requires NFkB activation and other inflammatory responses. High doses of aspirin also cause other potentially dangerous complications, such as short-circuiting oxidative phosphorylation of mitochondria and increasing nitric oxide free radical production. Still, the impact of high dose aspirin on some diseases is so amazing that it is being actively and carefully pursued.

What’s the Opposite of Inflammation?

I want to commemorate the writing of my 100th article on Blogspot by discussing a new insight into inflammation.

I have been searching the last several years for an anti-inflammatory system to balance inflammation. Now I realize that there is no opposite to inflammation. There is only completion of inflammation to return to the original state. Inflammation is a process that includes resolution or recovery from the defensive, destructive state of immunological activity.

Inflammation is the martialling of resources for battle by offloading lymphocytes from the blood stream, engaging the enemy by triggering the release of toxic secretory vesicles from leukocytes, and cleaning up the carnage by macrophages engulfing cellular fragments. Each step in the inflammatory process induces the next step until there is a return to the origin. Inflammation is not balanced by anti-inflammatory processes.

Inflammation is triggered by molecules characteristic of viruses, bacteria or fungi binding to membrane receptors (TLRs). The result is activation of the inflammatory transcription factor, NFkB (illustrated holding DNA), that turns on the expression of dozens of genes that code for cytokines (IL-1, IL-6, TNF) and enzymes (COX-2) that produce signal compounds. Among the signal compounds are the inflammatory eicosanoids (PGE2) produced from the omega-6 fatty acid arachidonic acid (ARA).

The complex signaling pathways that lead to PGE2 synthesis subsequently initiate transcription of genes that code for the enzymes that make lipoxins (resolvins and protectins) from eicosapentanaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA are the two omega-3 fatty acid components of fish oil and a shortage of these dietary components blocks the next step, resolution of inflammation.

The lipoxins reduce the permeability of blood vessels, stop the offloading of lymphocytes, reduce responsiveness to inflammatory cytokines, recruit phagocytic macrophages to clean up debris and orchestrate a return to quiescence of the inflammatory system. Without adequate lipoxins, inflammation continues.

An interesting footnote to this discussion is the impact of aspirin on inflammation. Aspirin binds to the enzyme (COX-2) that converts ARA to inflammatory prostaglandins and leukotrienes. Acetylation of COX-2 by aspirin stops inflammatory eicosanoid synthesis and shifts the synthesis to anti-inflammatory lipoxins. Even ARA is used to make anti-inflammatory lipoxins in the presence of aspirin. This shift to anti-inflammatory signaling may occur naturally in the small intestines in response to aspirin-like compounds in vegetables. This would be a transitory response similar to taking aspirin with a meal. More constant use of aspirin would disrupt the normal and necessary actions of the inflammatory signaling to maintain the integrity of the gut.

Excess of dietary omega-6 oils and deficiency in omega-3 fatty acids corrupts inflammatory signaling by eliminating recovery and produces chronic inflammation. Another name for chronic inflammation is obesity/metabolic syndrome. Chronic inflammation is the foundation for the degenerative, autoimmune and cancer diseases that are so prevalent today.

Fortunately a shift to an anti-inflammatory diet and lifestyle provides a simple solution to chronic inflammation.

[Note added: Perhaps the opposite of anti-inflammatory is immunosuppressed, as in high use of omega-3 oils can increase the risk of tuberculosis of influenza.]

There Is More Than Antioxidants

Every time a plant product has an impact on a disease it seems to be attributed to its antioxidant activity. Plant products are active, because they bind to proteins. They bind to lots of different proteins.

Krill oil is a good example. The anti-inflammatory activity of krill oil is due to its omega-3 oil (DHA and EPA) content, but krill oil is more potent than expected. Krill oil also contains a terpene, astaxanthene, that is probably derived from its algae diet. Astaxanthene is labeled as an anti-oxidant, but that is much too easy.

Astaxanthene consists of two flat, hydrophobic paddles, connected by a flexible, hydrophobic chain. Those paddles are important, because of their inability to hydrogen bond with water, i.e. hydrophobicity, and therefore their propensity to get stuck in contact with other hydrophobic surfaces. The list of candidate hydrophobic surfaces includes the obvious smaller aromatic rings (e.g. phenylalanine), indole double rings (e.g. tryptophan), and the less obvious sugars (e.g. galactose), unsaturated lipid/prostaglandins and basic amino acids (lysine and arginine). These are dominant cellular interactions.

The interchangeability of the hydrophobic paddle-binders means that astaxanthene can get its paddles stuck in enzyme or receptor protein active sites that normally bind a wide range of ligands (target small molecules, e.g. enzyme substrates). It is likely, therefore, that astaxanthene has anti-inflammatory activity, because it blocks an inflammatory interaction.

The ubiquity of interactions of terpenoids, based on their general structural properties, also gives these molecules access to cellular cytoplasm. These molecules are too large to diffuse through membranes and if they got half way through, they would be permanently stuck in the membrane. Terpenoids will tend to stick to carrier proteins that have hydrophobic patches or slots. These carriers will transport and internalize terpenoids and other similarly shaped molecules, e.g. steroid hormones.

Metformin, the diabetes drug, is another example of a molecule with a flat, hydrophobic side. It is a stretch to call this an antioxidant, but it is useful for this discussion, since one of my students tested to see it it would stick to a tryptophan in the active site of a classic enzyme, beta-galactosidase. Galactose, in the typical substrate for this enzyme, lactose, will bind to the active site, because of a prominent tryptophan. The shocker is that my student showed that metformin also binds to that same site and competes with lactose. Astaxanthene would also be expected to bind in the same way.

Curcumin is one of the most potent anti-inflammatory compounds and the main ingredient in turmuric, binds to proteins that inhibit the inflammatory transcription factor, NFkB. I would expect astaxanthene to also inhibit NFkB.

Capsaicin is a related molecule that binds to the heat/pain sensor in skin and blocks pain sensation. That is how capsaicin is used as a topical analgesic. Castor oil, ricinoleate, binds to the same sensor and competes with capsaicin and also is an effective pain reliever. Note that ricinoleate is a modified fatty acid that could curl up on the same hydrophobic paddle surface as capsaicin.

