When we think of inflammation in the horse, it is often in the form of pain and swelling. Joint pain, stiffness, a wound or cut, sore back, sore throat, or even a skin infection. All of this is true and these conditions are associated with inflammation, but the overall concept goes much deeper, often being unrecognized clinically but all too closely tied with other health conditions. In the horse, chronic inflammation is linked back to lameness conditions with the tendons, joints and poor hoof health. It is also involved in metabolic conditions, including insulin resistance, allergies and uveitis. It is an important concept to grasp, even on the most basic level, as with this understanding, we have opportunities to intervene which may give us more opportunities to manage and even prevent certain conditions.
Chronic inflammation has been the focus of research for the past couple of decades due to connections with almost every health condition impacting people and the horse. This inflammation also predisposes to injury and even affects performance. The topic is very complex and not all of the answers are apparent at this time, but research has made some incredible discoveries that I feel are of value for complete understanding of health as it relates to natural substances, diet and pharmaceutical medications.
What is Chronic Inflammation?
One of the biggest discoveries is regarding how the process of inflammation is prompted and interacts with us and the horse at a cellular level. It goes much deeper than just pain and swelling. It is tied with poor healing, bone or cartilage degeneration, allergies, metabolic problems, respiratory ailments, injury predisposition and even cancer. We do know that during this inflammatory process, there is a marked increase in production of many inflammatory proteins or cytokines, which act as means of cellular communication, influencing cellular function on many levels. These pro-inflammatory cytokines are created as a result of gene translation on a genetic level. Knowing how intricately involved these proteins are in health and how an overabundance of them equates to problems, one key question has revolved around how to regulate their production? In years past, research has focused on inhibiting specific cytokines such as interleukins and tumor necrosis factor, which has produced some not so favorable results in clinical studies.
The ideal situation would be to figure out how to impact the production of several cytokines, instead of just focusing on one. The answer was revealed almost accidentally in the early 1980’s through the discovery of a transcription factor, NF-kB, that was connected to the production of most inflammatory proteins.
Nuclear Factor Kappa B and Initiation of Inflammation
Nuclear Factor Kappa B (NF-kB) is a protein complex located within the cytoplasm of almost every living cell and controls DNA transcription. In the cytoplasm, NF-kB is in an inactive form, but when activated, moves into the nucleus, attaches to specific gene sequences on the DNA and is responsible for the production of many inflammatory proteins (cytokines), immunoregulatory proteins, proteins associated with NF-kB regulation, growth factors, cell cycle regulators (regulators of apoptosis) and various oncogenes. Essentially, when these gene sequences are transcribed, proteins are produced with specific functions regarding health.
Activation of NF-kB is a complex process. The inactive form of NF-kB is actually a protein complex of both NF-kB and an inhibitor, termed IkBα. During activation, various events occur at the cellular receptor level which then activates IkB kinase (IKK), which then phosphorylates IkBα resulting in NF-kB activation, then subsequent relocation to the nucleus, where gene translation and protein by products are produced.
Aside from being responsible for the production of many inflammatory proteins, NF-kB also regulates cell survival and proliferation. If active, it causes the cell to resist normal programmed cell death (apoptosis) and enhances cellular survival, proliferation and division. If inactive, the cell experiences normal cell cycles, cell death and replication. NF-kB activation plays a role in cancer development and progression due to interference with normal cell life cycle and more uncontrolled cell growth.
NF-kB is not always a bad thing for our health and is necessary in cases of acute inflammation to help resolve infection and activate healing. It is also involved in healthy immune function as DNA transcription can lead to antibody formation and lymphocyte differentiation. NF-kB has positive roles in memory and learning due to production of growth factors, TNF-α and some kinases (PKAc).
The overall problem comes when NF-kB activation is unregulated and out of control, which contributes to ongoing or chronic inflammation, alterations in cell growth, death and replication. In the cases of chronic disease, NF-kB is almost always excessively active and considering the role that it plays, it is an area of heavy research in order to provide an opportunity to assist in health and disease management. The overall goal in health restoration would be to down regulate an overactive NF-kB, reducing levels more to a normal state, thus inhibitors of NF-kB activation are of tremendous interest. With that being said, we have to remember that NF-kB activity is needed for normal health on a certain level, thus complete inhibition or blockade is not desirable and can lead to serious side effects.
