Inflammation and Vitamin D Deficiency

Does Dietary Inflammation Reduce Skin Production of Vitamin D?

The media discovered the vitamin D deficiency pandemic last week. Amazingly researchers were recorded on camera saying that the D deficiencies are caused by insufficient exposure to ultraviolet in sunlight and inadequate consumption of vitamin D-laced milk. Have all of these people been avoiding the biomedical journals?

Have they noticed that my tan improved since I started eating anti-inflammatory?

Let’s shine some sunlight on these knowledge deficiencies:

• Serum vitamin D levels have been dropping (as chronic inflammation has been increasing) over the last three decades -- has something changed in our diets?
• Vitamin D deficiencies occur globally (not restricted to Northern latitudes or winter) -- related to diet?
• Women are more vulnerable, because of cultural modesty in some countries, but males are still D-deficient.
• A subset of people exposed to ample sunshine are still D-deficient.
• Vitamin D deficient individuals also have elevated TNF.
• Vitamin D deficiency and inflammation are risk factors in the same diseases.

It seems that the simplest conclusion is that chronic inflammation leads to vitamin D deficiency, even though vitamin D deficiency may also contribute to inflammation.

This also probably means that chronic inflammation makes it harder for skin to produce vitamin D during exposure to sunlight.

One would expect those who are inflamed to get sunburned more readily and people who eat plenty of omega-3 rich seafood probably produce more vitamin D, even if they are not in the sun as much.

Inflammatory starvation (or American fast food) diets high in starch and omega-6 vegetable oils, should produce vitamin D deficiency even on the Equator.

We should not be surprised that inflammatory degenerative diseases are associated with vitamin D deficiency. It would be interesting if vitamin D supplementation to eliminate deficiency, reduced inflammation and reversed degenerative disease.

Do statins reverse vitamin D deficiencies (and improve tanning) as they lower inflammation? [Statin lowering of LDL is unrelated to reduction in cardiovascular disease. Only the anti-inflammatory side-effect is important.]

Does NFkB activation (inflammatory signaling) inhibit vitamin D receptor activity and vice versa?

You can forget all of this confusion, if you just stick with an anti-inflammatory diet (that includes vitamin D supplements) and exercise frequently in the great outdoors.

Brilliant Blue Brains and Spinal Cords

Hibernation-Suppression and Trauma-Induction of Inflammation

Inflammation/hibernation is a complex story at the foundation of chronic diseases. Inflammation is the common thread -- activation of the inflammation transcription factor NFkB.

Trauma Causes Life-Threatening Trauma

Trauma, everything from a bee sting to a horrific traffic accident that causes head and spine injuries, results in initial tissue damage and subsequent inflammation damage. The inflammatory response to punctures and abrasions is usually appropriate and self-limiting. The immune response to serious injuries is frequently more life-threatening than the initial damage.

Transplanted Organs Suffer from Inflammation

Organs removed for transplantation are subjected to a certain amount of necessary trauma and oxygen deprivation. If the organ was simply popped into a waiting recipient biochemically unaware of the process, the initial damage would be readily repaired in its new home. Unfortunately, some of the organs overreact and become damaged by their own immune/inflammatory reaction to the surgery.

Hibernation Reduces Trauma Inflammation

Organ transplants between animals that are hibernating, are much more successful, because the damaging inflammation is suppressed. Hibernation in animals or in human organs can be induced by the use of opioid peptides, e.g. DADLE, and subsequent surgical procedures are more successful. Hibernation also provides protection against experimental stroke. Apparently, the activation of the opioid receptor suppresses activation of NFkB and avoids inflammation.

Opioids and Steroid Hormones Block NFkB Activation and Inflammation

Steroid hormones can also provide protection against inflammatory damage resulting from head trauma. Thus, the ubiquitous steroid receptors may also block NFkB activation and inflammation.

Trauma Releases ATP that Triggers P2X7 and NFkB

Extracellular ATP can activate NFkB activity and inflammation, and ATP accumulation at trauma sites may be particularly dangerous for spinal injuries. Inhibitors of ATP binding to the purinic receptor P2X7, block inflammation and provide dramatic improvement in the return of function in animal models of spinal injuries. Most of the common inhibitors of P2X7 signaling must be injected directly into the traumatized tissue to block inflammation, because they can’t cross the blood-brain barrier. An exception is Brilliant Blue G.

Brilliant Blue G Blocks Trauma Inflammation

Brilliant Blue G, a.k.a. Coomasie Brilliant Blue, should be very well known to molecular biologists, because it is the commonly used stain for proteins separated on SDS-PAGE gels. I used that dye literally thousands of times to stain gels and I even tried it to stain the extracellular matrix surround cartilage-secreting cells, chondrocytes, grown in culture. I have included one of those pictures just for old times sake.

BBG can be injected IV into mice and the result is amazing. Not only do the mice become blue, but they recover much better from experimental spinal trauma. BBG in the blue mice blocks inflammation due to the surge in tissue ATP and the mice heal their trauma and regain function.

It would be amazing if BBG worked on people with spinal injuries. I expect the rapid development of a suitable drug to help spine and head trauma patients.

Can Manipulation of Hibernation Cure Chronic Diseases?

A big question is whether or not similar drugs might be used to block inflammation that supports cancer and other forms of chronic illness. Alternatively, in some instances the problem is that bacteria are suppressing local inflammation and inducing tissue hibernation to produce chronic illness. Under these circumstances, the induction of local inflammation or elimination of hibernation may make the bacteria vulnerable to attack.

references:
Borlongan CV, Hayashi T, Oeltgen PR, Su TP, Wang Y. Hibernation-like state induced by an opioid peptide protects against experimental stroke. BMC Biol. 2009 Jun 17;7:31.

W. Penga, M. L. Cotrinaa, X Hana, H Yua, L. Bekara, L. Bluma, T. Takanoa, G.-F. Tiana, S. A. Goldman and M. Nedergaard. 2009. Systemic administration of an antagonist of the ATP-sensitive receptor P2X7 improves recovery after spinal cord injury. PNAS 106:12489

National Healthcare and Diet

Barack Obama's Anti-Inflammatory Breakfast Pulpit

Trying to improve the health of Americans by taking the advice of the healthcare industry is futile. Barack Obama must set the example of a healthy lifestyle.

The solution is to prevent the diseases that the healthcare industry is using as a source of profits and that means fundamentally changing diets and lifestyles. It has taken three decades to attack health by shifting from meat protein and saturated fats to starch, high fructose corn syrup and polyunsaturated (omega-6) vegetable oils. It will take a sustained, personal effort by President Obama to guide a relatively rapid return to a healthy, anti-inflammatory diet.

All of the degenerative and autoimmune diseases that form the core of current healthcare diagnosis and treatments are rooted in an inflammatory diet and lifestyle dictated by agribusiness and uninformed by science. The media nags about people eating too much and exercising too little. Our obese population is encouraged to lose weight by eating less. Food fat is demonized. Statins are prescribed with religious zeal to lower blood lipids to reduce cardiovascular disease. All of this “health” advice is wrong and unsupported by the biomedical literature.

It is about time for an authority figure, i.e. The President of The United States of America, to use some leadership skills and teach people how to eat and live. That would be much easier than trying to get doctors to order fewer tests from their own medical test companies or order fewer images through their own imaging companies. Are the pharmaceutical companies going to suggest that their pills should cost less and be pushed less frequently? Will the insurance companies step out of their lucrative middleman role between doctor and patient? It is more reasonable for The President to use his bully pulpit to change the U.S. diet and lead us back to health.

All that is needed is for President Obama’s image at the breakfast table to be judiciously used by a private, non-profit organization on a website:

Barack’s Breakfast

This would provide an opportunity for the President’s health agenda to be presented to the world through his prescription (and explanation of health benefits) for each morning meal:

Slow food
Local food
Low carbon footprint
Low carbs
High omega-3 to -6 fatty acid ratio
Praise eggs and saturated fats
Warn about grains

Vitamin D deficiency
No HFCS
No trans fats

Each meal would come with a source and description of each ingredient and its benefits. YouTube videos of the meal preparation could show the techniques needed. Occasionally The President could be seen enjoying the meal and animation could be used to show why hypoglycemic ingredients were used. Maybe The President would show solidarity to the diabetic victims of industry food fights by getting his finger pricked for a blood sugar test after a meal. It would be good to see him complain about the inaccuracy of several different typical meters. Imagine the close-up of all of the lancet marks needed to convince him that the readings are making sense!