The bottom line of this discussion is that if someone tries to convince you that resveratrol, the anti-aging ingredient in wine, is an anti-oxidant, be skeptical. Expect that resveratrol will have numerous interactions with proteins and many of those will not be known.

I Don’t Believe It ...

There are too many myths in biomedical science. I think that our fears are misplaced and if we just address the real threats, e.g. inflammatory vegetable oils, we can enter the New Year with realistic hopes for good health.

Don’t Worry about Genetic Predispositions to Disease

Mendel was wrong in asserting that there is one gene for each phenotype. Modern clearinghouses of genes reveal the relationships between gene sequences and numerous protein functions. In the Human Protein Reference Database (HPRD), for example, each human gene is listed with all of its synonyms. The synonyms frequently reveal that genes lead multiple, unrelated lives and have sundry tangled relationships with dozens of other proteins. So the idea that there is one gene for each physical trait, phenotype, is a misleading simplification.

The good news is that the complexity would only be a problem, if our individual genetic composition was important to our health. In most cases, I think that our individual genetic predispositions to disease would only be important, if we stress our bodies (usually with an inflammatory diet) to the point of failure. With a healthy diet and lifestyle, I don’t think that most genetic predispositions to disease would ever affect health. To be specific, most people should be able to live until 80 with few physical compromises. This is very hopeful.

Don’t Worry about Drug Side-Effects (avoid the need for drugs)

Drugs have many side effects, simply because we don’t know enough about the interactions of small drug molecules with all of the possible protein targets. Take heparin, for example. Heparin is one of the most commonly used drugs to inhibit blood clotting. There is a clotting assay to measure how well heparin blocks clotting and injecting more heparin makes clotting slower. It appears that heparin binds to a protein involved in clotting. Heparin does bind to anti-thrombin, which in turn inhibits thrombin that is needed for clotting. Heparin also binds to several other proteins required for clotting and also binds to a dozen proteins involved in the complement system needed to kill pathogens or infected cells. Heparin binds to hormones, growth factors and their cell surface receptors. There are hundreds of proteins that use heparin to facilitate attachment to other proteins, to change shape and activity or to enter or leave cells. The point here is that heparin is a vivid example of a drug used to treat blood clotting, while at the same time dozens of other major interactions are ignored.

All drugs have multiple interactions with myriad proteins, but during screening, a drug is identified as having a significant desired affect. All drugs have side effects, because they are not completely specific. The side effects are often exploited as off-label uses for the drugs. Statins, for example, can impact lipid metabolism and change LDL blood levels. Unfortunately, research shows that lowering LDL does not affect heart disease. Fortunately, statins also lower inflammation and inflammation causes heart disease, so statins can be used as very expensive anti-inflammatory drugs.

The hopeful side is that most drugs are not necessary and there are other approaches that are more effective and cheaper to prevent and treat disease.

Don’t Worry about Your Gut Flora

There is a major NIH initiative to identify all of the bacterial species that live in or on the human body. That sounds potentially very useful in the context of all of the hype about pre- and probiotics. Your gut flora are important and people are doing very dumb things by killing off the bacteria that protect their skin from pathogens. The problem is that the concept of species of bacteria is wrong. In your gut, there is so much transfer of DNA between all of the different types of bacteria, that the idea of bacterial species doesn’t work.

Consider the pathogenic, toxin-producing E. coli strain. E. coli gets a bum rap, because we have created a new bacterium by treating cattle with antibiotics. The antibiotics increase fat accumulating in the beef, by altering the gut flora. The antibiotics eliminate some bacteria that normally live by adhering to the rectal areas of the cattle. E. coli can colonize the vacancies, but only if the gut lining releases nutrients and the E. coli is resistant to the antibiotics. The solution comes in the form of a plasmid from another bacterium. The plasmid is a small segment of DNA that carries genes for resistance to several different antibiotics and a toxin that causes intestinal cells to leak. The cattle don’t care much about the new Frankenstein E. coli, but if that plasmid-toting E. coli goes from cowpie to hamburger, and replaces your natural E. coli, it can be deadly.

The point is that the bacteria needed to fill all of the niches in your gut environment are created by approximation from the myriad genes of your whole gut flora community. You are constantly creating new “species” of bacteria. The problem is that you produce your own gut flora based on what you eat and by interactions with your gut. Those interactions can make you healthy or keep you sick. A single bottle of formula, for example, can permanently compromise the gut flora of a breastfed baby. We are learning how to control the development of healthy gut flora, probiotics, by supplements containing particular polysaccharides and oligosaccharides, i.e. prebiotics.

The hopeful side is that diets that have been shown to be healthy also produce healthy gut flora. That isn’t much of a surprise.

Don’t Worry about Toxins

The world is a dangerous place, but people have been there and done that. Plants have been standing around synthesizing a witch’s brew of natural toxins for millions of years. They are so good at it that even the most highly evolved species, bacteria, can’t eat them and survive. You can find a plant toxin that will interact with every human protein. That is why most human drugs are derived from plant toxins.

We know not to eat green potatoes, but pregnant women who make the mistake of eating rotten potatoes will regret the birth defects in their babies. There are so many toxins in plants that we have to be careful to watch what toddlers put in their mouths and every poison control center has to be able to identify plants over the phone to recommend emergency treatment. Pregnant women have a built in system to avoid plant toxins during the embryo’s most vulnerable first trimester. It is called morning sickness. A healthy diet during this time is to avoid vegetables and stick to meat and starch. Women build up baby fat to get through this sensitive time without exposure to plant toxins that their bodies may not be able to detoxify.

The happy thought here is that environmental toxins of human origin are not what make us sick, any more than eating plants generally is not a problem. With a healthy diet, even one modestly contaminated, we will not get sick. With a diet that compromises our health, even natural toxins become a threat.

Don’t Worry about Environmental Estrogens (except to save the rest of the animals)

There is an abundance of synthetic molecules that mimic human sex hormones, but once again, plants have been producing estrogen mimetics for millions of years. The second most abundant biological polymer (macromolecule), after cellulose, is lignin. Lignin is what makes up a large part of plant tissue and is what permits plants to be stiff. Lignin is also the “organic” material in fertile soil. This polymer is black in soil, because it is so complex that it has molecular structural components that can absorb all wavelengths of light. Lignin has no defined structure, but rather it is essentially a combination of thousands of structures.