Conditions associated with up-regulation or excessive activation of NF-kB are numerous and include:
- Ageing (Csizar, et al 2008)
- Allergies (Cousins, et al, 2008)
- Headaches (Reuter, et al, 2003)
- Pain (Tegeder, et al, 2004)
- Cardiac Hypertrophy (Sen & Roy, 2005)
- Muscular Dystrophy (type 2A) (Baqhdiquian, et al 1999)
- Diabetes type I (Eldor, et al, 2006)
- Diabetes type II (Chen, 2005)
- Obesity (Gil, et al 2007)
- High Cholesterol (Wilson, et al, 2000)
- Atherosclerosis (Li & Gao, 2005)
- Heart Disease (Valen, et al, 2001)
- Chronic heart failure (Gong, et al, 2007)
- Stroke (Herrmann, et al, 2005)
- Pulmonary Disease (Christman, et al, 2007)
- Chronic Obstructive Pulmonary Disease (Rahman & Kitty, 2006)
- Kidney Disease (Guzik & Harrison, 2007)
- Gut Disease (Neurath, et al, 1998)
- Endometriosis (Gonzalez-Ramos, et al, 2007)
- Asthma (Pahl & Szelenyi, 2002)
- Arthritis (Okamoto, 2006)
- Crohn’s disease (Pena & Penate, 2002)
- Glaucoma (Zhou, et al, 2005)
- Inflammatory Bowel Disease (Atreya, et al, 2008)
- Inflammatory Lung Disease (Park & Christman, 2006)
- Sepsis (Abraham, 2003)
- Aids or HIV (Hiscott, et al, 2001)
- Autoimmunity (Bacher & Schmitz, 2004)
- Lupus (Okamoto, 2006)
- Stress disease (Bierhaus, et al, 2004)
- Parkinson Disease (Mogi, et al, 2006)
- Multiple Sclerosis (Satoh, et al, 2007)
- Rheumatoid arthritis (Greetham, et al, 2007)
- Alzheimers (Collister & Albensi, 2005)
- Cataracts (Yang, et al, 2006)
- Hearing Loss (Lang, et al, 2006)
- Tendon/ligament injuries (Gumina, et al, 2013)
- Cancer (Lee, et al 2007)
This list is extensive and only abbreviated above. For the complete list and full references, please visit http://www.bu.edu/nf-kb/physiological-mediators/diseases/. It is noted that many different forms of cancer have been correlated with improper regulation of NF-kB and this webpage details many specific forms ranging from breast cancer to bladder cancer with full references.
Activators of NF-kB and Inflammation
There are many activators of NF-kB and often the situation is compounded by multiple factors working together, which include:
- Stress (physical and emotional)
- Cytokines (inflammatory proteins)
- Free Radicals (oxidative stress)
- UV Radiation
- Oxidized LDL cholesterol
- Bacteria and Viruses (ie: LPS and HIV)
- Lifestyle factors (smoking, drinking, lack of exercise, poor diet)
- Genetic risk factors
As we can see, this list is extensive and more often than not, there is more than one ‘activator’ playing into a situation. We can have a person, horse or pet that is experiencing joint degeneration, but is also highly stressed for various reasons and consuming a poor diet. In order to gain full control, one has to address all players in the game.
Inhibitors of NF-kB and Inflammation
There are many inhibitors, natural or pharmaceutical, that have demonstrated efficacy on various levels. In some cases, many medications have demonstrated the ability to inhibit NF-kB, but their original purpose was different such as in the case of certain antibiotics or narcotic pain medications.
There are two things to keep in mind when it comes to any medication or natural substance: safety and efficacy. In many instances, we have medications that ‘could’ inhibit NF-kB adequately and to a desirable level, but the dose needed for those medications could pose problems in regards to safety.