This single approach would cost the American people nothing to implement and would save billions of dollars in healthcare expenses over a few years, as citizens of all socio-economic classes changed to diets that were less inflammatory, and degenerative and autoimmune diseases quickly declined.

Low Carbs Lower Triglycerides

Blood Triglycerides Depend on Diet Carbs, not Fats

I don’t know why the medical community keeps pushing the low fat diets to modify blood lipids. The medical literature shows that a low fat, high carbohydrate diet (more than 50 grams of starch/sugar in a meal) produces high triglycerides, and a low carb diet ( less than 50 grams per meal), regardless of saturated fats and meat, produces lower triglycerides.

In seems reasonable that fats in the diet should mean fats, triglycerides, in the blood, but that ain’t so. It’s the rise in blood insulin in response to a rise in blood sugar due to high glycemic index foods in a meal, that yields high blood triglycerides.

The low carb, low triglycerides facts of life were brought to may attention by my wife’s blood chemistry. She knows better, but refuses to follow my preacherly suggestions about an anti-inflammatory diet. She follows most of the use of supplements and prohibitions about vegetable oils, but loves carbs. She eats two thick slices of bread in a sandwich and I cut a thinner slice and eat mine open-faced. I can’t eat her pancakes or French toast. Ok, I eat lots of dark chocolate, but I don’t have flavored syrup in my lattes.

She was stressed by a high triglycerides (292 mg/dl) in her blood work and her doctor wanted to start her on meds. I was sympathetic. Not really. I actually said, “carbs, carbs, carbs,” until she threatened me. I nagged heavily to just junk the junk and wait on the meds. She started counting grams of carbs with each meal. Actually she tried to average over the whole day, I nagged, she finally relented and stuck to the plan. No more than 50 grams of carbs in any meal. (I think 30 grams, would actually be better.)

One month later, her blood work showed triglycerides down 57% to 127 mg/dl. Individual results may vary, but this is pretty straightforward. Carbs are important -- avoid them. The food pyramid is for chumps. The highest glycemic food you will encounter is a French baguette (95), compared to pastas in the 30s or table sugar at 70.

The facts are:

• Saturated fats in meat are no big deal, and much better than...
• Vegetable oils (most are rich in omega-6 oils, except olive oil) are inflammatory.
• Fish oil (omega-3 DHA/EPA) is anti-inflammatory (unless there is also too much vegetable oil.)
• Starch and sugar increase blood triglycerides and are only needed to gain or keep body fat. Losing weight is much easier without starch/sugar.
• Most people are deficient in vitamin D and C (even with plenty of solar exposure).
• High fructose corn syrup is ten times more damaging than starch/sugar, and is especially bad for diabetics. It doesn’t raise blood sugar as much as starch, it just causes damage, e.g. glycation, at an extraordinarily high rate. It also ages skin by accelerating cross-linking of collagen. Very bad stuff even in fruit juices.
• Eating plant anti-oxidants protects unsaturated fats as they pass through the oxidizing environment of the stomach, so nuts are better unroasted and eaten with veggies.

Autoimmunity, Allergies and Basic Triplets

Basic Triplets Only in Primate Forms and Allergens

I have examined the proteins, autoantigens, that are the focus of a dozen autoimmune diseases and a similar number of allergens. All of these proteins have basic triplets that I previously associated with heparin-binding. I have had two recent revelations. First, these triplets appear to not be involved with heparan sulfate proteoglycans for internalization. In fact, HSPGs don’t appear to be involved, even though the process is inhibited by heparin. So this suggests a transport system, perhaps using the LDL receptor or the mannose-6-phosphate receptor, (or a protein with an acidic triplet or quartet.)

The second interesting observation is that the mouse, cat, dog, etc. versions of the human autoantigens lack the basic triplets. This suggests that these diseases cannot occur in non-primates by the same mechanisms. So what is the role of these basic triplets in humans? They didn’t evolve to cause problems under unusual conditions of chronic inflammation, so what is their adaptive advantage?

I think that the answers to these questions could yield the identification of a fundamental cellular transport process and associated cellular phenomena that could be worth a Nobel prize in medicine and it could be unravelled by a group of high school kids doing some straightforward bioinformatics.

Oh. I just remembered that IL-1 beta, the inflammatory cytokine, has a basic triplet. I just checked NCBI, and that basic triplet is found in all of the mammalian IL-1 betas. Oddly, the soluble receptor for IL-1 beta has an acidic quartet. I looked up the protein structure of the IL-1 beta bound to the IL-1 receptor and did a quick illustration using Chimera:

I put the surface on the IL-1 beta and left the IL-1R wrapping around it in as a ribbon. The basic triplet of IL-1 beta is in blue and the acidic quartet of the receptor is in red. One of the basic amino acids is stabilized by hydrophobic bonding over the face of a tyrosine, in yellow. Clearly, there is a simple ionic, plus-minus charge, bonding between the basic and acid amino acids. I don’t normally see this interaction between basic heparin-binding domains and other proteins. Other proteins that bind to heparin-binding domains use aromatic amino acids to make hydrophobic bonds with the hydrophobic arms of the basic amino acids, e.g. importin and nuclear localization signals or tryptophan/arginine ladders. The use of simple acid-base connections (with the projection of each stiffened by adjacent prolines) shows that this interaction is selected to be irreversible.

I don’t know all of the ramifications of basic triplets, but they are very important and are the basis for most modern allergic and autoimmune diseases.

Celiac Causes Allergies and Autoimmune Diseases

Anti-Tissue Transglutaminase Can Lead to Hashimoto’s Thyroiditis

Celiac, gluten intolerance, causes intestinal inflammation and immunological presentation of the common intestinal protein, tissue transglutaminase (tTG). The result is anti-tTG autoantibodies that stimulate an immune attack on intestines and other tissues.

Heparan-Binding Proteins Involved in Autoimmunity and Allergy

Those familiar with my blog know that I am obsessed with heparin-binding protein domains. The reason that I am focused on these parts of proteins, is because most cells rapidly sweep heparan sulfate polysaccharides across their surfaces from sites of secretion to sites of internalization. During inflammation, proteins with strong heparin-binding domains, consisting of triplets of basic amino acids, e.g. KRK (lysine-arginine-lysine), are internalized along with the heparan sulfate. The result is an aberrant presentation of these internalized proteins to the immune system and production of inappropriate antibodies, e.g. autoantibodies.

Basic Triplets in Hasimoto’s Autoantigens

One of my hobbies is checking for the unusual occurrence of basic triplets in autoantigens and allergens. I have found dozens of examples. The most recent is associated with Hashimoto’s Thyroiditis. I knew that attack on the thyroid was common in celiacs, because the celiac autoantigen tTG (it has a basic triplet) is also present in the thyroid and the celiac autoantibodies to tTG also cause an attack on the thyroid. But the autoantigen for Hashimoto’s Thyroiditis is thyroid peroxidase (TPO).

I was momentarily perplexed, but then examined the TPO amino acid sequence and immediately found a couple of basic triplets (KKR and KRK).

MRALAVLSVTLVMACTEAFFPFISRGKELLWGKPEESRV
SSVLEESKRLVDTAMYATMQRNLKKRGILSPAQLLSFSK
LPEPTSGVIARAAEIMETSIQAMKRKVNLKTQQSQHPTD
ALSEDLLSIIANMSGCLPYMLPPK...


Hashimoto’ Thyroiditis Linked to Celiac

Then, I did a PubMed search for “celiac and Hashimoto’s”. As expected, there is a recent paper (see below) that shows that celiac commonly leads to Hashimoto’s Thyroiditis.

An obvious explanation is that the initial attack on the thyroid by anti-tTG autoantibodies of celiac leads to thyroid inflammation and presentation of TPO, with a second round of autoantibodies produced to TPO resulting in Hashimoto’s Thyroiditis. Celiac may be the initial autoimmune trigger for many other autoimmune diseases and allergies.

