The Pancreas has Two Hormones that control Blood Sugar

 Most of the studies of the pancreas are related to the hormone insulin. This hormone is produced by a group of cells called beta and its job is to lower  high blood sugar levels.  Blood sugar increases and the betas are signaled and insulin released. It takes the glucose and transfers it out of the blood and into tissues, mainly muscle and liver.

The other , neglected hormone, glucagon is secreted by the alpha cells of the pancreas and its job is to release sugar from its storage areas if the blood level is too low.  Recently more information about how glucagon works in diabetes has been found.  The action of glucagon is usually very short and as soon as the blood glucose level is normal it shuts off.  This shut off signal is from the hypothalmus in the brain.  However, in diabetes this does not work. The cells to shut off the glucagon action are resistant and no signal to stop is given. The alpha cells keep secreting and the stores of liver are constantly being transported to the blood.   By stimulating a protein in the hypothalmus , PKA, the resistance is stopped and the shut off signal returns.

Another method of controlling glucagon is by receptors on the alpha cells that respond to insulin. When these are activated by insulin the glucagon secretion stopped. In diabetics this does not happen.  In experiments blocking the insulin receptors on the alpha cells elevated glucagon levels and created abnormal blood glucose levels.It maybe that the constant amounts of insulin injections has caused resistance. the result is elevated glucagon level and blood glucose levels.

If the action of glucagon at the liver could be blocked then blood sugar would be much easier to control.  However, the glucagon has other functions at the liver and these are vital.  There is a specific pathway that glucagon activates to release the glucose stores in the liver.  This has a protein, CaMKII, and when this is blocked the release of extra glucose stops.  A drug to do this may be a very important treatment for diabetes.

How important might this be?  A experiment that used altered mice with no glucagon receptors, did not develop diabetes  even when they had no functioning beta cells ( no insulin).  For blood glucose control if you don't have Glucagon you don't need Insulin

Writers and Reader of our Cells Proteins.

The subject of epigenes is a ongoing discovery of how our complex cell chemistry works.  Originally it was thought that the DNA, nucleic acids, were the only blueprint for our cells actions. These could be changned through mutations.  These mutations were thought to be somewhat rare since an actual removal of a nucleic acid was at the heat of this mutation.  Radiation, pesticides, abnormalities in cell division with changes in the chromosomes were all included in the mechanism.  Pairing of two "recessive" genes also contributed.

We now know cancer is caused by mutations and cancer is too common and many causes of mutations other than direct damager to the genes must be part of this.  The idea of certain molecules that can add methyl or acetyl groups to certain areas of the genes or their protein products is becoming the answer to this.

In epigenetics there are writers, readers and erasers.  The  writers make modifications to the proteins after they are formed without changing the underlying gene sequence that encoded them.  These written changes can be due to many environmental effects on the cells chemistry. (see blog on epigenes, follow the cancer pathways).  This writing  change (adding acetyl groups or removing methyl) signals other molecules , the readers, to engage with these marked proteins in different ways.  This produced new functions of these in the cell.  Then the erasers can remove these written markers when no longer wanted.  These changes are  a very important part of cancer changes in the cell.

An example of the above system is shown by a protein found in all cells cytoplasm NF- Kappa B. (NFKB). It normally sits quietly among the other thousands of proteins in the cells cytoplasm. However, when a disruption occurs, a virus or bacteria, a sudden release of damage signals (example cytochrome C from the mitochondria) it  travels to the cell nucleus and passes into the gene field.  Here it releases many various genes to repair and protect the cell from the damages.  This is for a limited time and then the action is stopped.

In cancer cells there is a form of NFKB that remains active in the nucleus at all times. It is constantly promoting things to protect the abnormal cancer cell from self destruction (apoptosis).  Why does this protein suddenly change its behavior? There is a group of proteins that are part of the family of proteins that recognize markers on other molecules and then it binds with these to make the marked protein perform new tasks. This group are part of the "readers". One of these , BRD4, is the one that binds to   the NFKB.  It has been tagged (by a writer) with a acetyl group that is the signal to the reader to go into action and change the molecules original function.  This marker and binding of the BRD4 prevents the normal stopping of the NFKB function. Like the cancer cell itself,  it becomes "immortal".

By blocking the ability of BRD4 to act on the NFKB the function of the molecule goes back to its original task of protecting the cell for only a short time and then it is removed by the cells "clean up" molecules.  The cancer is now exposed to many immune actions to self destruct.

The action of the immune system is key to the stopping of early cancer changes.  Once the immune system alerted that the cell needs repairs it secretes certain cytokines that began the healing process.  Interferon is one of these. However, if the immune system is not working properly it can promote cancer growth.  If Interferon or tumor necrosis factor are not among the cytokines released the cell can go onto a mature cancer.  These changes to stop the tumor must occur early and have the right cytokines.  The early warning of the NFKB is important to start this process.