Now imagine the mucky, black, lignin-laden banks of a forest stream. Tons of complex organic molecules leach into the stream and many of those molecules can mimic the shape of estrogens and bind to human molecules, receptors, that would normally bind to estrogen. It is possible to have excess estrogen leach from a sewage treatment plant, because it is not specifically targeted for removal, and the estrogens could temporarily reach a level to affect sensitive aquatic species, but there are already so many natural sources of estrogenic compounds, that the impact on humans would be expected to be unmeasurably small.

It is certainly possible for humans to pollute streams with other molecules, antimicrobial toothpaste ingredients, for example, that have unusually high environmental stability and bind with unnatural strength to estrogen receptors. Those would be problems like DDT. It would make sense to avoid exotic compounds and use natural plant products where possible, just because biological systems can digest them more readily.

The hopeful perspective here is that we already have ways of avoiding most of the problems with manmade estrogens and although these may be environmental hazards, they probably won’t affect human fertility.

An Anti-Inflammatory Diet and Lifestyle Is the Simple Solution

Prevention is the easiest way to stay healthy and since chronic inflammation is the foundation of degenerative, autoimmune and cancer diseases, an anti-inflammatory diet and lifestyle avoids most of the diseases. These same diseases also provide a modern description of aging, i.e. the consequences of mismanaged chronic inflammation. A healthy body is also the best protection from environmental threats, genetic weaknesses and the dangers of modern medicine.

The hopeful perspective for the New Year is eating and living well can keep you healthy and physically fit into your eighth decade.

ASP, C3 and Lipid Metabolism

Each gene codes for a protein with multiple molecular actions.

I was recently reading Nigee’s Diet and Nutrition Blog and was reminded of the interesting complexity of the molecular underpinnings of physiology. Nige was discussing fat metabolism and indicated that a protein called Acylation Stimulation Protein (ASP), increased triglyceride synthesis and that ASP levels in the blood increased after a lipid-rich meal.

Since I could recall nothing about ASP, I started to examine the gene that codes for ASP and soon found that it was called C3, as in complement C3. So the lipid manipulating function is part of the repertoire of the C3 protein that also regulates the innate immune system and is sometimes referred to as an anaphylaxin, in tribute to its ability to stimulate acute inflammatory responses (anaphylactic shock).

It is not unusual for a gene to code for multiple proteins with mix-and-match domains, as a result of alternative splicing events at the mRNA processing level. That is how different classes of immunoglobulins, IgG vs. IgE, can have the same variable regions for antigen binding, but different conserved regions for binding to other parts of the immune system. In the case of complement factor C3, a single protein interacts with dozens of different proteins and is involved many different cell and tissue functions.

The versatility of C3 is partly a result of having multiple pairs of basic amino acids that can participate in binding to heparan sulfate proteoglycans (HSPGs) on the surface of cells. C3 and all of the other proteins of the complement cascade have heparin-binding domains. Thus, the complement proteins are all bound together on the surface of cells by the strands of heparan sulfate. This brings the proteins all together for interactions and during an immune assault the complement components are ultimately assembled into tunnels that breach invading cells.

The ASP-C3 story shows that the complement system is also wedded to lipid metabolism. Another juxtaposition of lipids with immune function is the lipid deposition in athersclerosis and also the association between the ApoE4 type of lipoprotein and susceptibility to Alzheimer’s disease. Clearly, lipid metabolism is intimately associated with degenerative and autoimmune diseases, as well as cancer.

Synuclein and Amyloid Diseases

NSAIDs, such as ibuprofen and aspirin are possible treatments to inhibit the aggregation of proteins (synuclein, beta amyloid) on charged polymers in amyloid diseases, such as Parkinson’s disease, Alzheimer’s disease, etc. Contradictory studies show that intracellular aggregate formation may be protective, since dimers are more toxic than aggregates.

The list of amyloid diseases is long and there are few effective treatments. In each case a protein starts to accumulate in fibers that form amyloid plaques inside or outside the cells. The large aggregates outside are toxic. Inside it appears that the large aggregates are not as toxic as small clumps, oligomers, of the protein.

The amyloid proteins are stacked up in the fibers in a very organized way, so that the same portions of the protein are lined up on each side of the fibers. Outside the cell, the regions with basic amino acids interact with heparin, and in Alzheimer’s disease, for example, the beta amyloid plaque is half heparin. In test tube experiments, fiber formation from protein solutions is accelerated by adding heparin.

Amyloid fibers also form inside cells in the case of the tau fibers of Alzheimer’s disease or the synuclein aggregates in Parkinson’s disease. In theses cases, there should not be any intracellular heparin, and it is not known what polyanion (RNA?) serves to accelerate fiber formation in these cases.

Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and aspirin, reduce the incidence of Parkinson’s and Alzheimer’s diseases. It has recently been shown that in test tube experiments, NSAIDs also decrease the formation of amyloid fibers from synuclein.

Amyloid fibers can be stained by Congo Red and thioflavin. Curcumin is the active component of tumeric and it has a structure related to Congo Red. Curcumin has been shown in recent studies to block synuclein amyloid formation.

In addition, the heparin in the fiber complexes can be stained with berberine. Berberine is a traditional herbal treatment for arthritis. It would not be surprising if it was also effective against Alzheimer’s amyloid plaque.

The large extracellular plaque aggregates appear to be toxic, but the small, oligomeric aggregate of protein appear to be the toxic form in cells. Recent experiments show that facilitating the formation of large intracellular aggregates minimizes the toxicity in animal models of Huntington’s and Parkinson’s diseases. It appears that the large visible aggregates are not the form that kills the cell.

For the time being, the only safe treatments that focus on amyloid fiber formation are the NSAIDs, curcumin and perhaps berberine.

references:
Hirohata M, Ono K, Morinaga A, Yamada M. 2008. Non-steroidal anti-inflammatory drugs have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro. Neuropharmacology 54(3):620-7.