There is also variability in regards to how well those substances or medications inhibit NF-kB, which impacts the end result of cytokine production and gene regulation. In some cases of medications or even natural substances, it appears that inhibition seems to result in less production of one or just a few specific cytokines. We have to remember that the activation of NF-kB isn’t just about the cytokines or inflammatory proteins, but there is also activation of various oncogenes, hormones, cell cycle regulations and even other transcription factors, so the ideal goal would be to get a more ‘broad spectrum’ inhibition keeping safety in mind.
Natural Inhibitors of NF-kB can occur at various levels and are numerous, including:
- Alpha Lipoic Acid (Sen et al, Biochem Biophys Res Comm, 1998)
- Alpha tocopherol (Islam et al, Circulation, 1998, Nov)
- Ashwaghanda (Ichikawa, et al, mol Cancer Ther, 2006, June)
- Beta-Carotene (Bai et al, Exp Mol Med, 2005, Aug)
- Boswellic Acids (Syrovets, et al, J Biol Chem, 2005, Feb)
- Cocoa Polyphenols (Lee et al, J Nutr, 2006, May)
- Coffee (Chung et al, J Agric Food chem, 2007, Aug)
- Cordyceps (Huang, et al, Zhong yao Cai, 2007, Mar)
- Curcumin (Singh & Aggarwal, J Biol Chem, 1995, Oct)
- Green Tea (Yang, J Nutr, 1998, Dec)
- Exercise (Goto, Appl Physiol Nutr Metab, 2007, Oct)
- Gandoderma (Zhang, Life Sci, 2003, Sept)
- Glutamine (Singleton, et al, Shock, 2005, Dec)
- Glutathione (Cho et al, Biochem Biophys Res Comm, 1998, Dec)
- Hyaluron (Yasuda, T. Nakamura, T. Mod Rheumatol, 2007, Oct)
- Melatonin (Li et al, Mediators Inflm, 2005, Aug)
- Milk Thistle (Min, et al, Arch Pharm Res, 2007, Oct)
- Olive Oil (Sangiovanni, Phytother Res, 2012, Oct)
- Pomegranate (Mukherjee, et al, J Nutr Biochem, 2013, Dec)
- Quercetin (Peet, GW. Li, J., J Biol Chem, 1999, Nov)
- Red Wine (Bianco-Colio et al, Circulation, 2000, Aug)
- Spirulina (Ku, Cs. et al, Biochem Biophys, 2013, April)
- Strawberry (Wang et al, J Agric Food Chem, 2005, May)
- Vitamin C (Son et al, Arch Pharm Res, 2004, Oct)
- Vitamin D (Cohen-Lahav, et al. Nephrol Dial Transplant, 2006, April)
- Dandelion (Park, J. Ethnopharmacol, 2011, Jan)
- Parsley (Johnson, Cancer Lett, 2011, June)
A more complete list can be found at: http://www.bu.edu/nf-kb/table-1/
Each natural substance listed above has its own strength or ability to down regulate or inhibit NF-kB, some being stronger and more complete than others. One of the most complete NF-kB inhibitors in regards to safety, efficacy and spectrum is Curcumin, when compared to most others. Again, we have to take into consideration dose used and safety accompanying that dose. In some cases, we could potentially increase the ability of vitamin C to down regulate NF-kB, but it would take considerable dosing which would like be inhibitive, as compared to a substance such as curcumin which has demonstrated ability at a much lower dose. Considering that some substances may demonstrate efficacy but require high doses, it may prove valuable to explore combinations.
One thing to keep in mind with most of these natural inhibitors, is that they often also demonstrate potent antioxidant properties, helping to quench free radicals. Considering this, they can down regulate NF-kB directly, but also indirectly by minimizing free radicals and their activation of NF-kB.