The fact that we are controlled by many different molecules (mostly proteins) and these can be changed easily by addition or subtracting other molecules has been the driving force of our evolution. Proteins are complex molecules and are 3 dimensional with many foldings. These include small "pockets" that are sites of binding with other molecules. It is estimated that we have at least 500 binding sites available.  So a protein designed to bind at one specific site might be able to bind at many others. Perhaps this is part of the side effects that certain drugs cause along with their cure.  We must remember that these "drugs" may have many unexpected targets to bind with.

Due to the chemistry and physics of making these vital proteins they create similar binding sites on many different proteins not related to the same functions.  When life was started it was the chemistry and physics  laws that created many proteins that evolution chose to use. The proteins were not evolved but were borrowed to allow evolution.

An example of this is the lack of a protein in Rheumatoid Arthritis called P21. This protein controls the immune system to not attack its own cells. Without it the immune system is out of control.  By taking the P21 protein apart and creating 5 different series of amino acids (peptides) it was found that one of these reacted with a protein in the immune cells in the joint to achieve the action of the P21 and stop the destruction.

By interacting with various areas of the environment many molecules are introduced to the body and some of these will find a binding site and will change that proteins function. This is what the epigenetic changes are all about.

How can we Control our Leptin Fat Hormone?

The previous post discussed the importance of Leptin as the master regulator of many metabolic processes in our body. It is such an important hormone and maybe at the basis of many chronic diseases and aging. Too much and the system is disrupted and bad things happen.

Too much is associated with excess caloric intake. Once we have increased our adipose tissue and we have allowed increased levels of Leptin then we have Leptin resistance and the natural protective cycle is lost. By reducing calories we can lower Leptin. however this is much harder to do if one is very overweight. The Leptin levels are stubborn and the resistance remains compared to normal weight people.

Leptin has a natural cycle of release with higher levels in the AM and less at night. The higher levels release cortisol and allow the morning wake up energy. The lower levels at night allow many repair processes to go on as well as burning of fats. One of the things to do is to eat your last meal at least 3-4 hours before sleep. If not the Leptin levels will remain up and the important repair processes and oxidation of fats will not occur. Since melatonin is related to the AM-PM cycle and it has been shown to be related to lowering levels of Leptin this may be a helpful supplement.

Eat a breakfast with a good amount of protein. This will increase your metabolism by 30%! A strong carbohydrate one is only a 4% increase. Eat meals at least 5 hours apart. Do not snack between meals. Triglycerides are formed after meals and if they are not metabolized they will elevate Leptin and also interfere with the message to tell the brain to not eat. Snacks interfere with this process.

Eat smaller portions at each meal and eat slowly so you can recognize when full. STOP when 3/4 full. Lower the amount of carbohydrates eaten and try to make these fruits and veges.

At least 30 minutes of exercise each day seems to allow the leptin to function better. Try for at least 8 hours of sleep. This is when all the vital cellular repairs are happening and the fasting time is needed.

It has been found that alpha 3 omega acids appear to play a role in lowering leptin levels. People with high levels of this have 1/4 the levels of Leptin. Other supplements tried in rat experiments to have success in lower Leptin levels include LCarnitine,and Conjugated Linoleic acids.

Regardless of the lowering of Leptin levels the above dietary ideas are the wise thing to do. (See previous blog on a healthy diet).

Obesity is a Complicated Inflammatory Disease.

Leptin (thin) hormone is becoming a key chemical in the evaluation of the deadly metabolic syndrome. This includes high glucose, insulin resistance, hypertension and high cholesterol and other fatty levels in the plasma. Almost all of these patients are overweight or obese.

Attempts at lowering the blood pressure, glucose, cholesterol etc. have not been shown to be effective in preventing serious damages to the body. Billions of dollars are spent on drugs to lower these to "normal' levels with minimum results. These  problems appear to be the results of a much more basic abnormality.

The production of lipids by the body is a normal result of our energy metabolism. Lipids are toxic and at higher levels can attack the cells (heart, pancreas) and actually destroy them. It is thought that the actual cause of damage by the metabolic syndrome is due to increased lipid levels destroying important cells. After absorption from the gut the fat is sent via the lymph and blood to the liver, Various types of fats are made (chylomicrons,VLDL,LDL,HDL) and then sent to the cells of the body. At the cell level they are transferred into the mitochondria and through  oxidative metabolism are made into ATP (energy). This allows energy production and gets rid of the potentially toxic fat.

The overloading of the cells ability to metabolize these excess fats causes a breakdown and stress. This sends messages to the immune system of a problem. This results in a inflammatory response.