Autism has been associated with maternal autoimmunity and placental abnormalities. Guess where tTG is found in high abundance?

reference:
Bardella MT, Elli L, Matteis SD, Floriani I, Torri V, Piodi L. Autoimmune disorders in patients affected by celiac sprue and inflammatory bowel disease. Ann Med. 2009;41(2):139-43.

Chronic Disease, Cryptic Infections, Hibernation

Suppression of Inflammation and Surviving Cytokine Storms

There are numerous unanswered questions in modern medicine. What is aging, for example? Why do people become more inflamed as they age? What’s with all of the chronic, degenerative diseases? Why is lipid metabolism (LDL, HDL, triglycerides) linked to degenerative diseases, along with immune system function and inflammation? I am only going to start the answers here.

I might as well continue to be cryptic and give you the string of words/concepts I am trying to connect to answer the other questions:
Hydrogen sulfide (H2S), endorphins, hibernation, nuclear receptors (PPARs), antibiotics, chronic inflammatory diseases (fibromyalgia, arthritis, chronic fatigue, Lyme, Morgellon’s, Alzheimer’s, prostatitis, pancreatitis, cancers, etc.), autoimmunity, leaky gut/kidney/brain barrier, autism and H1N1.

First a word of advice: Beware of assuming that molecules are specific, i.e. with unique interactions, and that a small molecule will bind to one and only one protein target. [There are lots of bizarre exceptions to the assumption: Aldolase acts as a structural protein for Toxoplasma motility. Fluorescein is added to make protein fluorescent, but the fluorescein is also transported into cells on its own, i.e. fluorescein and rhodamine labeling can give different results. Heparin binds to most extracellular proteins and it is mostly a hydrophobic interaction -- heparin is not just for clotting anymore.]

Observations from the literature:

• Maternal autoimmunity is linked to autism.
• Autism is linked to leaky gut and chronic inflammation.
• Gut/kidney/brain barriers are based on integrity of extracellular matrix (heparan sulfate) that is compromised by inflammation.
• Chronic diseases require inflammation and circulating inflammatory cytokines (TNF, IL-1, IL-6) are elevated..
• NSAIDs induce leaky gut and release of bacteria toward liver.
• Phagocytosis of bacteria leads to transport of some bacteria, e.g. Chlamydia pneumoniae to other sites of inflammation, e.g. gut to joints.
• Opiods can induce hibernation in rodents.
• Sulfides can induce hibernation in rodents.
• H1N1 my cause lethal pneumonia by lung cytokine storm.
• Inflammatory cytokines and inflammation result from activation of NFkB.
• Hibernation involves PPARs (another nuclear receptor transcription factor).
• Omega-3 fatty acids reduce inflammation via COX-2 prostaglandins, but also by binding to PPARs.
• For most of the diseases under consideration, suppression of inflammation will eliminate symptoms.
• Antibiotics can impact all of these diseases in unpredictable ways. In some cases complete remission can be achieved and in other cases antibiotics can produce lethal cytokine storms.
• Bacterial cell wall components, e.g. lipopolysaccharide, lipid A, are intensely pyrogenic, i.e. inflammatory.

Cryptic Bacteria in our Tissues

The role of bacteria in numerous diseases, including cancers, has been proposed since the early isolation of bacteria from human tissues. Many of these bacteria are difficult to culture and have variable forms viewed by microscope. Because these bacteria are difficult for microbiologists to handle with conventional approaches, their existence and significance has always been questioned. Use of antibiotics to treat chronic, inflammatory conditions has seemed inconsistent with the unproven existence of a bacterial cause. Thus, there is surprise when the inappropriate use of antibiotics leads to a cure.

Cryptic Bacteria Suppress Local Inflammation and Promote Chronic Inflammation

I think that the fundamental problem is the assumption that human tissue is sterile, i.e. free from microorganisms, such as bacteria, unless there is overt infection. Part of the sterile assumption derives from the intense inflammatory response to bacteria. In order for bacteria to survive in tissue, the bacteria must suppress inflammation and the tissue must tolerate the slow leaching of inflammatory bacterial materials.

Chronic Disease Hypothesis

Based on the cryptic bacterial infection hypothesis, many, if not all chronic diseases are initiated by inflammatory events that release bacteria into the blood stream carried in phagocytic cells. The cells migrate and take up residence at a region of inflammation. The bacteria produce molecules that produce tissue hibernation and quell local inflammation in response to the bacteria. The bacteria are, however, a source of ongoing irritation to the tissue and a chronic inflammatory disease results.

Eradication of Cryptic Bacteria

Antibiotics would be a typical choice for killing infecting bacteria. In the case of cryptic, chronic infections, however, application of therapeutic antibiotics may be problematic. The established infections may have produced privileged locations isolated from the vascular system and protected by a bacterial community, e.g. a biofilm. Alternatively, the death of the bacteria and release of pyrogenic factors my produce life-threatening inflammation, that requires careful support.

Hibernation in Rodents Provides Treatment Clues

The compromise of tissue inflammation in response to cryptic bacteria is similar to the physiology of rodent hibernation. In both cases, systemic inflammation is suppressed. At the cellular level, this means that other signaling pathways silence the inflammatory NFkB expression pattern. One of the major nuclear receptors that is activated in hibernation is PPAR. PPAR is activated by opiods and H2S, which also induce hibernation in rodents. There are numerous analogs, inhibitors and H2S donors that could be used to disrupt hibernation (free local suppression of inflammation) or reduce symptoms by suppressing systemic inflammation.

Inflammation Compromises Tissue/Blood Barriers

Inflammation causes a disruption of the integrity of the endothelial extracellular matrix at sites of local inflammation. NFkB activation shuts down the expression of genes involved in heparan sulfate proteoglycan (HSPG) synthesis makes the tissue/blood barrier leaky. Locally this facilitates the recruitment of lymphocytes and neutrophils for defense, but systemically it leads to leaky gut/kidney/brain barriers that permit bacteria to cross.

Convergence of Therapies to Attack Cryptic Infections

The central approaches to attack cryptic infections are a combination of antibiotics and suppression of cytokine storms. These approaches are used in Marshall’s Protocol [http://bacteriality.com/ ], which also exploits a vitamin D receptor antagonist, Olmesartan, that also inhibits NFkB and inflammation.

A similar protocol has been developed by Dr. Michael Powell to inhibit hibernation and attack cryptic infections:
http://www.faqs.org/patents/app/20090163448

These approaches are similar to the lengthy use of antibiotics for the treatment of chronic Lyme disease.

It is very interesting to note that some of the most effective treatments for a long list of degenerative chronic diseases, autoimmune diseases and cancers, use essentially the same protocol that should attack cryptic bacteria and provide support for ensuing inflammation.

Flu Susceptibility and Anti-Inflammatory Fish Oil

Omega-3 Oils Reduce Inflammation, but May Increase H1N1 Infection Risk

The goal seems to be to reduce inflammation and reduce disease, but it isn’t that simple. Inflammation is not bad. Chronic inflammation is the problem for degenerative diseases. After all, inflammation is just what we call the mobilization of our immune system to fight infection. The problem is that inflammation needs to be properly controlled to be invoked only when needed, to be kept localized and to be brought to a proper conclusion.

A recent article extended studies of fish oil and various types of infections, to influenza. It used a mouse model that focused on the local, lung aspects of flu infection. Some mice were fed fish oil in a 4:1 ratio to corn oil (fish group) and the controls were just fed corn oil (corn group), as the lipid part of the diets.

Both fish oil and corn oil groups got sick when exposed to flu virus. The lungs of the fish treated group were less inflamed, but there was more virus and an increased death rate. The fish oil effectively reduced inflammation, but the inflammation in the corn oil, inflamed, mouse was useful in controlling the spread of the virus. Does this mean that chronic dietary inflammation is protective?

How close does this mouse system model human H1N1 infections? A lot can be learned from animal models, but not all aspects of the human disease are reflected in this model. There is no single H1N1 strain, for example. Flu viruses mutate thousands of times faster than even the most variable bacteria. Thus, people in various parts of Asia may be experiencing a different H1N1 than people in South America. Some H1N1 infections involve organs other than the lungs and cytokine storms can also be deadly.

If H1N1 is raging, is fish oil a good idea? It would be prudent to reduce other sources of inflammation, by eating an anti-inflammatory diet and getting plenty of exercise. The answer would seem to be to use only enough fish oil to reduce remaining symptoms of chronic inflammation, e.g. aching joints. The mouse model may have reduced the ability to produce an inflammatory response beyond elimination of chronic inflammation.