Pandey N, Strider J, Nolan WC, Yan SX, Galvin JE. 2008. Curcumin inhibits aggregation of alpha-synuclein. Acta Neuropathol. 115(4):479-89.

Bodner RA, Outeiro TF, Altmann S, Maxwell MM, Cho SH, Hyman BT, McLean PJ, Young AB, Housman DE, Kazantsev AG. 2006. Pharmacological promotion of inclusion formation: a therapeutic approach for Huntington's and Parkinson's diseases. Proc Natl Acad Sci U S A. 103(11):4246-51.

Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, Volk CB, Maxwell MM, Rochet JC, McLean PJ, Young AB, Abagyan R, Feany MB, Hyman BT, Kazantsev AG. 2007. Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease. Science. 317(5837):516-9.

Is a Belly Bad?

A protruding midsection can mean many different things. It can be obesity, starvation/kwashiorkor or sarcopenia. It can mean there is a layer of fat outside, sagging organs poorly supported by weak abdominal muscles or fat surrounding the organs and stretching the muscles outward.

Alternatively having the same “lean” profile at 60 as at 16 could be a sign of a decline of muscle and an increase in fat surrounding organs. You can always have a porthole put in to see what is going on, or you can check the calendar and your C-reactive protein level.

If you are over fifty and your doctor has told you that your CRP, a measure of inflammation, is starting to creep up, then you are starting to suffer from age-related loss of muscle, sarcopenia. That is, you have begun to replace your muscle mass with fat, and the fat is producing inflammatory signal molecules, cytokines, that are the same as those produced by your immune system cells in response to an infection.

Most of the symptoms we associate with aging are just poorly managed chronic inflammation, as a result of replacing muscle with fat. The fat is metabolically lethargic, so you actually need less food, as your muscle mass declines. The result is that it is progressively easier to put pounds on. That is the bad news. The good news is that building muscle requires at least one of the inflammatory cytokines produced by fat, IL-6, so gaining muscle should be easier until you get back into shape. Losing weight is also anti-inflammatory, if the loss is fast enough to produce a fasting physiology.

All of the diseases associated with increasing age are just the accumulation of problems that result from increasing levels of chronic inflammation. Most of the increase is the result of inflammatory diet, but the increasing inflammation also decreases the desire to be physically active, with the result being a loss of muscle mass. Adjustment to an anti-inflammatory diet and lifestyle, can reverse the aging process.

It is also possible to be physically active and have a youthful muscle mass, but still have an inflammatory diet. The result will still be chronic inflammation, and cryptic inflammatory diseases that accumulate with time and produce sudden failures of joints, coronary arteries or cancer. Estrogens are also naturally anti-inflammatory, so women will find that menopause reveals any inflammatory diet/lifestyle that has been hormonally camouflaged. Thus, menopause may produce any of the typical signs of inflammation, e.g. acne, depression, back problems, arthritis, etc.

The bottom line is that a weak gut and/or extra body fat will cause problems at any age. And at any age, the diseases that are associated with inflammation can be minimized or avoided by an anti-inflammatory diet and lifestyle/exercise.

HIV TAT and Methamphetamine -- TNF

HIV infection and methamphetamine both cause inflammation of the brain and together they are paralyzing.

What’s worse than a TNF typhoon resulting from methamphetamine use? The answer is a TNF typhoon resulting in dementia from HIV infection of the brain.
Combine methamphetamine with HIV in the brain and the result is a Parkinson’s type of paralysis.

This sounds like very morbid subject matter to pursue out of curiosity, but if you put heparin into the equation, as I always do, it all becomes very interesting.

Here are pieces to the big picture:

HIV, the AIDS virus, infects cells of the immune system and causes chronic inflammation. The inflammation causes a disruption of heparin metabolism and since heparin is a major part of the matrix that holds together the endothelial cells that line the capillaries that feed the brain, the capillaries leak, i.e. there is a leak in the blood brain barrier. HIV-infected cells can pass out of the capillaries and into the brain. Here comes the insidious part, HIV produces a protein called TAT.

I drew a graphic of TAT with the basic amino acids in blue. The sequence of this nasty little protein shows how it gets around. It is secreted from cells, attached to heparan sulfate proteoglycans. It sticks tightly to heparin (yellow and red stick figures, sticking to ribbon of TAT), because of the patches with three and four adjacent basic amino acids. Frequently, the TAT will just be secreted and then sweep over the surface of the infected cell and be brought back into the cell on the circulating HSPG.

DPVDPNIEPWNHPGSQPKTACN
RCHCKKCCYHCQVCFIKKGLGI
SYGRKKRRQRRRPSQGGQTHQ
DPIPKQPSSQPRGDPTGPKE

A protein with three adjacent basic amino acids will get swept into a cell. All allergens that I have examined have this internalization triplet of basic amino acids. TAT is so powerful, that if it is chemically linked to the larger fluorescent protein from jelly fish (left with green, fluorescent amino acid derivative down the center), the whole fluorescent protein is dragged into cells.

The TAT can move from the HSPGs of an HIV-infected cell to neighboring cells with HSPGs. The TAT then gets taken into the cytoplasm of the next cell. Four adjacent basic amino acids are the signal that transports a protein to the nucleus and into the nucleus. It is in the nucleus that TAT really causes trouble. The TAT can move from an infected immune cell in the brain to neurons. TAT can kill neurons and stimulate other cells to produce TNF.

Methamphetamine also causes a TNF storm in the brain. This is a quick way to start the wasting symptoms that TNF in known for -- it is also call cachexin, after the wasting process of cachexia. If methamphetamine is given to someone with neurological symptoms of HIV, then the neuropathology is further exaggerated into a Parkinson’s type of paralysis. The TNF production of both is additive.

TNF production by methamphetamine brings up the consequences of the very closely related compound amphetamine (Adderall, Dexedrine) used by children and young adults (college age) as a treatment for ADHD.

reference:
Theodore S, Cass WA, Nath A, Maragos WF. 2007. Progress in understanding basal ganglia dysfunction as a common target for methamphetamine abuse and HIV-1 neurodegeneration. Curr HIV Res. May;5(3):301-13.