With an excess of carbohydrates the body will spare the use of fat as a energy source and use the excess glucose. This allows the fat to be selectively spared and stored as triglycerides. The high CHO allows the accumulation of too much glucose and the cells begin to actually form fatty acids out of the glucose. This occurs in the cytoplasm and endothelial reticulum bodies. These fats are then stored in the fatty tissues. This "de Nova" fatty production from excess carbohydrates is very minimal in normal weight people. However excessively high levels of calories over time will lead to fat metabolism sparing and storage of fat in the adipose tissue. The normal oxidation of fatty acids is done in the mitochondria and this is promoted by leptin.

 Fat cells have a change in their epigenic histones due to the high calorie intake. Once this occurs it is a mutation that changes the function of the gene. These change the protein types or amounts from the gene. Fat cells produce over 60 different proteins that cause effects. Fat cells are not sleepy , quiet cells but very active in metabolism and other functions.  These changes do not go away with a change in diet. The epigenic changes persist and may be a reason obese people do not respond to decreased calories. They have acquired mutations from the previous high calorie intake.

Capsaicin in Red chili peppers is able to lower the weight of obese mice 8%. It has a chemical configuration that changes the levels of at least 20 of the fat produced proteins and allows more efficient fat metabolism.

Fat stored in the fat cells of normal people have a turnover rate of 6 times during the 10 year life span of the fat cell. Obese  people have a much reduced rate and do not get rid of the fat stored. 

The mitochondria also have a connection to our immune system. A protein in the mitochondria (UPI1) allows fatty cells to burn off the energy as heat rather then store this as fat. This is more prevalent in brown fat but can be found in white fat cells as well. A gene (IKKe) is one of a group involved in inflammatory changes in the body. Low level inflammation is produced by obesity and this gene is involved. This gene limits production of UPI1 (involved in releasing heat) and when it is absent the mitochondria release more UPI1 and the fatty cells burn off energy as heat and do not store fat. The finding of the TOR gene and its relationship to longer life and less disease may be due to its immuno restricting effect allowing restriction of the inflammatory immune response. Diabetes and other disease is associated with these low levels of inflammation.

Fat cells are now known to be very active and produce a variety of important chemicals. These communicate with different cells throughout the body.  Adipose (fat) cells can become inflamed when the immune system sends macrophages into the fat cells.  Many of the inflammatory chemicals in the obese person is due to these macrophages. This inflammation causes insulin resistance and diabetes. When these macrophages were inhibited by drugs the Insulin resistance was stopped.

Diabetes II is associated with a change in the methylation of DNA . This is an epigentic change which changes the function of a gene, PGC-1a . This gene in the muscle cells controls glucose metabolism. The methylation change is promoted by increased fatty acids and cytokinase. The increase in fat also effects the function of the important endoplasm reticulum in the cells. This structure assembles and folds vital proteins for the cell.With increase fat levels its function is decreased and the complex of proteins that protect it are lowered. The ER becomes stressed, the proteins are not produced and vital cell functions are lost. This has been shown as an important factor for Diabetes 2.

The resulting increased blood sugar  starts a process of glycation. These sugars combine with vital proteins and change their ability to function.  Many think glycation a key part of accelerated aging.

Leptin has a very strong effect on the bone cells (osteoblasts).It increases the activity and also causes more calcitonin to be produced. This calcitonin is a hormone that increases the production of insulin, increases the production of adipokine (a hormone produced in fat cells) , which increases insulin sensitivity. It also increases the production of testosterone.

It is actually adipose tissue (white and brown) that produces most of the leptin in our bodies. Other organs including the liver, muscle, stomach  can also can produce this hormone. A second hormone, adiponectin, is also produced. The leptin actually affects the cells ability to oxidize fatty acids (lipids) and the adiponectin causes lipids to be stored in fatty cells (increases insulin sensitivity). These two mechanisms control the level of lipids and protects the body cells from damage. Leptin also plays an important role in our sensation of hunger by acting on the brain stem to release serotonin to let us know when we have eaten enough.

Leptin acts on the brain stem to release at least two types of serotonin. One acts on the hypothalamus to increase appetite. (More weight, less glucose tolerance). Another acts on the bone to increase bone mass. Obese people with lots of leptin have less osteoporosis.  The serotonin from the intestinal areas has a decrease bone mass effect.

A protein Epic,  blocks leptin activity in the brain. This protein is activated by a common metabolic enzyme ,  Cyclic AMP, and by blocking this it maybe possible to lower the leptin levels.