Most people who eat a high carb diet, with the typical inclusion of vegetable oils, starch and high fructose corn syrup would probably benefit from fish oil supplements, even in the context of influenza risk. It would take a lot of fish oil to compensate for the other inflammatory parts of their diet. Obesity is both a symptom of dietary inflammation and a source of chronic inflammation. Reluctance to engage in physical activity is another indicator of inflammation.

It would be helpful if epidemiologists studying the H1N1 swine flu pandemic would determine if chronic inflammation is a risk or benefit in surviving the disease. It would also be helpful to know what simple dietary or other interventions, e.g. nicotine, caffeine, would be helpful for various symptoms of the disease.

ref:
Schwerbrock NM, Karlsson EA, Shi Q, Sheridan PA, Beck MA. Fish Oil-Fed Mice Have Impaired Resistance to Influenza Infection. J Nutr. 2009 Jun 23. [Epub ahead of print]

An Autoantigen for Pancreatitis

Pancreatic Secretory Trypsin Inhibitor (PSTI) Has Internalization Basic Triplet

Pancreatitis is an inflammation of the pancreas resulting from lack of adequate inhibition of proteases. Autoantibodies against PSTI would explain some forms of pancreatitis.

I was researching the maintenance of baby gut flora by mother’s milk, when the reference discussed here was brought to my attention by my wife, who happens to be a lactation consultant. The paper showed that PSTI is present in colostrom, the first milk that a baby gets, before the true milk comes in. PSTI protects the new gut from digestion by its own pancreatic proteases, since PSTI is a protease inhibitor that sticks to the gut.

I naturally assumed that PSTI stuck to the gut by heparin-binding domains that would stick to the heparan sulfate proteoglycans on the gut surface. [Recall that it is via these HSPGs that viruses and bacteria infect the gut and the HSPGs in turn are protected during infections by the release of heparin from mast cells. The heparin in the guts of cattle and pigs are used to make commercial heparin to block blood clotting.] So I looked up the structure (above, with basic amino acids in blue and basic triplet on right) sequence of human PSTI at NCBI:

>gi|190694|gb|AAA36522.1| PSTI
MKVTGIFLLSALALLSLSGNTGADSLGREAKCYNELNGCTKIYD
PVCGTDGNTYPNECVLCFENRKRQTSILIQKSGPC

The basic triplet (RKR,arg-lys-arg), from my perspective, should result in presentation to the immune system during high levels of inflammation, and as a consequence result in autoantibodies against PSTI. The result would be the neutralization of the protease inhibitor and damaging production of active protease to attack the pancreas, i.e. pancreatitis.

It would be fairly easy to test this hypothesis by looking for the anti-PSTI antibodies in some people with pancreatitis. Other autoantibodies, e.g. against tissue transglutaminase, might also be checked, because the inflammation that produced one autoantibody may produce others and both PSTI and tTG are produced in the intestines. In fact, celiac may be the cause of some cases of autoimmune pancreatitis.

Note added in proof:

I just checked the literature on PubMed and found that PSTI is in fact an autoantigen in pancreatitis and produces antibodies against PSTI:
Raina A, Greer JB, Whitcomb DC. Serology in autoimmune pancreatitis. Minerva Gastroenterol Dietol. 2008 Dec;54(4):375-87.

and
I found that pancreatitis is often found associated with celiac (gluten intolerance):
Patel RS, Johlin FC Jr, Murray JA. Celiac disease and recurrent pancreatitis. Gastrointest Endosc. 1999 Dec;50(6):823-7.

ref:
Marchbank T, Weaver G, Nilsen-Hamilton M, Playford RJ. Pancreatic secretory trypsin inhibitor is a major motogenic and protective factor in human breast milk. Am J Physiol Gastrointest Liver Physiol. 2009 Apr;296(4):G697-703.

Diet, Carbs, Fat and Weight Loss

Glucose and Insulin Are Required to Gain or Retain Body Fat

The essential fact of weight gain or loss is that fat (triglycerides, TGs) stored in fat cells (adipocytes) is made from glycerol (from glucose) and fatty acids (from the blood or recycled from previously stored fat droplets.) Adipocytes must import glucose to make glycerol and TGs.

Glucose Is a Carbohydrate

Glucose is a sugar or carbohydrate. Once again the word tells the story, i.e. carbohydrates consist of carbons that each have a hydrogen, -H, and a hydroxyl -OH attached. Since each glucose has six carbons, then it can be roughly approximated as (H-C-OH)6. This is convenient notation, because this lets glycerol be considered as a three carbon sugar, i.e. (H-C-OH)3.

Glycolysis Can Convert Glucose into Two Glycerols

The central metabolism of all cells is called glycolysis, literally breaking glucose. The products of glycolysis are usually high energy electrons (carried by NADH), two pyruvates and ATP (chemical energy). Active cells with access to oxygen can use their mitochondria to accept the high energy electrons and pyruvate, and generate lots of ATP and CO2. Fat cells can bring in glucose by glucose transporters, make glycerol instead of some of the pyruvate and use the rest of the pyruvate by mitochondria to make fatty acids (instead of ATP.)

Fats Have Three Fatty Acids Attached to Glycerol: Triglycerides

Fats, triglycerides, are made in a series of biochemical reactions catalyzed by enzymes. The enzymes first make glycerol phosphate from glycerol and NADH, from glycolysis. Then the fatty acids are attached. The fatty acids can come from three sources: from glycolytic pyruvate, from fatty acids offloaded from the blood stream and from constantly recycled stored fat. Regardless of the source of fatty acid, new glycerol phosphate is needed for TG production in fat cells

Insulin Is Required for Glucose to Enter Adipocytes

Glucose is transported into adipocytes by specialized proteins embedded in their cytoplasmic membranes. A few glucose transporters are always present to supply enough materials and energy for basic maintenance of the adipocytes. Even with very high blood sugar (glucose), the glucose uptake of the adipocytes will not be increased without an increase in the number of glucose transporters in the cytoplasmic membrane. Insulin released into the blood by the pancreas in response to an increase in blood sugar, stimulates the adipocytes to introduce more glucose transporters into their membranes and glucose is actively transported into the adipocytes. The adipocytes then convert the glucose into glycerol, fatty acids and ultimately stored fat.

Without High Blood Sugar and Insulin, Adipocytes Lose Fat

Fatty acids in adipocytes are constantly be converted to fats and then released from storage as they are enzymatically removed from the fats to reappear as free fatty acids. As a consequence, the absence of extra glucose in the adipocytes will mean a shortage of glycerol and a net accumulation of free fatty acids from stored fats. Excess fatty acids will mean that fatty acids will be removed from rather than deposited in adipocytes.

Weight Gain Occurs with High Blood Sugar Regardless of Fats Eaten

Fat will be produced in adipocytes if there is high blood sugar and insulin production, because the fat already stored in the adipocytes will be recycled into fat, any fat in the diet will be converted into stored fat and glucose transported into adipocytes will be converted into fat. In addition, protein in the diet and potentially in muscle, will also be converted into stored fat.

Weight Loss Occurs with Low Carbohydrate Diets Regardless of Fats Eaten

Fats that are eaten without sufficient carbohydrates to cause a rise in blood insulin, are metabolized for energy in liver and muscle. Excess fat ends up being secreted into the gut by the gall bladder and lost as feces. Type I diabetics without insulin cannot get enough glucose into their cells to make fat and cannot gain weight without insulin. The amount of glucose, as simple carbohydrates (sugar or starch), needed to raise blood sugar to trigger a rise in insulin production is typically 30 to 50 grams per meal. Hunger, a response to a drop in blood sugar, prior to the next meal is a typical indication of insulin production and fat storage.

Lyme Spirochete Binds to Heparan in Blood Vessels

Borrelia burgdorferi Sticks to Host Cells via Heparin-binding Proteins

A research group at the University of Calgary has watched the binding of fluorescent Borrelia burgdorferi spirochetes, the Lyme disease pathogen, to the surface of blood vessels in mice. (ref. below) A small heparin molecule was shown to block this interaction between the spirochete surface protein BBK32 and the heparan sulfate proteoglycans of the endothelial cells of the skin blood vessels.

