Nitric oxide whose chemical symbol is NO may be one of the key players in the stem cell regenerative medicine world. I call it one of the "holy grails" of stem cell therapy. Nitric oxide is probably one of the most important signaling molecules in our body. It has an effect on almost everything from maintaining blood pressure to preventing many disease conditions to dramatically stimulating stem cells. Our immune system is very intimately related to NO production. During the past two decades, nitric oxide (NO) has been recognized as one of the most versatile players in the immune system. It is involved in the pathogenesis and control of infectious diseases, tumors, autoimmune processes and chronic degenerative diseases. To regulate immune responses, NO will trigger the eradication of pathogens on the one hand and on the other hand modulate immunosuppression during tissue-restoration and wound-healing processes. Much of these effects comes from the effects NO has upon immune cells. Mesenchymal stem cells are immune modulators. They will quill the inflammatory response that the body produces in many different conditions. Nitric oxide works hand in hand with mesenchymal stem cells and macrophages to make the stem cell environment more conducive for stem cell repair. There is essentially no pathological condition in the body where NO does not play a role in the management of the condition.
The discovery that a simple molecule produced as a gas could perform so many essential and critical biological and physiological functions established a new paradigm in cell signaling. Cell signaling is very important in the field of stem cell science. Cell signaling is the intercellular communication system of the body. Most of the aspects of cell signaling involves cytokines. Their release has an effect on the behavior of the cells around them. Cytokines work as immunomodulation agents. Meaning they will directly affect the immune system either causing inflammation or closing it down. Cytokines include among other things chemokines and interleukins all of which are growth factors typically produced by stem cells, platelets and various immune cells. On the other hand, NO is a gas that can do similar things. The NO molecule will many times affect certain genes causing them to be "turned on" and instruct the cell to produce a variety of biochemical compounds. Some of these compounds will have conflicting actions depending upon the environment. One method of how NO works in signaling involves the concept of hyperbaric oxygen. It has been a long-standing principle that hyperbaric oxygen can increase healing. There is very little dispute to this principle. One very surprising fact is that hyperbaric oxygen works by the principle of the production of nitric oxide. Thus, hyperbaric oxygen gets people better not by increased oxygen but by the production of NO. This research was presented by Dr. S. Thom of the Univ. of Penn. Dr. Thom showed that hyperbaric oxygen produces NO which effects a certain enzyme in the bone marrow which simulates the release of stem cells from the bone marrow. This is the true mechanism of how hyperbaric oxygen works. Remember, ultimately it is the body's cells that repair a condition.
Harnessing the power of the cells is the fundamental basis of Stem Cell Regenerative Medicine. Nitric oxide is very important in harnessing these cells. One good example of this aspect is the treatment of Osteoporosis. I am actively involved in the use of stem cells for the treatment of Osteoporosis which is a weakening of the bones. We have had excellent improvements in bone densities with our propriety treatments of osteoporosis with a specific type of stem cell and growth factors. I am also aware that nitric oxide also plays a significant role in the regulation of osteoporosis. If too little NO is present in the body than this stimulates the production of osteoclasts which break down bone leading to a weakening of the bone and osteoporosis or its less severe cousin osteopenia. On the other hand, if increased amounts of NO are present than this stimulates the production of osteoblasts which produce bone and thus strengthen it. All of our osteoporosis patents are advised to take a NO supplement.
As we age, we lose our ability to produce Nitric Oxide. When our ability to produce NO diminishes we are susceptible to a host of chronic diseases. By the age of 40, most adults produce only about 50% of the NO produced when they were 20.
We now know that NO production or the lack of it is a very early marker of chronic disease. Low levels of NO are associated with a variety of cardiovascular diseases, diabetes, Alzheimer's disease, and general poor health. Many lifestyle and dietary habits that lead to chronic disease are linked to insufficient NO. These lifestyle changes are lack of exercise, a poor diet and some of the medicines that we are prescribed for certain medical conditions. Dietary nitrate is also an important source of nitric oxide in mammals. Green, leafy vegetables and some root vegetables (such as beetroot) have high concentrations of nitrate. When eaten and absorbed into the bloodstream, nitrate is concentrated in saliva (about 10-fold) and is reduced to nitrite on the surface of the tongue by a biofilm of commensal facultative anaerobic bacteria. This is a very important reason for avoiding mouthwashes. The mouthwash may kill the very bacteria that is designed to keep you healthy by their NO production. The Nitrite produced by the bacteria is swallowed and reacts with acid and reducing substances in the stomach.
A number of supplements have been tested and certain ones that have been found to have a profound impact on NO production in the body. After much due diligence, I found the best product for stimulating NO production in the body is called Neo-40. This is produced the company called HumanN. The original research on this product comes from the Univ. of Texas. Thus, the pedigree of the product can be traced back to Univ. of Texas. The research on Neo-40 was performed by my colleague Dr. Nathan Bryan. He is considered one of the world’s experts on NO.