As we gain weight and increase our food intake above what we need the fatty cells are increased in size as they absorb more fatty acids and also produce more leptin. The idea that our fat cells are actually an active metabolic organ that produces a hormone is a somewhat new idea, Unfortunately, as the leptin levels increase the body has a tendency to quickly become resistant to its action. The cells should be taking in the fatty acids and metabolizing in the mitochondria are reduced and the fatty acids accumulate in the cells and cause a toxicity to the cells. This leads to an inflammatory reaction seen in most chronic diseases. Macrophage infiltration of the fat cells.  An actual lipotoxicity results.The ability of the fat cells to absorb lipids is also decreased. The result is lots of dangerous fatty acid lipids now in the body. At a lower rate of weight increase the fatty cells actually work to try and regulate the metabolic process and protect the cells from toxicity. But soon the amount of new fats overwhelm the ability and the process of resistance and toxicity begins.

We are aware that obese people have a high incidence of many types of inflammatory diseases. Heart, Diabetes, Rheumatoid Arthritis etc. This may be related to the inflammatory changes in the fat cells spreading to other regions.

Fat cells in the knee (and other joints) produce a protein that is part of the immune complement system. (see blog on the other part of the immune system). Called pro factor D which creates a Factor D related to arthritis.  Blocking the factor D stopped the arthritis.

This high level of Leptin, due to the increased fat cells size and the development of resistance, actually stops the leptin  signals from reaching the hypothalamus and the message of "stop eating" is not given. The normal mechanism to stop eating since the fat stores are adequate is lost and the person continues to eat and even more fat is stored. Normally the brain will stop excess food intake if Leptin levels normal. Leptin levels actually increase as we age and this is one reason older people have tendency to gain weight more easily then younger folks. This is especially true for women with loss of estrogen.

It is thought that the insulin resistance seen in diabetes 2 is a protective mechanism where the cells slow down the intake of glucose to stop the production of even more fatty acids,which are produced by the excess glucose . We see increased levels of insulin and glucose. But these are reactions to the real cause of the  problem, the changes in Leptin activity.

Fructose is an even greater problem since it promotes all of these bad things at a greater rate 20 times that of glucose. Much of our processed foods contain fructose.

As the lipids cause their toxicity in the cells the cells react with a generalized inflammatory reaction. This is an attempt to minimize the damage. Many of the "markers' seen in the various diseases are due to these inflammatory reactions. Again they are responses, not the cause, of this problem.

Leptin regulates parts of our immune system, blood pressure, blood clotting, heart function, insulin levels and even artery constriction. It is indeed the master regulator of our metabolism.

Microdoses of leptin can be given and it effects a gene in the liver that lowers glucose and increases insulins ability to act.

Proper leptin levels controls our food intake, metabolizes and stores lipids, allows normal glucose metabolism, and allows proper action of insulin. It also effects our bone mass.

Another important hormone controlling weight is alpha MSH. This is made in the hypothalmus and has two functions, one to decrease the activity of cells that make us feel hungry and  another to increase the activity of the thyroid gland to burn more calories.  To get the proper levels of this hormone the cell has a area, the endoplasmic reticulum (ER) that makes and folds a protein enzyme called POMC. This  enzyme is the producer of MSH.  When mice are fed high calorie and fat diets and get obese the ER is stressed and makes mistakes making POMC. The levels fall and MSH levels drop.  If the ER are treated with a special drug to restore function (TUDA) the function returns to normal.  Lean mice have no abnormal ER function and normal levels of MSH.

A breath test can reveal which bacteria  dominate in our guts.  A special bacteria that produces methane is found in the bowels of obese patients in large numbers. A breath test shows the high methane levels and tips off this imbalance. It maybe that this bacteria causes an overgrowth of bacteria that allow more calories to be absorbed per unit of food then normal. More calories per mouthful if this is the main bacteria.  The stool samples from obese people show abnormal bacteria numbers of certain types compared to normal weight people.

Recently it has been shown that at least a part of the healthy effects from gastric bypass surgery is related to bacteria changes in the gut. After bypass surgery (in mice) they developed very different bacteria populations then the control (no surgery) mice.  The new microbes are related to signals to the body for metabolism and seem to trigger off fat burning as a method.  Mice given these bacteria types also lost weight. Mice given the original bacteria of the operated animals (before surgery) gained weight.  Bacteria , again. show important effects on obesity.

Our Cellular Antennae to Sense the Environment

Cilia, tiny hair like structures , are found throughout the body. They are in the kidneys, ears, lungs, in cartilage (sense pressure), in the eyes (sense light,   in the heart (blood flow). They are attached to cells and they sense many different environmental changes and send signals to alter the cells functions.  A defect in the cilia producing genes , BBS,  causes cystic kidneys, blindness, mental defects and extra toes and fingers. They also become obese.

Cilia are formed by bundles of microtubules made of a protein called tubulin. The molecules are placed in position by a small protein motor called kinesins (kinesin 2).  It was long believed that cilia were for movement only.   If there is a defect (mutation ) in the gene to form the tubulin proteins the cilia are abnormal. Many diseases are the result of malformed cilia.