What If Medicine Was Scientific?

A view of the future of medicine, if the health of each patient was the highest priority.

2020 Somebody read the biomedical literature and decided to save a few bucks on the national healthcare system.

It has been a couple of years since everyone began favoring their right butt cheek. The “BioMed” subcutaneous, WiFi, microchip implants were controversial, but the economic argument was compelling. In the first year after the BioMed became mandatory and implantation accompanied every office visit, the expenditure on medical treatment in the US dropped by 10%. There was a lot of complaining about what a literal “pain in the butt” the prevention program was, but the prodding of the BioMed got results.

Once subQed, the BioMed enforced a simple dietary and exercise regimen. Violation of the regimen produced progressively more severe itching of the cheek, until the real “pain in the ass” set in. Surcease from this sorrow was Poetic in its justice. Sufferers could pay for temporary relief in conveniently marked toll stalls, called “Craigs.” There was a certain amount of public opprobrium associated with use of these facilities, but they brought relief. Those compelled to use the stalls complained of being “Idahoed.”

The prescribed diet was high in omega-3 oils and complex carbohydrates, but proscribed large amounts of starch, sugar and other hyperglycemic carbohydrates. Ten minutes of daily solar exposure (vitamin D) on the cheeks was monitored by the BioMed and “mooning” was replaced in the vernacular by “BMing.” Twenty minutes of daily exercise was enforced based on the BioMed’s analysis of physiological (pulse, blood pressure, blood sugar) and physical (GPS, accelerometer) measurements. Sustained, sedentary activity was not possible.

The BioMed provided identity verification for each patient and every datum on the patient was accessible by any medical official. Absolute privacy was provided by a variant of Apple’s DRM. Prescriptions for each patient were verified at purchase and were confirmed by access to a wireless expert system. Correct timing of medication was enforced by BioMed reminders. Compliance soared.

In the second year, 2 BM, office visits began to plummet. Doctors in private practice saw their incomes drop by 20% and there was already talk of a surplus of medical staff. Prices of the stocks of the major food processors began to drop as people shifted away from fast food, common vegetable oils, corn and soy products, and began to purchase more local meat and produce. Breastfeeding gained new popularity spurred by the introduction of the BioMedNip, a nipple implant to enhance the health of newborns.

The third year, 3 BM, brought appreciation for the BioMed and “kiss my cheek” was first used as an invocation of good luck. The decline in chronic inflammation decimated cases of depression, obesity, arthritis and allergies. Detection rates for cancer and degenerative diseases of the elderly plateaued. Cancer and geriatric specialists took credit for the efficacy of their latest therapies. Infant mortality in America began to approach that observed in developed countries. Pharmaceutical stocks tanked. Lactation fashions reach the catwalks. Hospital closures begin. Advertising for cold medications, drugs and baby formula is banned. American worker productivity soars.

It is amazing that at any given time, the US is just a couple of years away from medical utopia. The cure for chronic inflammation, diet and exercise, is available to all.

Medicine Can Treat. Why Can’t It Cure or Prevent?

Prescription for all diseases: Anti-inflammatory Shock Treatment

Cancer death rates may be finally slowing. Why has it taken so long? Medicine has some cobbled-together treatments for allergies, asthma, Alzheimer’s and atherosclerosis, but all of these are still increasing. Cures and prevention are always ten years away. Something is fundamentally wrong with medicine and the fatal flaw is obvious in the biomedical literature. Causes are not mentioned. Treatments are tested and evaluated. Pharmaceuticals are developed for therapy, not for cures.

Examination of medical websites reveals a public interested in why they get sick, but there is no explanation. There is a recent tendency connected to the concept of personal medical solutions, to attribute sickness to the unique genetics of the individual. Certainly there are some molecular genetic diseases, but this obscures the issue. In most cases the genetics only gives a predisposition. Biomedical research does not pursue why some people get the disease and others with the same genes do not.

The research literature shows abundant evidence that various diets and lifestyles dominate the outcome in health, but the medical industry fails to apply these factors. Why should someone spend a lifetime on drugs, if two weeks of intensive diet/lifestyle therapy provides a cure? Is a surgical intervention preferable over a gut flora exchange?

There is compelling evidence that chronic inflammation due to diet and lifestyle is the foundation for most degenerative and autoimmune diseases, and yet simple changes to avoid or eliminate inflammation are not emphasized by doctors to prevent or cure most diseases. It is quite possible to design a one-size-fits-all primary treatment for all diseases, an “Anti-inflammatory Shock Treatment.“ It would be a two week controlled diet and exercise program that provided the anti-inflammatory benefits of controlled carbohydrates, adequate protein, balanced omega-3/6 fatty acids, anti-oxidants, vitamins, exercise and meditation. Careful control of probiotic gut flora would be a priority. This system could be designed based on current research and would be generally applicable. The prescribed system for each patient would match severity of the disease with intensity of the anti-inflammatory intervention.

Lectins - Heat’em and Eat’em

Lectins are proteins common in seeds. They bind to sugars attached in chains to proteins, i.e. glycoproteins, and are displayed on the surfaces of cells that line the gut. Lectins could inhibit digestion of raw beans, but cooking makes them digestible.

Fear of lectins is puzzling. Lectins are proteins that have binding sites on their surfaces for specific single or small sequences of sugars. They are present in seeds to protect the seeds from herbivores.

A seed is mostly food (starch, protein, fat) for the plant embryo that will grow from it. This is also true of a chicken egg and just like the egg, the seed contains defensive proteins to inhibit the growth of bacteria, fungi and egg/seed eaters.

The egg has enzymes to degrade bacterial walls and proteins that bind iron, vitamins, etc. needed by bacteria and humans. Eating many raw eggs can lead to vitamin deficiencies. Boiling the eggs, unravels the defensive proteins and makes them digestible and nutritious.

Seeds block being digested by containing proteins that foul the digestion system of would be devourers. For example, soybeans have trypsin inhibitor that binds to our digestive enzyme and makes eating raw soybeans nonproductive and uncomfortable. Boiling soybean meal to produce a curd, i.e. tofu, agglutinates the denatured soy proteins, including the lectins and washes away the soy trypsin inhibitor. Tofu is free of digestion inhibitors and lectin activity.