As mentioned before, we also have a variety of medications ranging from antibiotics to pain medications that have been shown to inhibit NF-kB on some level. One popular subset of medications are the non-steroidal anti-inflammatories (NSAIDs), which would include aspirin, ibuprofen, acetaminophen, naproxen, celecoxib (Celebrex®), phenylbutazone and firocoxib (Previcox®). These medications were designed to inhibit or reduce the formation of the COX enzyme which is responsible for production of various proteins termed prostaglandins, which are associated with pain. The COX enzyme is a byproduct of NF-kB activation. In the COX family, we essentially have two subtypes, COX-1 and COX-2. Many medications such as aspirin, ibuprofen and acetaminophen actually are non-selective inhibitors, meaning they inhibit both forms of COX. The problem here is that COX-1 is actually needed for many normal parts of health including the stomach lining and even kidney health. If we block COX-1 to a high degree, then we could see stomach side effects and even kidney problems. So, ideally, we would want to just inhibit COX-2, which is where more selective medications such as Celebrex® for humans and Previcox® for horses and pets comes into theory.
The problem that has developed with these medications is that the dose required to inhibit NF-kB to the degree to reduce COX-2 has posed some potential health issues, especially in the human market. Strict COX-2 inhibitors have shown to increase cardiovascular effects in people, sometimes contributing to heart attacks and death, which is why some of theses medications have been removed from the market. The reasoning behind this is that human vascular endothelial tissue, blood vessels, actually require COX-2 to create an anti-thrombotic effect, which helps to reduce blood clots. If we completely block COX-2, then the blood clot or thrombotic potential is increased, which then contributes to cardiovascular effects.
This has not been demonstrated in horses or companion pets to the best of my knowledge, but overall, the increased expense behind these specific COX-2 inhibitors combined with questionable added benefits and potential side effects lead us to wonder if they are worth it? Side effects of all COX inhibitors exist, regardless of whether we are targeting one form or the other and include stomach ulcers, kidney disease, liver damage , increased risk of bleeding and even cardiovascular effects. The reasoning behind the side effects is that a fairly potent dose is needed for these medications to achieve enough blockade of NF-kB to reduce pain for the patient, and with this we impact normal cellular function. They are so specific and targeted in their actions, that they begin to interfere with normal cellular function.
As I’ve been told before by one of the foremost researchers on Curcumin and NF-kB, “health is about balance from within.”
End Targets or Effects of NF-kB Activation
Activation of NF-kB has many broad reaching effects impacting health on a positive and negative side if overexpressed. These include:
- Cytokines/chemokines (inflammatory proteins)
- Immunoreceptors (immune response)
- Proteins involved in antigen presentation (immune response)
- Cell adhesion molecules
- Acute phase proteins (inflammation)
- Stress response genes
- Cell surface receptors
- Regulators of apoptosis (cell death)
- Growth factors
- Transcription factors and regulators
A complete list of NF-kB gene targets can be seen at: http://www.bu.edu/nf-kb/gene-resources/target-genes/
The bottom line is that activation of NF-kB is directly associated with inflammation and appears to be the primary if not only route in which inflammation is produced in the body.
Chronic Disease and Inflammation
Chronic disease is a common problem almost becoming an epidemic, impacting people and animals. It is actually a part of life and in fact, aging and age related deterioration are directly associated with inflammation and oxidative stress. According to the CDC, as of 2012, over half of all Americans are suffering from one or more chronic diseases, accounting for over 117 million people. This amounts to billions of dollars in medical expenses and lost time at work on a yearly basis. Likely this same number of people are on at least one form of prescription medication. Chronic disease is such a major factor in our society that the CDC has actually created a campaign on preventative measures to reduce the impact, which can be viewed at: http://www.cdc.gov/chronicdisease/pdf/2009-power-of-prevention.pdf
Looking at the research data and coming to the realization that our lifestyle and many other factors contribute to an increased activation of NF-kB, which then contributes to negative effects on our health, we hopefully begin to understand the consequences of our actions and see a need to intervene. We live stressful lifestyles with a diet that is poor in nutrient value, often termed ‘empty calories’, that offers no protection to us and minimal ability to help us heal.
In the horse industry, we often have young horses put into heavy exercise at an early age, enduring high levels of stress and little free time to just be a horse. Bones are still growing and muscles are developing. Often this high level of stress and subsequent inflammation triggers gastric ulcers, attitude problems and lameness conditions that can be extreme, resulting in a life of pain or possibly euthanasia. We seem to fight it with prescription medications, injections of various sorts and heavy doses of pain medications. Could it be prevented in a more correct manner?