  Each cilia is like a small hollow tubule and has many different protein molecules inside.  90 % of the cells proteins can fit inside the cilia. However,  most of these have not been found in the cilia.  It may be some wander in but only a few select ones remain.

The signaling monitors inside the cilia are specific and some may activate or suppress DNA, to produce more or less of a protein needed for that condition. The only entrance is through a hole in its base. This is where the proteins from the cell enter and leave.  The cilia are very small,1/10,000 the volume of the rest of the cell.

The cilia are found on almost all cells in the body. They are the cellular antennae and not only sense changes but communicate with each other.  Cilia from different cells attach to each other thru glycoprotein molecules, and the contact can last hours or days. These communications are lost in certain diseases.

In the past cilia on brain cells were thought to be a left over of the past. Now, it is found that these are very active and important structures for the  brain cells function.  They receive signals (chronic hedgehog) to spur the creation of new brain cells.  Hydrocephalus, brain stem abnormalities, all associated with cilia that were not formed properly. Cilia are found on brain dividing cells. In developing brain cells cilia can be seen extending and contracting.  As neurons are formed and migrate into the cortex they do this in steps,. At each step the cilia are very active and seem to be locating the position for a cell to place itself.  Genetic mutations that cause neuro developmental disorders have abnormal cilia action.  A gene , Arl 13B, is mutated in these disorders and a short, stubby cilia is developed.  These cilia were unable to extend and retract and the cells were malpositioned.

Cilia are also involved in inflammation.  Cartilage cells, with cilia, exposed to cytokines (IL-1) the cilia began elongating showing a 50% increase in length. If this elongation prevented the cartilage cells had much less inflammatory change. (?A new target for arthritis treatment).

Cilia are involved in obesity. Mutations in the genes to develop cilia in cells in the hypothalamus caused scrambled signals in the cells and promoted overeating.  With these abnormal cilia the cells cannot dock the melanin concentrating hormone (MCH) a key appetite suppressor.  Unable to regulate the appetite the patients become obese.

Cilia are involved in osteoporosis.  How does bone sense mechanical  loads?  When bone bears weight bone cells are subjected to fluid flow.  This is detected by cilia in bone cells.  A protein enzyme (AC6) in the cilia tubules,  is inactivated by the fluid flow signal and starts a  cascade of events that activates the bone forming genes. (? new area of anti osteoporosis drugs).

The Complex Brain and Disease

Glia is a greek word meaning glue. This is the word given to all of the brain that was not neurons. It was thought to be an inert substance that held the neurons together. The brain is 90% Glia cells. There are three major types of glia cells, Astrocytes, Microglial and oligodendrocytes. These three cell types each turn on a different set of genes to express themselves.

All of these cells have very important and different functions besides being the stuff the neurons are surrounded by.

Astrocytes make up about half of the brain cells. They look like stars with long thin projections. One job is to clean up after the messy neurons. When an electrical signal jolts a neuron synapse region neurotransmitter chemicals are released. This very important function is monitored by the Astrocytes. They supply nutrients to allow the synapse to work and rebuild the chemicals at the synapse. They "clean up" the area to be sure no residual chemicals left after a reaction to assure a new clean reaction.

Perhaps most important they determine where and when synapses will occur. One astrocyte can cover thousands of synapses at a time. The production of new synapses appears to be due to a protein, thrombospondin, secreted by the astrocyte. This protein is produced during brain development and when maturation is complete it stops production. The exception is the astrocytes in the hippocampus where current memories are stored. This structure forms new synapses every day and the thrombospondin is necessary to allow this. With a brain injury the astrocytes in the area begin production of thrombospodin. The gene for thrombospodin is found in humans and primates. Astrocytes also monitor the synapses and when more activity they can regulate the amount of glutamate needed for the conductions.

Astrocytes control the flow and stimulation of neural stem cells by secreting certain molecules. They are in contact with the stem cells and moderate the change from stem to adult neural cell.  When the body needs neuroregenerative  changes (Trauma,stroke)  the astrocytes are the  cells that promote this. Stem cells live in  a special niche in the brain , the subventricular zone,  and produce new neurons and glia in a proportion related to clues from the surrounding tissues.  After a injury the proportion of astrocytes produced increases. These cells migrate to the area of injury to help make an organized scar and stop the bleeding. If these are blocked the bleeding was not stopped and healing was delayed. These special post trauma astrocytes also secrete a special protein, metallothionein, (MT), and secrete it to surrounding nerves. It  attracts the free radicals and metal ions free by the trauma and prevents them from damaging the surrounding normal cells.