It is not an accident that lectins bind to human red blood cells. The sugars displayed on the surface of red blood cells are the blood group antigens. Different sugars on the end of the sugar chains decorating RBCs characterize the A, B and O antigens. These same sugars are present on the surfaces of various bacteria. Immune systems don’t produce antibodies to self antigens, so a person with type A blood produces antibodies only to B antigen sugars it encounters on bacteria. A person who is type AB doesn’t produce antibodies to A or B sugar antigens. There aren’t antibodies to O, because that sugar structure is the basis upon which both A and B are made, and some of the
structure is present on all RBCs. Lectins are specific for A or B or other common bacterial sugar antigens.

I did some modeling to show a lectin with lactose (red and gray) bound to sticky tryptophans (yellow) in two places on the surface. In one case a lysine (blue) is draped on the other side. That shows that sugars bind both to aromatic amino acids and to the hydrophobic arms of basic amino acids.


Some people think that humans and other mammals must be protected from lectins and that this protection is shown in human and cow’s milk in the form of antibodies against lectins. This seems to be a misunderstanding. For example, human antibodies secreted in breast milk are secretory IgAs. These antibodies are glycoproteins, i.e. they are proteins with attached sugar chains. Some lectins will bind to these antibodies, because of the attached sugars. These are not lectin-specific antibodies, but rather glyco-specific lectins. The lectins are binding to the glycoprotein antibodies, not the other way around.

It is possible for people to be allergic to lectins, but this is unlikely. For example, peanut allergies involve proteins other than the peanut lectins.

There are some dangerous lectins. For example, ricin is a very nasty, but effective, toxin produced by the castor plant. Ricin is a lectin, in that it binds very specifically to sugars found on the surface of gut cells of insects and humans. After the ricin binds to surface proteins, it is brought into the cells where it chops up the protein synthesizing machinery. That is a dangerous lectin. It takes very little ricin to kill each cell and only a tiny amount to kill a human. Ricin is a terrorist toxin. Yet oil extracted from castor beans contains so little contaminating ricin that it is safe to eat. [Castor oil is wonderful to apply to aching feet overnight for painfree, luxuriously soft feet in the morning.]

The bottom line is that seed lectins add to the nutrition of cooked beans and grains that have been the foundations for several thriving civilizations. The longest living members of the bean and grain cultures are typically older and more fit than comparable individuals with a modern, inflammatory diet based on omega-6 oils.

A Paleolithic Perspective on Biomedical Literature

Homo sapiens seems to be inflammation prone, based on its assortment of biochemical deficiencies. All of the following lead to inflammation: hyperglycemia, vitamin C deficiency, fish deficiency, vitamin D deficiency, grilling meat. Is this an adaptation to agriculture and high population/communicable disease risk?

I was just visiting Diet Rosso and his article on the paleolithic diet flashed me back to some thoughts that I had on the evolutionary benefits of inflammation. So, Rosso made me think about this.

Inflammation is a big health problem in the US. All of the major diseases are inflammatory and all are exacerbated by the inflammatory US diet. But why is the fast food diet so inflammatory? Why is our corn/soy agricultural economy so hazardous to our health?

Corn and soybeans provide a good balance between carbohydrates, fats and protein. The amino acid composition of the combo is also fairly good, and corn and soy oils are high is unsaturated fats. So why does a corn/soy diet lead to degenerative and autoimmune diseases?

I think that the answer is that inflammation is getting a bad rap; as long as our immune system produces effective local responses to pathogens, we are pleased, but when the immune system cranks it up in response to a deluge of disease, we complain. I argue that our current inflammatory response to fast food is just a slight embellishment of the first dietary-based increase in inflammation that provided adaptive protection against the dangers of agriculture.

As I see it, agriculture had a series of dramatic impacts on the evolution of plants, animals and humans, in particular. Taming of plants and animals altered the human diet. Agriculture also institutionalized grilling and grouling, which meant bringing together carbs and protein at high temperatures. The result was an increase in dietary starch, seed/grain oils and advanced glycation endproducts (AGEs). There was also a decrease in fish, leafy vegetables and complex carbohydrates/fiber. Agriculture also led to a dramatic increase in population density.

I imagine that the first villages or very large family groups that resulted from sustained planting of harvestable crops resulted in plagues. Lots of people in close proximity with minimal hygiene is a prescription for infectious disease. Agricultural development required an immunological adaptation to higher loads of communicable diseases. That adaptation was inflammation triggered by agriculturally-associated diets high in starch and low in browsed veggies.

Hunting/gathering, especially along coasts, provided dietary vitamin C, as well as a high ratio of omega-3 to omega-6 fatty acids. Early humans defective in the ability to synthesize vitamin C or omega-3 fatty acids, would not suffer if they ate plenty of leaf veggies. Wild fish and game, as well as leafy veggies, have a high ratio omega-3 to omega-6 fatty acids, so these people would be safe from inflammation-based disease and infertility.

Agriculture focused on seed harvest results in a dramatic shift in diet and disease. Communicable disease was not a problem for hunter/gatherers, because of the necessarily widely distributed small population groups. Agriculture concentrates populations around the crop lands and increases the benefits of physiological energy expenditures on heightened immune activity to provide consistent protection against pathogens. Agriculture required chronic inflammation for disease protection.

Inflammation triggered by cues in the agricultural diet would have a high selective advantage. Individuals who increased their chronic level of inflammation in response to high blood sugar, compounds produced during cooking, i.e. AGE, vitamin C deficiency, vitamin D deficiency (low exposure to sun) and/or omega-3 oil deficiency, would have survival advantage in high population densities associated with agriculture.

The fast food diet is nothing more than an exaggeration of the agricultural diet and it produces and an exaggeration in the human adaptation to agriculture, high chronic inflammation and a suite of inflammatory diseases. Metabolic syndrome is another name for high chronic inflammation. Obesity is inflammatory. A sedentary lifestyle is inflammatory and aging is a suite of symptoms associated with inflammation. Hunter/gatherers didn’t show the same signs of aging as modern humans, and probably had comparable longevity (although there were many other risks.)