How To Intervene Against Inflammation?
Looking at our list of natural inhibitors, most of them can be derived directly from our diet or through supplementation. The key connector here between all of them is that they are naturally occurring and through proper nutrition, it is quite possible to minimize or ward off chronic disease. Some would say that nature actually provides all that we need in regards to health, but we fail to take full advantage. The increase in incidence of chronic disease may actually be directly related to our poor diets full of empty calories, low nutritional value and processed foods, in addition to our stressful lifestyles.
Many people and animals are on NSAID medications to help reduce the impact of joint disease and even various injuries. As discussed before, these medications do inhibit NF-kB, but do so somewhat selectively by reducing the end product of COX (cyclooxygenase) production. One study actually compared the ability of various NSAIDs to natural ingredients on ability to down regulate NF-kB by 50%. In this study, it was determined that the strongest inhibitors based on dosage included Tamoxifen, Celecoxib, Dexamethasone, and then Curcumin. The ninth ranked was phenylbutazone and least potent was aspirin. That same study also evaluated for response in inhibition of 50% tumor cell population of the same ingredients and found the same ranking with Tamoxifen first, Curcumin fourth and aspirin last.(8) This study demonstrates the ability of Curcumin and other natural substances to work on the same level as even the strongest prescription medications, but without the side effects.
Concept and Potential of Synergy:
The bottom line goal, based on what research reveals , is that a more complete down regulation of NF-kB could offer more health protective benefits. Most prescription pain medications being used today are only tackling one small aspect of the inflammatory process, leaving much to be desired and/or gained, and sometimes with side effects.
We are already aware of numerous research papers documenting the ability of these natural NF-kB inhibitors to impact various cancer cell lines, reduce pain and even slow bone degeneration associated with arthritis, but is there potentially more to be gained?(7) One concept to be explored is the combination use of various prescription NF-kB inhibitors with natural occurring substances. Could there be a synergistic effect, taking advantage of both while minimizing risk to the patient while improving the outcome? What about the combination of several natural NF-kB inhibitors? Could it provide more results for the patient than using one alone? We have to remember that in all cases of chronic disease, there are many activators of NF-kB and by just taking one approach, we may not be reaching all that could be accomplished. Oxidative stress is a major component to the inflammatory process, leading to production of free radicals, NF-kB activation and even cellular damage at a DNA level. (10,4) Through the use of NSAIDs or other similar medications, we are doing very little to combat these free radicals. In cases of chemotherapy or even radiation, we are often generating free radicals that are contributing to the inflammatory process and patient decline. Through a combination approach, we may be able to provide more enhanced effects through further NF-kB inhibition but also through secondary antioxidant properties.
In one study, it was noted that combination of Curcumin with Celecoxib provided benefits in osteoarthritis and may allow for reduced dose, which would minimize long term side effects. (6) The combination of Curcumin with Celecoxib was also noted to provide benefits and lowering of dose in cases of myocardial ischemia. (9) In another study, it was noted that Curcumin when combined with methotrexate in experimental arthritis indicated a combined effect on reduction of clinical signs and reduced side effects.(1)
What about the impact on cancer, can synergy occur? If we look at many current cancer therapies, including chemotherapy and radiation, they are often targeting the cancer cell specifically with the goal of elimination through various pathways. All too often, those pathways affect normal cells; which creates massive side effects for the patient. In some cases, we also have cancer cell lines that develop resistance to the chemotherapies or recur likely due to cancer stem cell production, which are usually resistant to traditional measures. What if we impacted the NF-kB pathways known to exist in combination with current therapies?