The heparin-binding domains in the spirochete protein, BBK32 are easy to spot in the amino acid sequence of this protein that I downloaded from the NCBI protein database:

>gi|19072701|gb|AAL84596.1| BBK32 [Borrelia burgdorferi]
MKKVKSKYLALGLLFGFISCDLFIRYEMKEESPGLFDKGNSILET
SEESIKKPMNKKGKKIARKKGKSKVSRKEPYIHSLKRDSANKSN
FLQKNVILEEESLKTELLKEQSETRKEKIQKQQDEYKGMTQGSL
NSLSGESGELKETIESNEIDITIDSDLRPKSSLQDIAGSNSISYTDE
IEEEDYARYYLDEDDEDDEYYEDDYEEIRLSNRYQSYLEGVKYNV
DSAINTINKIYDTYTLFSTKLTQMYSTRLDNLAKAKAKEEAAKFTK
EDLEKNFKTLLNYIQVSVKTAANFVYINDTHAKRKLENIEAEIKTL
IAKIKEQSNLYEAYKAIVTSILLMRDSLKEVQGIIDKNGVWY
Basic amino acids are K=lysine, R=arginine

The minimal heparin binding pairs, e.g. KKVKSK are shown in red and the strong heparin-binding triplets, e.g. KRK, are shown in blue. Notice that one triplet is augmented with several pairs to further enhance heparin binding.

I would also expect that BBK32 would be internalized into host cells and transported into the nucleus, where it may alter transcription, a la HIV-TAT. The existence of multiple, strong heparin-binding domains may also serve to bind the BBK32 (or the spirochetes) to multiple different heparan sulfate proteoglycans and interfere with the HSPG circulation system. This may have a toxic effect.

reference:
Norman MU, Moriarty TJ, Dresser AR, Millen B, Kubes P, Chaconas G. Molecular mechanisms involved in vascular interactions of the Lyme disease pathogen in a living host. PLoS Pathog. 2008 Oct 3;4(10):e1000169.

The Cause of Allegies and Autoimmune Diseases

Keyhole Limpet Hemocyanin (KLH): Internalized Antigen

Scanning the literature for a common protein that can be used as an experimental antigen, it becomes quickly obvious that a favorite is KLH. This would seem to be an odd choice -- why a keyhole limpet protein? But that is the wrong question.

Why is KLH such a good antigen, i.e. why is it readily presented to the host immune system? If you have been reading my posts, you might be thinking about triplets of basic amino acids and that is the answer.

As soon as I remembered the prominent use of KLH as an antigen, I checked the NCBI protein database and immediately found an unusual KKK (triple lysine) near the amino terminus of hemocyanin II ( it comes in two pieces). This triplet explains why KLH is such a good experimental antigen, because it is internalized into antigen presenting cells by its strong heparin-binding domain. Other components, adjuvants, are typically added to the KLH for injection to make sure that a strong local inflammation occurs.

Autoantigens Have Strong Heparin-Binding Triplet

I also learned that Hashimoto’s thyroiditis is an autoimmune disease mediated by the autoantigen thyroid peroxidase. A quick search reveals that thyroid peroxidase is an autoantigen, because it also has a triplet of basic amino acids that can enhance presentation under inflammatory conditions. Grave’s disease of hyperthyroidism is an autoimmune disease in which the thyroid receptor (with a basic triplet) is an autoantigen. The same kind of triplet of basic amino acids was found when I searched today for fire ant antigens and mosquito antigens.

I have also looked for the triplets in protein databases. The triplets are rare in cytoplasmic and extracellular proteins. The proteins that have triplets are usually identified as autoantigens in some disease. The triplets are common in nuclear proteins, since heparin-binding and nucleic acid-binding share the same basic amino acid domains. The nuclear internalization signal also results in rapid cellular internalization, e.g. HIV-TAT, heparanase, IGF-binding proteins. Nuclear proteins are common autoantigens in lupus.

Inflammation Plus Heparin-Binding Internalization: Allergy, Autoimmunity

Chronic inflammation can produce antibodies against proteins (foreign or self) with strong heparin-binding domains (triplets or sometimes neighboring pairs of basic amino acids, lysine or arginine). The generalization explains why particular proteins in pollens, foods, insects, pets, mites, asthma, MS, lupus, celiac, etc. produce antibody responses.

Diet, Nutrition and Health

These are my generalizations (some would say prejudices) from 40 years of experience in plant biochemistry and molecular biology:

Plant Secondary Compounds Are Defensive and Toxic

The development of plant secondary compounds (all of the compounds that are not part of metabolism or structures) is in response to pathogens, herbivores and pollinator/disseminator attractants -- development of these compounds has nothing to do with humans. Examples: Nicotine and caffeine are very toxic to herbivores and are present in plants for protection. Humans learn to play with toxic plant chemicals, just as they have learned to play with fire and explosives.

Plants Are Not There For Us

People have learned to exploit local plants for protection against local human pathogens, but there is no selective advantage to plants (except for domesticated plants) for useful plants to grow near humans. This logic would suggest that rats and mosquitoes, that flourish near human habitations, are there because of their human utility. Human live near places were useful plants grow.

Grains Are Unhealthy

One of the biggest problems with food processing is separating the inflammatory parts = starch and omega-6 oils, from the nutritive parts, the so-called anti-oxidants, vitamins, proteins, etc. Grains, even so-called whole grains, are simply too enriched for starch and inflammatory oils to be healthy. They are not safe to eat in large amounts. Leafy plant parts are healthy, but even those parts are not good in large amounts from a single plant species. Humans are browsers, because the plant secondary compounds are uniformly toxic, but can be tolerated better in a mixture of different toxicities.

Starch Is Inflammatory

Starchy foods should be treated like a fish. The starch should be pared away and discarded, like the fish gut and bones. (The guts and bones could actually be processed to make them nutritious. Not so with the starch. The starch should be fermented.) The potato skin should be eaten and the rest discarded, just as an aphid secretes as honey dew the extra sugar it sucks in from a plant leaf.

Cereals Are Inflammatory

Breakfast cereals are a dietary abomination. They contribute immensely to obesity, inflammation and chronic disease. Oatmeal for cardiovascular health is a total fraud. The fiber might be useful, but the high starch causes cardiovascular disease. Grains/cereal are the foundation of the chronic disease pyramid.

Fructose is Toxic

Fruit juices are another fraud. The juice (fructose) should be removed and discarded. The fructose is very unhealthy. Mice are given type II diabetes for research purposes by feeding them fructose (especially high fructose corn syrup.) Fructose is avoided in the beef industry, because it causes rapid cross-linking of collagen and leads to tough meat. The same thing happens in humans who eat fructose, it causes aging of the skin and other tissues. High fructose corn syrup is a commercial addiction -- it is hugely profitable as a sweetener -- and that is why it is still used, even though it is grossly unhealthy. It will eventually be removed from the market after the industry is protected from subsequent law suits. It is equivalent to the tobacco industry -- too lucrative to eliminate.

Phytic Acid

The active ingredient in fiber that provides its benefits is phytic acid, the same chemical that people are trying to eliminate. Phytic acid acts as a chelator. I don't think it is actually a problem. The problem comes from extracting cations from the phytic acid before it is eaten. Phytic acid should go in saturated, so that it doesn't contribute to deficiencies. The actual problem is that the diet is already low in minerals, because of eating processed foods that are mineral deficient.

Enzymatic Detoxification: P450, Glycosylation and Secretion

Humans are adapted to plant secondary metabolites by the abiltiy to enzymatically detoxify [using p450 and glycosylating (adding glucuronic acid)] and secrete the toxic compounds. These chemical modifications that occur in the intestines and liver are usually effect. They also work on drugs and that is how we eventually clear these compounds from our systems. Grapefruit and black pepper inactivate these enzymes and alter the way we metabolize plant toxins and drugs. The detox enzymes can also convert innocuous compounds into toxins and carcinogens. That conversion is the basis for using liver enzymes in the Ames Test for carcinogens. The activity of the enzymes is dependent on recent diet, so it would make sense to gradually change the amount and type of vegetables that are eaten in a meal to permit the detox system to adjust.