Lastly, I want to ponder the modern decline in fertility. Fertilization and implantation requires suppression of inflammation in the female reproductive system. Semen is uniquely rich in omega-3 oils and women who have a high frequency of unprotected coitus with a man with a high level of omega-3 in his semen, are much more likely to become pregnant and carry a pregnancy full term. The fetus requires high levels of omega-3 fatty acids for brain development and can rapidly deplete the omega-3 fatty acid a mother with a deficient diet. Omega-3 deficiency is associated with preeclampsia.

Early males and females with an inflammatory agricultural diet would tend to be infertile, because of omega-3 oil deficiencies and chronic elevated inflammation. Periodic exposure to an abundance of omega-3 fatty acids, such as feasting on migrating salmon, would synchronize fertility and subsequent births. It is humbling that a current research program in land-locked regions of South America uses cans of anchovies to remedy the same pregnancy problems that plague North America and its inflammatory fast food diets.

Niacin Flush

Niacin is a B vitamin that is cheap and highly effective at raising HDL and lowering LDL. HDL and LDL were previously called good and bad cholesterol, resp., but since the data from numerous studies show that they don’t have a big impact on health, it is probably easier to just call them heavy and light reflecting less and more lipid content. If you still want to adjust your blood lipids, then niacin is more effective than the costly statins. Unfortunately, niacin also causes an uncomfortable (itchy and hot) flush.

The niacin flush is part of the inflammatory process that includes the classic tetrad of symptoms: rubor (redness), calor (increased heat), tumor (swelling), dolor (pain). Flushing in response to niacin shows that the immune cells in the skin respond to ingested niacin that is flowing through the capillaries. Mast cells in the skin have receptors that bind niacin and the cells secrete inflammatory prostaglandins. The prostaglandins act on the capillaries to cause dilation and flushing. Mast cells have secretory granules that fuse to the cytoplasmic membrane and release their contents outside. The granules contain histamine, heparin and tryptase. The histamine stimulates histamine receptors on pain/itch nerves and the tryptase stimulates receptors on a second set of pain/itch nerves.

Prostaglandins are produced by membrane bound enzymes on the surface of mast cells. When the mast cells are stimulated, additional enzymes are added to the surface through fusion of the secretory granules. The combined enzyme complex produces prostaglandins by releasing arachidonic acid (ARA) from phospholipids of the membrane (phospholipase A2, PLA2), converting the ARA to an epoxide prostaglandin (cyclooxygenase, COX-1) and stepwise producing additional prostaglandins. These prostaglandins cause the dilation of capillaries that is seen as flushing.

Niacin also binds to receptors on fat cells, adipocytes, and blocks release of fatty acids from the triglycerides stored in these cells. It is this action that is responsible for the increase in HDL and the lowering of LDL in blood serum.

An extension of the niacin skin flushing reaction is the use of this response to demonstrate the presence of arachidonic acid and a functional immune system in the skin. A recent study used topical application of niacin and skin reddening to test the idea that schizophrenia exhausts ARA as a result of inflammatory processes in the brain. Tests showed a tendency for schizophrenic episodes to be accompanied by a diminished flushing response to niacin. This result also suggests that a lowered system-wide ARA level should show up in a predisposition to gut problems.

It would be very interesting to test the interplay between inflammatory provocations, e.g. infection, serum omega-6/omega-3 fatty acids, and measures of inflammation, e.g. C-reactive protein on niacin flushing. Inflammatory depletion of ARA may be important in the decline in the integrity of tissues that is observed in inflammatory diseases of the gut (Helicobacter-based ulcers, IBD, Crohn’s disease, celiac), autoimmune diseases (arthritis, atherosclerosis), skin diseases (vitiligo), etc. It would also be interesting to test the impact of helminth infections to reverse ARA depletion.

reference:
Benyó Z, Gille A, Kero J, Csiky M, Suchánková MC, Nüsing RM, Moers A, Pfeffer K, Offermanns S. 2005. GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing. J Clin Invest. 2005 Dec;115(12):3634-40.

Antioxidants or Fermenting Gut Flora?

Long life is the result of a good diet and exercise. Plant antioxidants are eaten to sop up the reactive oxygen species (ROS) and omega-3 fatty acid-rich fish oils are consumed to reduce the production of inflammatory prostaglandins. Avoiding inflammation that has been linked to essentially all degenerative and autoimmune diseases should make us live better and longer. Unfortunately it is more complex than that, and studies in the simple nematode, Caenorhabditis elegans, show that your gut flora may have something to say about your longevity.

C. elegans nematodes live in the laboratory fed on Escherichia coli, the common colon bacterium. Since the bacteria are the sole diet of the worms, to change the worm’s diet, mutant bacteria must be used. To study the impact of various vitamins on longevity, mutant bacteria unable to synthesize particular vitamins were fed to worms and their average length of life was measured.

Deleting coenzyme Q (10) resulted in a surprising increase in longevity. It was assumed that since coQ10 was needed for effective bacterial electron transport, the disruption would result in an increase in inflammatory ROS. What actually happened was that the bacteria shut down their use of aerobic metabolism and turned on fermentation.

Fermenting bacteria are probiotic in human guts and it appears that the same is true of worms. These results suggest that probiotic, fermenting gut flora may be profoundly important in determining longevity. What we eat may determine how long we keep eating.

reference:
Saiki R, Lunceford AL, Bixler T, Dang P, Lee W, Furukawa S, Larsen PL, Clarke CF. 2008. Altered bacterial metabolism, not coenzyme Q content, is responsible for the lifespan extension in Caenorhabditis elegans fed an Escherichia coli diet lacking coenzyme Q. Aging Cell. 7(3):291-304.

Menstrual Pain is Inflammatory

Inflammation is essential to the menstrual cycle. At key points inflammatory prostaglandins are made from omega-6 arachidonic acid to trigger ovulation and menses, the discharge of the blood-engorged lining of the uterus. Chronic diet-based inflammation can result in disrupted ovulation, infertility due to an inability to suppress an inflammatory response to egg implantation, menstrual pain/cramps and premature birth.