Aquaporins are proteins to transfer water on the cell membranes. They allow the flow of water to be regulated by various factors. Cell movement is related to Aquaporin 13 which allows water in, traps it between the cell membrane and the endoskeleton of the cell and a protrusion is formed. This sticks out from the cell and the cell follows. The cell moves.  Mice with a defect in aquaporin 4  gene (another of the 13 aquaporins)  had reduced inflammation with various inflammatory diseases of the brain.  This seems to downgrade the reaction of astrocytes to stress (inflammation). By blocking this water transferring protein inflammation may be reduced in the brain.

It is now known that calcium reactions ("flares") occur from astrocyte to astrocyte in the cerebellum. When this occurs ( with motion) the blood vessels nearby expand in size. This did not occur with rest. It appears the astrocytes monitor the neurons electrical activity levels by generating calcium flares and cause local blood vessels to supply more nutrients.

Synapse death is an important part of a normal brain. The developing brain develops many more synapses then it uses. These require nutrition and maintenance. The astrocytes cause some synapses to be covered with a protein, Clq that marks the synapse for destruction. This protein production is shut off in the adult brain but is abnormally active in many neurodegenerative diseases. Alzheimers disease has loss of 80-89% of synapses. Astrocytes appear to be the key in neuron health and maintenance. Protect the astroctye function and the neuron will survive. Astrocytes differ from one region of the brain to another, just like neurons.

Microglia constitutes 10% of the brain cell mass, (14 billion cells!) serve as the immune function in the brain. They are of immune cell origin and probably reach the brain before the blood brain barrier is developed. These cells also have long , slender projections that extend to the surfaces of neurons, blood vessels and astrocytes. these extensions are constantly moving, probing various areas of the above cells as if monitoring their well being. They make a complete sweep of the total brain every few hours. If a damaged area discovered numerous microglia converge and clean up the debris. These cells are very active in building and destroying synapses.

They produce enzymes, cytokines, that are related to stress and inflammation. If these enzymes are overproduced normal neurons can be destroyed. This may happen in older individuals and loss of neurons in the hippocampus causes memory loss.  ( see blog on memory ) . More and more diseases of the brain are being tied to the activity of these cells and the enzymes they produce. It does appear that a chemical, luteolin, found in certain foods (red peppers, celery, carrots) protect the neurons from the overactivity of the cytokines.

 A protein called P13K gamma  is involved in the activation and movement of immune cells.  By blocking this (with a available oral drug) the reduction in the inflammatory reaction occurs and the progression of myelin destruction was stopped and signs of the demyelinating disease disappeared.

Multiple Sclerosis and other diseases  have destruction of the fatty myelin sheath that allows the passage of signals from one neuron to another (s).  A protein , Mitochondrial translocated protein (TSPO)  found on the outer membrane of these energy producers  is related to this problem. Giving a anti anxiety drug, etifoxine, restores this TSPO and the symptoms of the disease are reduced.

Beta amyloid is a protein produced in the brain at synapses and acts as a moderator of signal strength. Too strong a signal and the amyloid molecule is produced to reduce the intensity. Beta amyloid has a precursor, Leucine, and amyloid production is constantly going on and the molecule normally remains in the brain for about 8 hours. It is then disposed of and new amyloid produced.  This is an important part of normal brain function.

As we age the disposal decreases and this also happens in Alzhiemers Disease (AD). A current theory is that this decreased disposal allows the abnormal build up in AD. The Amyloid normally is excreted by a protein pump thru the blood brain barrier. If this pump is shut down the amyloid accumulates in the brain.

All proteins, including Beta amyloid, are the results of a gene encoding RNA  and then a thin line of amino acids , in a specific sequence, is formed into a long thin line. Next, at the endoplasm reticulum  and ribosome the protein line is folded into a 3 D shape.  This is what gives it its specificity to act .  If there is a misfold the protein becomes an unorganized clump and often traps other proteins in its folds.  The clump adds projections of  small bits of proteins called fibrils. These can break off and travel through the brain. They are now called oligomers and are toxic to neurons. They use another protein called Tau to form plaques

These small amino acids (6 in length) that connect the miss folded plaques we see as B amyloid are called fibrils.  When these are separated and examined it is found they are able to bind many inflammatory molecules and keep them from acting. Interleukin 2 and 6 are two of these. Mixing these with human blood showed they acted as a sponge absorbing many inflammatory  products. Using these in MS mice the fibrils decreased the signs of inflammation. However, it may be these are the protectors of the  amyloid plaques in Alzheimers as described above.

The toxic sticky proteins in the brain seen with Alzheimers  (B amyloid) are connected to the loss of memory of this disease. The glia contains macrophages which can remove these plaques. The plaques cause the glia to go into a inflammatory phase with many chemicals secreted. However, the microglia cannot remove the plaques as it would normally do to foreign fragments.   By using a human  polyclonal (many antibodies) globulin the inflammation of the glia to the plaques was minimized and new neurons in the hippocampus were protected.  This treatment has been successful in a small number of patients. It seems that the amyloid may All proteins inthe brain are produced by a gene (s) encoding a mRNA  and then this signals a tRNA be interfering with the microglia functions to remove them.  It is in the final phase of clinical testing.