Glucose and Insulin Cause Fat Accumulation

Fat accumulation is dependent on dietary carbohydrates and insulin. Fat and serum lipids accumulates with a high carbohydrate diet and decrease on a low carbohydrate diet. This is more important than the number of calories consumed.

Inflammation Not Serum Lipids Cause CVD: Statin Are Unnecessary

Inflammation is the source of chronic degenerative diseases. Serum lipids are only secondary factors. Statins lower serum lipids, but do not impact cardiovascular health unless they also lower inflammation. Lowering inflammation lowers serum lipids and decreases cardiovascular disease. Statins appear to be a very expensive way of treating cardiovascular disease dependent on their side effect on inflammation. Modest dietary and lifestyle changes are much more effective, cheap and safe than statins.

Insulin-like Growth Factor, Diabetes Autoantigen

IGF Binding to Heparin is Basis for Receptor Interaction, Internalization and Immunization

Examination of the protein sequence of insulin-like growth factors reveals strong heparin-binding domains (triplet of basic amino acids) that are also associated with internalization. Similar heparin internalization domains are also found on allergens and autoantigens. It was a small leap to expect that IGFs would also become autoantigens under inflammatory conditions that minimize heparan sulfate proteoglycan production.

Triplets of Basic Amino Acids Internalize Proteins

In several articles on this blog, I have discussed proteins that are internalized by their heparin binding domains. Heparin binding domains consistent only of a pair of basic amino acids, e.g. RK, flanked by one or more basic amino acids within a hydrophobic sequence of protein, are not sufficient to mediate internalization on heparan sulfate proteoglycans. A triplet of basic amino acids is usually required. Simple inspection of amino acid sequences is sufficient to identify these regions.

Internalization Triplet Identified in Insulin-like Growth Factor Binding Proteins

I noticed in a paper that insulin-like growth factors bind to epidermal growth factor receptors. I have previously written an article showing that EGF1 binds to its receptor via heparin, i.e. both the EGF and the receptor have heparin-binding domains. So I suspected that IGFs also had heparin binding domains. Inspection of the sequences readily identified simple heparin binding domains with pairs, but not triplets of basic amino acids. A search of the literature confirmed that heparin mediated IGF binding to receptors. A further search indicated that the heparin binding domains from proteins that bind and control the activity of IGFs could mediate internalization of proteins into cells and also into nuclei.

Internalization Triplets Are Associated with Allergens and Autoantigens

I have previously noted that all allergens and autoantigens have internalization triplets of basic amino acids. The presence of these triplets in IGF binding proteins suggested that IGF binding proteins might also be autoantigens. A quick check of the literature showed that antibodies against IGFs themselves frequently occur in type I diabetes. This suggests that the IGF-binding protein complexes are internalized and IGFs are immunologically presented during inflammation to produce anti-IGF antibodies. It is interesting that the other autoantigens for type I diabetes, e.g. transglutaminase, also have the expected internalization triplets.

references:
Maruyama T, Murayama H, Nagata A, Shimada A, Kasuga A, Saruta T.
Anti-insulin-like growth factor-1 autoantibodies in type 1 diabetes. Ann N Y Acad Sci. 2002 Apr;958:267-70.

Miao D, Yu L, Eisenbarth GS. Role of autoantibodies in type 1 diabetes. Front Biosci. 2007 Jan 1;12:1889-98.

Goda N, Tenno T, Inomata K, Shirakawa M, Tanaka T, Hiroaki H. Intracellular protein delivery activity of peptides derived from insulin-like growth factor binding proteins 3 and 5. Exp Cell Res. 2008 Aug 1;314(13):2352-61. Epub 2008 May 29.

Suffering from Inflammation?

How do you know if your symptoms result from inflammation?

My interest is the molecular basis of inflammation, how inflammation is triggered and how inflammation contributes to numerous diseases. I try to expose the inflammatory underpinnings of various diseases by initially linking a disease to inflammation and then unraveling the molecular events that lead to and make up the disease.

How Do I Link a Disease to Inflammation?

My first task is to check the biomedical literature to see if there are research articles that support anti-inflammatory interventions that prevent or limit the disease. I just do a PubMed search the disease name plus anti-inflammatory treatments, e.g. omega-3 fish oils, vitamin D, NSAIDs, etc. It is also possible to see if a disease, such as diabetes, that produces chronic inflammation is a risk factor for the new disease being examined. It is shocking to me that omega-3 fish oils (EPA/DHA) or even flax seed oil, have been found to be effective treatments for numerous diseases that range from allergies, arthritis, inflammatory bowel diseases, depression and even septic shock and multiple organ failure. Aspirin has been used to treat infertility and post partum depression, and at high levels to treat cancer.

Dietary Suppression as Prima Fascia Evidence of Inflammatory Cause

If I find that omega-3 oils have been used successfully to treat a disease, then I attempt to link inflammation to the molecular events that initiate the disease. The biomedical literature is of minimal help here. [Biomedical research is usually limited to assessing the impact of drugs on the symptoms of diseases, so the biomedical literature typically does not provide information on the cause of diseases or ways to cure diseases. Causes and cures do not receive research funding.] I have to learn the basic workings of the organs involved and the alterations of function associated with the disease. I have also found by long experience, that major molecular components are systematically missing from typical explanations of function.

Heparan sulfate/heparin Is Missing in Action

Heparan sulfate proteoglycans (HSPGs) dominate the extracellular environment and yet they are systematically excluded from biomedical research. On this blog, I have provided dozens of examples of the essential role played by HSPGs and disruption of these roles by heparin. The majority of cytokines, growth factors, clotting events, complement cascades and even lipid transport (LDL) act via HSPGs. Leaking of proteins into the urine, across the intestines or the blood brain barrier is controlled by HSPGs, is reduced by inflammation and can be partially repaired by heparin. Autoimmune and allergic diseases are initiated by disruptions in HSPG metabolism. Viral and bacterial pathogens bind to human cells via HSPGs. Cancer cells reduce their HSPGs and start to secrete heparanase in order to metastasize. Mast cells secrete heparin! HSPGs and heparin are major players in tissue function and yet the major cell biology text book does not even discuss them. HSPGs are not mentioned in medical school training even though heparin is the most commonly administered drug.

One of the insights that I bring to my conceptualization of diseases is the role of heparan/heparin in cellular physiology. It explains a lot.

Check for Inflammatory Symptoms by Trying the Anti-Inflammatory Diet

If your symptoms are due to inflammation, there is an easy way to find out. Since diet is the biggest source of inflammation and most of the cells of the immune system congregate in your intestines, it makes sense to check to see your health problems are rooted in inflammation by making simple changes in your diet. Since this is just a test, don’t worry about whether or not this is diet for the rest of your life. Just stick to it for a week and see if it changes your life.

The Basic Anti-Inflammatory Diet and Lifestyle Guidelines are here.

(Vitamin D and omega-3 fish oil amounts are minimal levels. More severe examples of inflammation will require higher levels. Vitamin D up to 10,000 IU per day has been found safe. Some individuals require up to 12 fish oil capsule per day to experience relief from symptoms. Increases should be gradual over weeks of time.)

Try it for a week and let me know if your symptoms disappear. The prevalence of diet-based inflammation, makes me confident that you will be glad that you tried these simple, healthy changes. For immediate relief of pain, see my articles on capsaicin, castor oil and menthol/Vicks.

This is not medical advice and is used only in appropriate support of primary medical care.

Prostate, Prostatitis, Cancer, Causes and Cures

Prostate problems are pervasive, and progressive in the U.S. -- approximately a quarter of a million prostate cancers are diagnosed each year. Chronic inflammation due to age or diet enhances prostatitis and cancer.

Prostate Surrounds Male Urethra

The prostate is a sexual organ. It responds to sexual stimuli, both physical and hormonal, and as a consequence is vulnerable to the same hazards: infection, inflammation, cycles of elaboration and cancer. The prostate straddles the male urethra and inflammatory swelling of the prostrate can strangle the flow of urine from the bladder. The prostate contributes part of the seminal fluid and backward flow of bacteria from the urethra into the prostate can be a source of infection.