Several studies have shown that reducing diet-based inflammation by eating supplements containing long chain omega-3 oils, e.g. fish oil, decreased menstrual pain and cramps. The reduction in chronic inflammation was associated with decreased production of inflammatory prostaglandins that are the cause of the pain and intense uterine contractions. Normally, the diet would provide a balance of omega-3 and -6 fatty acids, which would yield a mixture of anti-inflammatory and inflammatory prostaglandins, and produce an effective discharge through more moderate uterine contractions.

A more recent evaluation of numerous studies on the impact of omega-3 oils on pain associated with menstruation, arthritis, inflammatory bowel disease, etc., showed a uniform decrease in inflammation and pain. The simple summary is that an inflammatory diet rich in omega-6 vegetable oils leads to pain, suffering and premature aging. A more normal diet with a balance of omega-3 and omega-6 fatty acids leads to health and reduced aging.

Typical symptoms of an inflammatory diet are: menstrual cramps, infertility (gestational problems: preeclampsia, prematurity), joint pain, back pain/sciatica, acne, allergies, asthma, autoimmune diseases. There is increasing evidence that obesity not only produces inflammation, but that an inflammatory diet can lead to obesity. An inflammatory diet, especially if augmented with antibiotics, disrupts the normal gut flora and leads to an inflammatory replacement flora that supports chronic inflammation throughout the body.

Chronic inflammation and much of the damage caused by chronic inflammation is reversible by a shift to an anti-inflammatory diet and lifestyle (described elsewhere on this blog.)

references:
Deutch B. 1995. Menstrual pain in Danish women correlated with low n-3 polyunsaturated fatty acid intake. Eur J Clin Nutr. 49(7):508-16.

Goldberg RJ, Katz J. 2007. A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain 129(1-2):210-23.

Bell RF. 2007. Food and pain: should we be more interested in what our patients eat? Pain. 129(1-2):5-7.

Leptin and Diabetes

Fat cells produce the hormone leptin. Early experiments showed that leptin could ameliorate some of the effects of mouse models of type I diabetes, but it was always thought that the leptin just improved the activity of the small residual amounts of insulin produced by the rats. A recent experiment with genetically insulin deficient NOD mice, shows that leptin expressed by a virus infection reverses the symptoms of diabetes.

The NOD mouse strain is defective in the hormone, IL-2, that preserves tolerance to self proteins. As a result, a high percentage of the NOD mice develop symptoms of type I diabetes melitis, high blood glucose and ketosis. These animals will die without injected insulin.

In recent experiments, the NOD mice showing symptoms of diabetes were injected with a strain of adenovirus that had been engineered to express leptin. The leptin-expressing NOD mice displayed a rapid reversal of diabetes symptoms and began to gain weight normally. The high blood sugar and ketosis in NOD mice was stimulated by glucagon release in response to lack of insulin. Leptin stopped the glucagon release and reduced additional production of glucose by the liver and lipid oxidation that yielded the ketosis.

Muscle access to glucose in the NOD mice was restored by leptin by the induction of insulin-like growth factor 1 and its receptor. The NOD + leptin mice had normal blood sugar, but ate half the normal amount and had no body fat.

These are very promising results for type I diabetics, because it indicates that insulin injections are not the only approach to treatment. Stimulation of leptin production may be very useful and this new approach is being intensely investigated.

reference:
Yu X, Park BH, Wang MY, Wang ZV, Unger RH. 2008. Making insulin-deficient type 1 diabetic rodents thrive without insulin. Proc Natl Acad Sci U S A. 105(37):14070-5.

Anti-inflammatory Octopus

I always envied the neurophysiologists who studied the giant axons of lobster, because they could always eat their failed experiments. I was working on a fungal disease of soybeans. It had no gourmet prospects. My revenge came decades later, when I took a “research” trip to Tuscany to study the impact of Mediterranean cuisine on inflammation. Fish, cephalopods, red wine and tiramisu were my test materials and I was the test organism. For a month, I felt no stress, no inflammation and no pain. Recent research articles support my subjective conclusion that seafood and red wine from Siena to Venice are anti-inflammatory.

Recent tests of the fatty acid composition of Mediterranean fish and octopus show that the ratio of omega-3 to omega-6 fatty acids in the fish and octopus is roughly 2:1. (In contrast, the US ratio is 1:20) The omega-7 fatty acid, palmitoleic acid, which appears to act as an anti-inflammatory hormone, was also present. The prominent place of seafood in the Mediterranean diet and the high omega-3-rich fatty acid composition of that seafood, combined with the absence of the inflammatory, omega-6-rich vegetable oils, corn, soy, safflower, of the inflammatory US dietand the use of olive oil, go a long way to explain the relatively low incidence of inflammatory diseases in people who eat a Mediterranean diet. Just add some sunshine and exercise, and you will live better and longer.

Oh, by the way, the tiramisu was my daughters’ project to evaluate local variation of that dessert throughout Italy. So we ate tiramisu at a different restaurant each day for a month. The differences were amazing and the best tiramisu in Italy is ...

But the bottom line is the same. The Mediterranean diet is nothing more than another variant of the anti-inflammatory diet and lifestyle that I have been discussing throughout this blog. Biomedical research says that the US diet is killing us. You can go to Tuscany or you can just shop, cook and live wisely wherever you are.

references:
Ozogul Y, Ozogul F, Cicek E, Polat A, Kuley E. 2008. Fat content and fatty acid compositions of 34 marine water fish species from the Mediterranean Sea. Int J Food Sci Nutr. Oct 29:1-12.

Ben-Youssef S, Selmi S, Ezzeddine-Najai S, Sadok S. 2008. Total lipids and fatty acids composition of the coastal and the deep-sea common octopus (Octopus vulgaris) populations: a comparative study. Nutr Health. 19(3):195-201.

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.

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.

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:
MLLLLLSIIVLHVAVLVLLFVSTIVSQW
IVGNGHATDLWQNCSTSSSGNVHHCF
SSSPNEWLQSVQATMILSIIFSILSLFLF
FCQLFTLTKGGRFYITGIFQILAGLCVM
SAAAIYTVRHPEWHLNSDYSYGFAYIL
AWVAFPLALLSGVIYVILRKRE

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.