A protein LRP is part of a pump that removes beta amyloid from the brain. When this is turned off the amyloid increases. It seems that antinflammatory drugs (indomethcin)  can block the message to turn it off. The pump works and the amyloid removed from the brain to the blood.  It may be that an inflammation process turns the LRP off.

Another approach that is being used is the use of Interleukin 6 (one of many signals to the immune system) Using this signal chemical in the microglia allowed a return of function and the plaques were removed.  The IL-6 caused the microglia to actually engulf the plaques and then to produce proteins that removed the plaques. This was done in mice but the findings should be the same in humans.

The microglia immune system is observed to have a change in function with Alzheimers.   Their ability to remove fragments and the ability to have mobility and move towards acute lesions are impaired. The microglia cells gather around the amyloid deposits but do not attack. By using antibodies against the amyloid allowed the function of the microglia to return. The plaques accumulate faster then the microglia immune cells can remove them.   Research is now looking at ways to allow the microglia to increase its ways to rid the brain of these plaques.

The small amino acids (6 in length) that connect the miss folded plaques we see as B amyloid are called fibrils.  When these are separated and examined it is found they are able to bind many inflammatory molecules and keep them from acting. Interleukin 2 and 6 are two of these. Mixing these with human blood showed they acted as a sponge absorbing many inflammatory  products. Using these in MS mice the fibrils decreased the signs of inflammation. However, it may be these are the protectors of the  amyloid plaques in Alzheimers as described above.

A protein , NAP, is involved with nerve repair by the microglia. It is shown that with amyloid formation  the microtubules in the cells are the rails and the tau proteins are the "ties". With disease the tau ties fall off and are free. The NAP prevents this.

A drug J147 (in mice) increases the production of a important brain protector BDNF. This increase allows healing of broken synapses, protection of neurons and the functions of the brain (memory, cognitive ) all are improved.

An interesting new genetic modified tomato was given a beta amyloid gene. It produced beta amyloid in the tomatoes. These were fed to mice and soon a antibody against beta amyloid was found in the mice blood. It may be we have a way to create antibodies against this chemical  by eating tomatoes.

Astrogila function as stem cells for neurons during early brain development. At a later more mature time, they can revert back to stem cell function, if they are exposed to regulating proteins found in neonatal brain tissue.

It is now known that vigorous exercise causes release of a chemical (noggin) that causes stem cells in the brain to turn into new neurons.

Oligodendrocytes account for 40% of the cell mass. They extrude a fatty material, myelin, that coats the surface of the neurons and insulates and promotes the electrical signals. Many diseases destroy the myelin surrounding the axons and nerve impulses cannot be transmitted.  By using cellular reprogramming the common fibroblast in the skin area can be converted to myelin cells. By manipulating 3 proteins the fibroblasts become stem cells to produce oligodendrocytes.  These then produce myelin in damaged nerve sheaths. 

Other products in the "glue' are also important. Palmitate is a saturated fat and is important to join with certain proteins such as NMDA that are receptors for various synapses. Glutamate, a neural stimulater, promotes the production of these proteins but palmitate is necessary to mark and direct them to the proper positions on the surfaces of neurons to create synapses. This is necessary to allow new learning and memory paths to be created.

Using a new Diffusion Tension imaging technique which tracks microscopic water molecule movement, allows the following of changes in the White Matter. Children, 8-10 years old,with reading problems showed defects in various areas of their white matter. After intense training for 100 hours, the reading skills improved and the defects in the white matter were corrected. Reading, like many skills, involves various areas of the brain and these areas are dependent on the connections and communications done by the white matter.

In the "normal" aging brain it is shown that the important connections between the frontal and posterior areas, related to memory and learning, decay and have less ability to communicate. This is associated with loss of cognitive ability. These pathways are made of the "white matter".

Certain proteins in the brain can completely change an injury such as stroke. Transforming Growth factor (TGF) is important in the development and formation of new brain tissue. Injecting this material into the brain can restore 100% of the function of damaged tissue. Nasal spray administration gave a 70% restoration. (Vs. 30% in controls). This protein stimulates new neuron growth and the new cells migrate to the area of injury and replace the lost neurons.

 Another protein GCSF, that helps form and protect neurons, reduces the size of the damaged area and increases function return when injected after a stroke occurs. This illustrates the capacity for regeneration of the various parts of the brain. A protein NOGO-A, is produced when the brain does not want any new neurons or axons produced. An example would be excess pain or uncontrolled motion and less neurons are better. However, an antibody against this protein stops its inhibitory action and the neurons do increase and develop new axons. When this antibody is given with strokes and other injuries new neurons and axons develop in the injured area.