Prostate Cells Require Testosterone for Growth

The prostate tissue responds to testosterone. The ebb and flow of testosterone, associated with sexual activity, results in increased production of prostate fluid containing proteins and other components that enhance performance of sperm in the female reproductive tract. The bottom line here is that prostate tissue and derived prostate cancer, responds to testosterone. For this reason, prostate cancer treatment has been based on blocking testosterone stimulation by removal of sources of testosterone and blocking testosterone receptors.

Testosterone Starvation Is Prostate Cancer Treatment

Testosterone, estrogen and vitamin D receptors are all cytoplasmic and the hormone/receptor complexes act as transcription factors to alter nuclear gene expression. It would be expected that prostate cancer, as well as breast, cervical, ovarian, testicular, etc. will respond in a complex manner to steroid hormones, including androgens, estrogens and vitamin D.

Cancer Requires NF-kB Activation

The common biochemistry supporting all cancers is inflammation that is required for proliferation in tissue. Central to inflammation is the transcription factor NF-kB. Inhibitors that block the activation of NF-kB also stop cancer. Most of these blockers are effective against cancer cells grown in culture flasks, because the inhibitors are taken directly into the cells and make contact with NF-kB (or stabilize the NF-kB inhibitor IkB.) Curcumin from turmeric, is one of the most potent inhibitors of NF-kB activation. It is very effective in cultures, but is only modestly effective against inflammation when eaten.

It is difficult to treat secretory tissues, such as prostate, breast, uterus, etc., because much of the tissue is separated from the blood circulation. Thus, infections in these tissues are harder to treat with antibiotics.

Prostatitis Results from Urinary Infections

The prostate is prone to chronic infections. Thus, urinary tract infections (UTIs) can lead to prostate infections (prostatitis). These chronic infections can contribute to chronic systemic inflammation. One symptom of chronic inflammation is depression (treated with SSRIs, antidepressants) another symptom is premature ejaculation (also treated with SSRIs.) Prostatitis-based inflammation can also set the stage for cancer.

Transglutaminase Autoantigen

Autoimmune diseases are also associated with chronic inflammation. One of the common autoantigens in autoimmune disease is tissue transglutaminase (tTG). Celiac is a classic example of the involvement of tTG, since tTG acts on the glutamine amino acids of gluten and converts them into glutamic acid residues. In the process tTG becomes covalently attached to the gluten. The strong heparin binding domains of tTG also facilitate its uptake and processing as an immunogen under inflammatory conditions and result in antibody production to both tTG and gluten. Anti-tTG antibodies and inflammation can also lead to attack on other tissues, such as the thyroid and skin, leading to a variety of celiac-associated autoimmune conditions.

The prostate produces its own transglutaminase. I think it is likely that prostatitis in some cases progresses to an autoimmune disease and prostate transglutaminase is a likely candidate for one of the autoantigens involved. This also predicts an association with celiac and a requirement for chronic systemic infection with a likely elevation of C-reactive protein and inflammatory cytokines (IL-1, IL-6, TNF). Deficiency of vitamin D and omega-3 fatty acids are probably major contributors. Increased risk attributed to consumption of a high fat diet and meat, is probably actually due to inflammation from a high carbohydrate diet and high omega-6 vegetable oils (or perhaps corn-fed meat.)

Protect Prostate with Anti-Inflammatory Diet

Prostate problems are frequently assumed to be a natural result of advancing age, but they are actually symptoms of mismanaged chronic inflammation. Men should not just stand and wait for prostate problems.

Avoidance and treatment of prostate problems seems to be an obvious application for an anti-inflammatory diet and lifestyle.

Lactoferrin: Natural Anti-Microbial Milk Protein

Nosocomial infections happen when the immune system is compromised through a medical procedure and common bacteria, such as Staphlococcus aureus, get introduced. From my perspective, that means that the walking bacterial reservoirs, i.e. gut flora of healthcare practitioners, provide an inoculum directly to the damaged tissue, or indirectly by contaminating the patients gut flora and then spreading the pathogens from the patient’s digestive tract to the damage site. This is what happens with ventilator-associated pneumonia and sepsis in critically ill patients.

The trick is to keep the patient’s gut flora healthy -- healthy as a breastfed baby’s. The typical medical approach is to kill off lurking pathogens with a dose of antibiotics. The problem with this approach is that it is both indiscriminant and selective, i.e. it kills both pathogens and beneficial bacteria, but it also provides a selective advantage for the antibiotic resistant hospital strains of opportunistic pathogens.

Humor break: Why do babies spit up half-digested breastmilk and then smile? Answer: Pepsin produces antimicrobial peptides from milk proteins. The baby smugly acknowledges that she knows that she has just protected her upper respiratory and digestive tracts against bacterial pathogens.

Pepsin hydrolyzes proteins next to aromatic amino acids and away from the basic amino acids, arginine and lysine. That means that heparin-binding domains, which consist of groups of basic amino acids in a hydrophobic environment, are clipped out intact from proteins by pepsin. Thus, babies sucking down milk make their own isolated peptides with heparin-binding domains.

Lactoferricin with basic amino acids in blue.

Many organisms, from fruit flies to frogs to humans, produce anti-microbial peptides. They also produce proteins with nucleic acid-binding domains and nuclear localization signals and heparin-binding domains and IP3-binding domains. If all of those binding domains are clipped out by pepsin and the peptides are compared to the anti-microbial defensive peptides, amazingly they are all the same. All have groups of basic amino acids among hydrophobic neighbors, and all are toxic to bacteria.

Lactoferrin is a major component of milk whey. It binds iron and heparin. It can be digested by pepsin into an an anti-microbial peptide, lactoferricin. Baby’s smile and spit-up on your shoes when you say lactoferrin.

Transgenic mice that produce porcine lactoferrin in their milk, transfer extra lactoferrin their little suckling mouse pups and that extra lactoferrin gives extra protection against bacterial and yeast pathogens. That is the experimental justification to suggest that treating patients at risk of nosocomial infections (I guess that would mean every patient in contact with a nurse or doctor) with oral lactoferrin should selectively eliminate the pathogens. Lactoferrin is prebiotic and supports the growth of probiotic gut flora.

ref:
Yen CC, Lin CY, Chong KY, Tsai TC, Shen CJ, Lin MF, Su CY, Chen HL, Chen CM. Lactoferrin as a natural regimen for selective decontamination of the digestive tract: recombinant porcine lactoferrin expressed in the milk of transgenic mice protects neonates from pathogenic challenge in the gastrointestinal tract .J Infect Dis. 2009 Feb 15;199(4):590-8.

Cure Acne, Back Pain, Tendonitis, Depression

Remedies Include Vicks Vaporub, Castor Oil and Anti-Inflammatory Diet

Simple anti-inflammatory treatments cure some of the most common health complaints. The big question is why people tolerate the problems rather than applying the readily available remedies.

It seems to me that one reason people don’t simply live anti-inflammatory lives and avoid health problems is that attacking the underlying inflammation by approaches that would have prevented the health problem in the first place, is inadequate for fixing the problem after it becomes established.

Health problems based on inflammation may have many different sources of inflammation. Many dietary deficiencies, for example, contribute to inflammation, so what we eat or don’t eat is a major health risk. Other common contributors to inflammation are dental cavities/infections and inadequate exercise.

Common Symptoms of Chronic Inflammation: Acne, Back Pain, Tendonitis, Depression

I have started to ask casual acquaintances if they have any aches or pains, because eliminating dietary sources of inflammation will be evident in relief of these problems. Common complaints are sore joints and tendons related to repeated use. An example is my barber who complained of pain in all of the tendons used to raise his arms to cut hair. Another friend just had her second child and suffered from shooting pains in the tendons of the arm she used to cradle the youngest when she used the other arm on some task.

Simple Anti-Inflammatory Diet Adjustments Get Quick Results

In many cases, a simple change in diet can lower chronic inflammation enough to provide relief from symptoms. Vitamin D deficiency is probably an underlying source of inflammation of most people in the US. So a simple supplement of 2000-5000 IU per day will have noticeable, anti-inflammatory impact on most people.

I recommended vitamin D and fish oil supplements to a friend suffering from chronic back pain. The back pain persisted, but his acne resolved. He stopped taking the supplements, but after physical therapy relieved the back pain, he returned to the supplements as an acne treatment. Now he has long term relief from all of his pains.