As I have said in many of my lectures I feel that NO is one of the holy grails of the stem cell world. We now know of certain methods of manipulating the production of Nitric Oxide such as using Arginine but this ability seems to diminish with age. Luckily, we now have some new weapons in our armamentarium such as Neo-40. I know that NO is not only very important for maintaining optimal health but also for stem cell production. Typically, optimal health and increased stem cell production go hand in hand.
In summary, we now know that nitric oxide is a many faceted compound including acting as a growth, immune, and neuro-modulator as well as a stimulator of stem cell proliferation. It has a critical role in analgesia, angiogenesis (production of blood vessels), and vasodilation. It furthermore acts as an anti-inflammatory, anti-cancer, and anti-microbial agent. Unlocking some of the secrets of nitric oxide will unlock some of the secrets of life. Thanks Dr. P
STEM CELLS AND THE IMMUNE SYSTEM (PART 2)
In part one we have discussed various effects that the stem cells have upon the immune system. Various stem cells will help in the release of certain type of immune cells. Some of these cells will stimulate an immune response while other will diminish the immune response. We are still missing one very important effect that they have on what we call macrophages and other cells.
As was mentioned in part one of the most important stem cells in dealing with the immune system is the mesenchymal stem cells (MSCs). As Dr. A Caplan states they are “medicinal signaling cells”. Their main function is not to cause tissue regeneration but to help in immunomodulation. In another word, they help water down an immune response. Without these cells, most repair would never be accomplished the area and the damaged area would remain unrepaired. The following diagram from one of my lectures is an excellent description of these cells:
As you can see like Navy Seals they are very specialized. They will not win the war but they can secure an area so that other forces (stem cells) can come in an accomplish repair. MSCs possess broad immunomodulatory properties. After activation, MSCs can secrete a variety of soluble factors, such as NO, IDO, PGE2, TGF-β, HLA-G5, TSG-6, CCL2, IL-1Ra, and IL-10. These are various growth factors or cytokines that are produced. Their names are not that important to the lay person. What we really need to know is that production of these factors can suppress the differentiation, proliferation, activation of various immune cell subsets. As a result, the immune response will be inhibited and local inflammation is suppressed by MSCs.
One effect of the MSCs that has not been mentioned is the effect that they have on macrophages. The Wikipedia definition of macrophages “Macrophages are a type of white blood cell that engulfs and digests cellular debris, foreign able to be accomplished. The body would destroy all reparative cells substances, microbes, cancer cells, and anything else that does not have the types of proteins specific to healthy body cells on its surface in a process called phagocytosis”. However, there is more than meets the eye here. The following slide from another of my lectures shows the importance of macrophages:
What we are able to ascertain from this diagram is that there are two types of macrophages. The following slide is an explanation of these two types of macrophages.
The MSCs will affect the microenvironment which ultimately determines the fate of the development of the macrophage. Obviously when we are fighting an infection we want to produce the M-1 type of macrophage to obliterate an infection. However, when we are performing a regenerative medicine procedure we want to produce an M-2 macrophage which will help with immune modulation. Anything we can do to help the MSCs will be a boon to regeneration. You may ask how do we do this very simply. If you were to look at the diagram you will see some growth factors with the following designations IL-1a, IL-10, and TGF-b. These are powerful growth factors that will nip inflammation in the bud. These are part of our propriety cytokine formulas. We are helping the regeneration. We are encouraging the release of M-2 macrophages which are immunomodulatory and also release growth factors which promote tissue repair. This is one reason why we do not feel it is wise to eliminate white blood cells of which macrophages are a part of that family from a Platelet Rich Plasma (PRP) mixture. We are also able to produce more M-2 macrophages by a process of photo-modulation. This occurs when a PRP product treated with certain wavelengths of light increases M-2 macrophage production. Macrophages are also important for other purposes. They help with what is called stem cell homing.
One more effect that the stem cells have upon the immune system involves the production of LL-37. LL-37 is a very interesting compound. It is one of the most effective anti-microbial compounds known to man and actually the only antimicrobial produced by man. It gives broad antimicrobial protection against bacteria, fungi and viruses. Human bone marrow-derived MSCs possess direct antimicrobial activity, which is mediated in part by the secretion of human cathelicidin LL-37. Another interesting fact is that the effect of Vitamin D-3 on the function of LL-37 and chemokine production as well as an important role in immunomodulation. These anti-inflammatory and anti-infective roles of Vitamin D are becoming increasingly important.
The actual mechanism of LL-37 production is thought to be turning on a gene which helps production of LL-37. The vitamin D turns on this gene. Is there any practical example of the relationship between stem cells, vitamin D and the immune system? Perhaps one of the best examples occurs when a woman has a period. During a menstrual period, there is a setup for an infection. We have bacteria present in the mist of blood products at a temperature conducive for bacterial growth. This is a recipe for infection. Yet infection almost never occurs. Why is this so? We must remember one thing. Menstrual blood is very rich in mesenchymal stem cells. These mesenchymal stem cells release compounds including LL-37 which will luckily squash any type of infection. I have just scratched the surface concerning stem cells and our immune system but I believe we see how these important stem cells may be used in the treatment of many different conditions. Thanks Dr. P
CYTO-AMINO-COMPLEXES: THE FUTURE IS NOW!!