Recently skin cells were changed from skin to neurons by activating 3 specific transcription "switch genes"factors (genes that tell other genes what to do). It may be possible to activate transcription factors in the glial or astrocytes cells to turn them into neurons in cases of injury to the brain.

Elephants have 97% Glial cells and only 3% neurons. Glia is definitely more then support and glue.

There may be clumps of amyloid in the brain that can actually store information. Prion proteins are usually associated with neuro degenerative disease. However, prion proteins can change shape and form clumps of amyloid like deposits that are not abnormal. These prion proteins are found in almost all healthy brain cells. This normal position maybe for insulation so the electrical communications will work. Certain proteins, CPEB, is activated by serotonin and causes other proteins to change shape. It is very short acting normally but the change in shape and the passing on of this to other proteins causes clumping and amyloid to deposit. This may strengthen the synapses between neurons. This allows a long term memory of the event to occur. If this shape change is blocked then the long term memory does not occur. Serotonin is important to allow this shape change and the long term storage of information. Prions may not all be infective but some may actually store information.

Like all organs, the brain has a continuous supply of undifferentiated stem cells. It has been shown that when a aerobic exercise is done, so that a chemical, noggin, is produced and carried to the brain ,these stem cells can be induced to form new neurons. This is one of the few things that has been shown to form new neurons from stem cells. Exercise also increases the amount of an important brain chemical, BDNF, which is found in the hippocampus and related to building memory.

The neurons are a whole and separate area of the brain. There are over 200 billion of them, trillions of synapses between them (about 1/1000th. mm apart) and over 125 trillion synapses in the cerebral cortex. Each synapse is like a microprocessor with memory storage and information processing elements with micro switches to recall and use information.

It seems all tissue in the brain has important functions and interact with each other continuously.

Food From Light, Photosynthesis ,a real Miracle.

The creation of chlorophyll and its ability to use light from the sun to make food and release Oxygen. The basic structure of chlorophyll is a porphyrin which is very like our blood component heme. Porphyrins are found in many light sensitive enzyme systems and have been isolated from astroids from outer space.

Every plant and algae has a small factory in its leaves called chloroplasts. These bacteria shaped structures are the source of this amazing reaction. Over 1 billion years ago a free bacteria, cyanobacteria, was ingested by a complex cell and it became a part of this cell.  After a while it transferred some of its genetic material into the host cell and kept some within its own self.  In plants it became the chloroplast and in animals the mitochondria.

 Basically a light photon from the sun activates electrons in the H2O molecule and they go to a higher level of energy. As they begin to fall back to their lower energy level there is excess energy released to be used by the cell. A second light photon again lifts the electrons to a higher energy level and even more energy is released as they go back towards their normal level. This energy is converted into a high energy molecule and this allows atmospheric CO2 to form a sugar-the basic food of all life. The most abundant protein in our planet , RuBisCo enzyme, helps this reaction. Along the way the oxygen is free and appears as O2 in our air. (No O2 in air before plants). This reaction allowed the many paths of evolution to begin.

The very early bacteria in the thermal vents had a different source of electrons and used iron and hydrogen sulfide. They would strip electrons, use the energy to react with CO2 and also form sugars. They probably used manganese rather then light as their beginning energy source. Manganese was very abundant in the waters billions of years ago and is a prolific electron donor.

Cyanobacteria developed this chlorophyll system and had another "accident' in which a metal cluster was incorporated into the cell and was adjacent to the chloroplast. This cluster of manganese, oxygen and calcium is similar to other metal clusters found in the thermal vents. This addition of the metal cluster allowed the bacteria to now get its electron by splitting the water molecule. Also, releasing free O2.

The Cyanobacteria,with this important factory, was probably ingested by a host and not digested. The ability to form this chloroplast-metal cluster metabolism was now part of the new host cell. The chloroplasts actually look like bacteria in the leaves of plants. It is not unusual to find DNA from bacteria that has been incorporated into new hosts this way. An example is the mechanism to digest cellulose by cows which came from bacteria.

Soon, all species of plants had the same food factory as algae. All of the DNA of these chloroplasts from all the many different species is the same. A common ancestor.

The sea slug is shown to posses the genes to actually make chlorophyl. This was probably a gene transfer some time in the past. However, the slugs must eat algae to complete the metabolic process from photons of light. The algae supply the chloroplasts and these along with the slugs own chlorophyl allow them to use photosynthesis to make food and live. These are the only multicellular animals known to be able to make food from light.

This process of photosynthesis allowed the tremendous explosion of varied life on earth. It is important to note that the mitochondria in humans and other animals (also bacteria at one time) take the glucose of plants, use O2 made by the plants, to convert this into ATP energy that allows all cellular reactions to occur. (See blog on mitochondria).