Elimination of Dietary Inflammation May Not Resolve Inflammation Based Health Problems

Health problems that start from aggrevated inflammation, may not be eliminated with resolution of the initial cause. My friend’s back ache, for example, didn’t respond to just elimination of deficiencies in his diet. It seemed that the back problems were self-sustaining. After he did exercises to remove the physical aggravation of his back, lack of dietary inflammation prevented the return of the back ache.

Complex Inflammatory Webs

A student of mine suffers from celiac. This is a complex autoimmune disorder of the intestines that is triggered by wheat gluten and is self-perpetuating. Of interest in this context is that celiacs frequently also have back problems. This indicates that the inflammation of the disease is systemic and impacts other tissues. Clearly, reducing dietary inflammation can go only so far in relieving this complex web of reinforcing sources of inflammation.

Simple Anti-inflammatory Interventions

My friend with tendonitis from holding her child got immediate relief from topical application of castor oil and dietary supplements eliminated the problem. Castor oil and capsaicin react with skin heat-sensing neurons to initiate an anti-inflammatory response in adjacent tissue. In a similar way, menthol acts on cold-sensing neurons and relieves pain by reducing inflammation. Vicks Vaporub is a common commercial source of menthol (other sources are blue Listerine mouthwash and Noxema lotion), which give faster relief than longer lasting castor oil for many connective tissue/joint aches. Exercise is another source of relief for inflammation-based aches and pains.

Health: Combinations of Interventions and an Anti-Inflammatory Diet

Anti-inflammatory drugs, such as aspirin, disrupt the molecular signals that produce inflammation and result in relief from inflammation and pain. The common ailments discussed here respond to anti-inflammatory drugs. Depression was mentioned to point out the psychological dimensions of inflammation. Reproduction/birth is controlled at many points by the processes that we call inflammation and the most inflammatory stage is birth. It is not surprising that disruption of the normally rapid resolution of inflammation following birth leads to postpartum depression. It is surprising that postpartum depression can be relieved by anti-inflammatory drugs.

Fighting Inflammation-Based Diseases

Complex diseases such as allergies, asthma, arthritis, vascular/heart diseases, inflammatory bowel diseases, cancers, etc. are all based on chronic inflammation, but they are also self-reinforcing inflammatory diseases. Cures will require elimination of sources of chronic inflammation, e.g. diet, plus disruption of the disease-supporting inflammation, e.g. food/gut flora-stimulation of inflammation of the bowel.

Fundamental to the cure of all diseases is a supporting anti-inflammatory diet and lifestyle.

Extreme Flu Remedies

Experimental Therapies for ARDS, Cytokine Storms

Do not do this at home. There are doctors and hospitals. Use them.

....But, if a doctor emailed me pleading for any ideas that I had to save a bunch of patients suffering from acute respiratory distress syndrome (ARDS) from Tamiflu-resistant H1N1, my first response would be to suggest therapies designed for ARDS from other origins, e.g. burns, septicemia, etc.

Cytokine Storms Are Out of Control
When too much tissue is injured, the local, molecular communication that normally occurs just between cells, spills into the blood stream and becomes potentially lethal. That is what happens in anaphylactic shock. It is also what happens in cytokine storms, where inflammatory cytokines that are normally short-lived and processed locally to progress into recovery, erupt into the blood stream and impact distant organs.

Major disruption of body function by aggressive blood infections or burns over most of the body, will be lethal without heroic medical interventions. These are injuries beyond the evolved adaptations of mammals.  Until recently there were no survivors.

Influenza has been around for a long time. Humans, other mammals and birds get the flu and get over it. Many body cells become infected, antibodies specific to the virus are produced within about a week, the infected cells are killed, the virus is digested and life goes on.

People die from the flu, because an opportunistic pathogen causes a lethal secondary infection, or the body over-reacts and damages itself in attempts to attack its own infected cells. This is a cytokine storm.

Silence the Storms
Cytokine storms can be weathered by blocking the signaling system. Cytokines are just small proteins that are complementary in shape to corresponding protein receptors that penetrate through the surface membranes of cells throughout the body. Binding of cytokine to receptor changes the shape of the receptor and transmits a signal into the cytoplasm of the receptive cell. This turns on aggressive behavior of immune cells and triggers more inflammatory signaling in other cells. This causes fever, malaise, etc.

...But, I was the one the doctor is pleading with to save the people. And I know that there is more to cytokine signaling than just cytokines and receptors. There are also heparan sulfate proteoglycans (HSPGs). Cytokines are not supposed to be broadcast throughout the body. Cytokines function in the space between cells, the extracellular matrix. Polysaccharides attached to membrane proteins, HSPGs, are secreted at one end of the cells, sweep across the surface and are taken back up at the other end. Cytokines have heparan-binding domains and so they stick to the heparan and are swept along. Cytokines can move from one cell to another as the sweeping HSPGs of adjacent cells come in contact.

HSPGs Mediate Cytokine Signaling
The critical point here is that cytokines bind to their receptors with the heparan between -- the cytokine and receptor are like two halves of a bun and the hot dog is the heparan. In fact the heparan bridges two cytokine/receptor complexes to make an active, signaling pentamer.

Heparin Can Block Cytokine Signaling
Heparin is a fragment of heparan sulfate produced by enzymatic degradation of HSPG. Commercial heparin, used to block blood clotting, is obtained from the mast cells of lungs and intestines of hogs and cattle. The mast cells release heparin and histamine in response to parasites or pollen. Since heparin is a short version of heparan sulfate, it can block the formation of active cytokine/receptor complexes.

Heparin is used in a mist to treat the lungs of burn patients. It is also injected into some infertility patients to suppress inflammation that is inhibiting implantation and gestation. It is also effective in treatment of autoimmune inflammation in Crohn’s disease. I think it should be tested as a therapy for H1N1 cytokine storms. It may be useful in nebulizing mists and oral treatment of intestines.

Berberine Binds to HSPG
Berberine is a phytochemical from Barberry traditionally used in the treatment of intestinal infections and arthritis. It also binds to heparan sulfate to form fluorescent complexes visible in microscopy. Berberine-treated mast cells glow brightly. Heparan sulfate can also be detected in Alzheimer’s plaque, atherosclerotic plaque and prion complexes. Because berberine binds to heparan sulfate, it should also disrupt cytokine signaling. It has been used successfully in treatment of septicemic ARDS.

Curcumin Blocks NFkB
One of the most potent chemicals that blocks inflammatory signaling via the inflammatory transcription factor, NFkB, is curcumin. Curcumin is a major component of the spice turmeric. Oral curcumin can be enhanced by co-administration of black pepper, because the piperine in pepper inhibits intestinal inactivation.

Anti-Inflammatory Diet
Of course, I would also recommend vigorous implementation of an anti-inflammatory diet and lifestyle to support any medical treatment.

Inflammatory Protection from Swine Flu

Inflammation causes allergies, autoimmune and degenerative diseases, and is the foundation for cancer, but it does provide protection against infection.

One of the reasons that older people are less prone to infectious diseases, is that their immune systems have already been exposed to earlier versions of pathogens. Another reason for the relative good health of the parents of baby boomers, is that chronic inflammation increases with age and protection against pathogens is the adaptive advantage of inflammation.

As of now, the new swine flu pre-epidemic is very scary in Mexico City, but doesn’t pack much of a punch north of the border. Maybe it is too early to be optimistic, but it is tantalizing to speculate that the diet-based chronic inflammation that stuffs the coffins in the US, may be good for something besides stuffing the coffers of agribusiness.

One of the symptoms of high chronic inflammation is many years without a day of sick leave. It is hard for a pathogen to get a foothold when the immune system is already provoked by inflammation. Even food and harmless pollen is attacked with vigor and lots of sneezing.

Swine flu is attacking the young and healthy in Mexico. King Corn has already wiped out those targets in the US. Obesity fed by starch, vegetable oils and corn-fed meat, produces chronic inflammation and a potential resistance to swine flu. The US diet provides the inflammatory benefits of old age for the young.

This explains why I live in Idaho. Here it is easy to maintain an island of health in a sea of inflammation. Few visitors with infectious diseases can travel from healthy countries fast enough to transmit the diseases before they show symptoms. Everyone else who reads my advice, lowers their inflammation and lives longer, healthier lives free of chronic diseases, had better start washing their hands and wearing face masks.