I feel quite privileged to work with Dr. Jo Serrentino. She is my colleague, a mentor, and a partner. She and I have been working on a few cutting edge of the cutting edge projects for a number of years. There is no doubt that her knowledge and inspiration have helped me design some very unique protocols. She is a fountain of knowledge. One day I may ask her how we can increase the effectiveness of stem cells injected into a joint. On another day I might call her up to discuss some aspect of a V cell treatment that potentially increases the overall effectiveness of the treatment. She has been instrumental in helping us develop our protocol for the treatment of Osteoporosis with stem cells and different growth factors. Although our series is still small we are obtaining improvements of from 15-30% in bone density values in one year.
I am most beholding to Dr. Serrentio for her guidance and teaching of cytokine therapy. Most every condition in medicine typically results from an imbalance in cytokines. If you are dealing with an osteoarthritis, tendinitis, or an autoimmune disease you can be sure that an imbalance of cytokines is at work. Cytokines are a broad and loose category of small proteins that are important in cell signaling. Their release has an effect on the behavior of cells around them. They are very involved with our immune system and help regulate it and balance it out. In Regenerative Medicine our immune system is of the upmost importance controlling the body's reactions. Cytokines and the immune system regulate the maturation, growth, and responsiveness of particular cell populations. Some cytokines enhance or inhibit the action of other cytokines in complex ways. We have used cytokine therapy to enhance our procedures for a number of years now. I repeatedly get asked the question "am I too old for stem cell therapy?" The answer to this is a resounding no when we are also utilizing Cytokine therapy. This is one of our secret weapons. A good clinical example of this is concerning a simple PRP injection. As we age the levels of Insulin Growth Factor-1(IGF-1) decrease significantly. IGF-1 is instrumental in the repair of cartilage tissue, tendons, etc. However, if you are starting with low levels because of age or advanced osteoarthritis the repair of that joint may not be forthcoming. This is the beauty of Cyto-Amino-therapy as Dr. Serrentino calls it. We can help correct these deficiencies and encourage repair. Age is no longer an insurmountable road block.
Cytokine Intercellular Communication
I asked Dr. Serrentino to write about cytokine therapy in her own words. She wrote the following summary for me: "Because cytokines are for research purposes only, they cannot be used liberally in commercial products. The controversy over growth factors for example has been ongoing for decades; restrictions in using these valuable signaling molecules in medicine is still an ongoing issue, despite the research data proving their countless benefits and safety". Therapy with signaling molecules or Cytokine Therapy as coined by the researcher who developed the modality, Dr. Serrentino, is indeed a boon to modern medicine. For example, the use of recombinant proteins such as IGF-1 to repair cartilage in osteoarthritis, or the use of recombinant Interleukin -10 as an anti-inflammatory can dramatically alter the results of a procedure. Hundreds of protocols have been established by Dr Serrentino, but the availability of actual Cytokines in the right combination and dosage has been difficult to source and to regulate. Sources of real cytokines in commercially available products are usually from homeopathic sarcodes or nosodes, (a sarcode comes from an animal part) but these provide only the precursor components not the real thing according to Dr. Serrentino. Recent advances in technology have enabled Dr. Serrentino to develop clones of signaling molecules that have shown better biological action than actual cytokines. Dr. Serrentino has coupled polyamino molecules with nano technology to create Cyto-amino® Complexes that mimic the signals and the biological activity of many cytokines.
Dr Serrentino further explains that: “Because these Cyto-amino complexes are engineered through nano technology, they do not work like a supplement but rather go directly to the extracellular matrix where they signal cellular tasks. Just like cytokines they tell the cells where to go and what to do. Amino acids are the building blocks of proteins, and cytokines are small proteins, so we can synthesize a clone through certain biochemical techniques with readily available amino acids. But these new molecules are not supplements of amino acids, they do not work like supplemental amino acids. They have a unique structure that gives them the capacity to mimic the action of a bonafide cytokine with extreme precision. They are not dependent on serum levels or need to be broken down like supplements, they work exactly like cytokines at signaling pathways, thus we can use them to program repair, which is the basis of Cytokine Therapy. This Cyto-amino Complexx ® goes straight to the extracellular matrix where it gives
cells directions in programming regenerative pathways. CYTO-AMINO COMPLEXES ® can provide some extremely effective practical products for medical therapy, especially regenerative medicine and stem cell therapies. Exclusive formulations have been developed for Dr Purita’s Stem Cell techniques and protocols and are solely available through his teaching venue."
Every day I continue to learn the intricacies of cytokine therapy. This therapy is truly unique in all stem cell therapy. As time goes on I am sure Cytokine Therapy will continue to make a difference not just in my practice but in that of a fortunate few others. In some circles there is a notion that stem cells are but a waypoint in our treatment modalities. Eventually, cytokine therapy may replace harvesting stem cells. Remember, cytokine therapy mimics stem cell therapy in a much more efficient way. Perhaps I should say in a different manner: Stem cell therapy tries to mimic Cytokine therapy. We will certainly hear more of this as time goes on. Thanks Dr. P
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