In one study, Curcumin was noted to increase Tamoxifen sensitivity and increase survival in endocrine resistant breast cancer.(5) The use of natural NF-kB inhibitors helped to resolve side effects associated with Tamoxifen when used as a chemotherapy agent, helping to reverse liver damage, using silymarin, Curcumin and black seed extracts separately.(2) In general, through the use of naturally occurring NF-kB inhibitors, we can essentially minimize the fuel for which the cancer cells craves, which is the inflammatory process. Through the reduction of cytokines or inflammatory proteins, we can potentially reduce the ability of the cancer cell to thrive and also impact various growth factors which may be imparting the cancer cell the ability to resist normal cells death and survive. If we combine this approach with a direct approach such as chemotherapy and/or radiation, then the outcome could potentially be improved for the patient.(3)
The NF-kB transcription factor is one key to inflammation that can be potentially controlled. Think of the disease as being your monthly utility bill. That bill can be cancer, arthritis, diabetes or even an injury. The bill can be high some months and demand control. Feeding that utility bill are numerous appliances, lights, computers and cellular devices, plugged in and consuming electricity. We could manage the power bill by unplugging one device or another, but wouldn’t it be more efficient if we had just one switch that controlled them all? We could completely flip off that switch or inhibit it, or we could just down regulate it by using a rheostat switch that allows us to just reduce to the power to the devices. That is the concept behind down regulation of NF-kB.
It is important for us to understand the scope of inflammation in health and even injury. All too often we are faced with a condition that has progressed to a more severe level, leading us to continue to seek the same traditional options without results. When we understand the scope of inflammation and how this process, when uncontrolled, has likely led to the current health state, then we see the importance of prevention and also seek new options of intervention.
In the end, we have to realize the potential for natural ingredients in regards to our health and that of our pets and horses. Inflammation is the central factor behind many chronic diseases including joint degeneration and even predisposition to injury. We have options and they are many. Science has shown us and now it is up to us to put it into play. A proper, balanced diet and one supplemented with specific herbs, often in combination may just offer us more than we realize. There is still much to learn and discover, but research has given us much to move forward with, we just need to apply it in our daily lives. Cures are hard to come by and may not actually exist, but the overall goal should be to restore health and regain quality of life. This is possible and can be achieved.
Knowledge is power and with understanding, we can help ourselves just a little bit more.
All my best,
Tom Schell, D.V.M.
Nouvelle Research, Inc.
- Banji, D et al. Evaluation of concomitant use of methotrexate and curcumin on Freund’s complete adjuvant induced arthrits and hematological indices in rats. Indian J Pharmacol, 2011, Sept; 43(5); 546-50
- El-Beshbishy, HA et al. Amelioration of tamoxifen induced liver injury in rats by grape seed extract, black seed extract and curcumin. Indian J Exp Biol, 2010, Mar; 48(3): 280-8.
- Garg, A et al. Chemosensitization and radiosensitization of tumors by plant polyphenols. Antioxidant and Redox Signaling, 2005, vol 7, no 11.
- Hyeon, S et al. Nrf2 deficiency induces oxidative stress and promotes RANKL-induced osteoclast differentiation. Free Radic Biol Med, 2013, Dec;63;789-99
- Jian, M et al. Curcumin induces cell death and restores tamoxifen sensitivity in the antiestrogen-resistant breast cancer cell lines MCF-7/LCC2 and MCF-7/LCC9, Molecule, 2013,Jan 8;18; 701-20
- Lev-Ari, S et al. Curcumin syngergistcally potentiates the growth of inhibitory and pro-apoptotic effects of celecoxib in osteoarthritis synovial adherent cells. Rheumatology,2006, Feb 45(2); 171-7
- Ma, X et al. Jolkinolide B inhibits RANKL-induced osteoclastogenesis by supporting the activation of NF-kB and MAPK singaling pathways. Biochem Biopohys Res Commun, 2014, Mar 7:445(2), 282-8
- Takada et al. Non steroidal anti-inflammatory agents differ in their ability to suppress NF-kB activation, inhibition of expression of COX-2 and Cyclin D1, and abrogation of tumor cell proliferation. Oncogen, 2004, 23; 9247-9258
- Wan, X et al. Visualization of network target crosstalk optimizes drug synergism in myocardial ischemia. PLoS One, 2014, Feb 5;9(2)
- Yokota, K. Combination of tumor necrosis factor alpha and interleukin-6 induces mouse osteoclast-like cells with bone resorption activity in both in-vivo and in-vitro. Arthritis Rheumatol, 2014, Jan 66(1), 121-9