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Advances Inflammation Advances


Quenching the Fire Within


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A Double-Edged Sword



chronic inflammation as a factor in the progression of cancer, diabetes, O R T H O M O L E C disease U L A R R E S E A R C H cardiovascular

Inflammation and Disease

Targets of Inflammation Natural Anti-inflammatory Agents O R T H O A MNote O on L Bioavailability E C U L A R R E S E A R C H

Natural Solutions for Inflammation






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Inflammation: A Double edged sword Inflammation and Disease Natural Solutions for Inflammation


Advances in Orthomolecular Research is published and distributed through integrative physicians, health care practitioners, and progressive health food retailers. The content of this magazine is provided for informational purposes only, and is not intended as medical advice for individuals, which can only be provided by a healthcare professional. Contents and design © 2012 AOR. Any reproduction in whole or part and in print or electronic form without express permission is strictly forbidden. Permission to reproduce selected material may be granted by contacting the publisher.
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Advances 3

INFLAMMATION A Double edged sword 4 Advances .

Epidermis (skin) Mast cells produce histamine and other chemicals in response to trauma. and death would result quickly. pain. This initiates the inflammatory response Injury White blood cells called Macrophages move out of the blood vessels and consume bacteria and other cellular debris Blood Vessel Mast Cell Bacteria Plasma Plasma leaks from the blood vessels into the affected area. The body initiates the repair process almost instantaneously upon injury. it is important to discuss the role of inflammation in the body. The Inflammatory response Understanding Inflammation Inflammation is a double-edged sword. Without inflammation. In general. many of which proceed concurrently. there are two distinct categories of inflammation: acute or short term inflammation and chronic or long term inflammation. causing damage to the body and ultimately leading to disease and even death! Whether inflammation will be beneficial or harmful depends on its type and duration. heat and loss of function. If inflammation can be so dangerous. More details about these five characteristics are included in Table 1. It is a highly intricate process that involves a complex cascade of processes. While short term inflammation plays a beneficial role in the body. and many different players including cells and soluble factors (chemicals called chemokines and cytokines) that work synergistically with each other in a very specific manner (see Note: What are Cytokines?). This causes redness and heat Figure 1. redness. These harmful effects will be examined in more detail in a subsequent section. it plays an important and beneficial role in the body. which we have all experienced when we get a cut or a sprained ankle: swelling. First. Each of these characteristics is the result of the body’s efforts to protect the damaged area and to speed up healing and repair. causing swelling and delivering clotting proteins and other healing factors Macrophage Blood vessels dilate. There are five key characteristics of inflammation. The Inflammatory Response: An Overview In a nut shell. long term or chronic inflammation can be very harmful. disease and damage would quickly progress beyond the body’s ability to recover. why does it occur in the first place? Inflammation plays a vital role in the repair process following injury or infection. inflammation is a system of information with multiple check points where a decision making process Inflammation is a double-edged sword. bringing more blood to the damaged or infected site. chronic inflammation can be deadly! Advances 5 . but it can also be very dangerous. While it plays an important role in healing and repair.

cells in the tissue called mast cells will produce certain chemicals. Histamine is a key chemical trigger of the body’s inflammatory response. Chemokines are chemicals that attract cells to other cells or a certain area. The body’s inflammatory response is controlled by the immune system. chemical agents or microbial pathogens. trauma or infection occurs. the interplay must occur. with different cytokines providing different messages to cells about how they should act or react in various situations. where they initiate a specific response. because unlike the body’s specific immune defenses. For example. In this way. In contrast. and is a highly programmed cascade of actions that occurs immediately in order to prevent the spread of pathogens. it acts in a non-specific manner to deal with a wide variety of threats or injuries. When damage. and a movement of 6 Advances . For example. Many interleukins play a very important role in the mediation of inflammation in the body. chemokines are responsible for attracting phagocytes from the blood stream to damaged areas as part of the inflammatory response. Finally. lymphokines are produced by cells called lymphocytes. interleukins and lymphokines. Cytokines act by binding to surface receptors on other cells. It is referred to as non-specific. minimize further damage to cells and tissues and to promote repair and healing. increased permeability of the blood vessel. Cytokines are produced by cells of the nervous system and also by cells of the immune system. a cytokine may cause a cell to start producing certain proteins or molecules. natural anti-inflammatory agents like curcumin have multiple mechanisms and a more balanced effect What are Cytokines? Cytokines are small protein molecules that play a key role in cell signaling. including the inflammatory response. Cytokines can be further broken down into three general categories: chemokines. they act as cellular messengers. The body reacts to challenges like foreign invaders or trauma much in much the same way that a computer makes decisions based on a “yes” or “no” format. especially of different cytokines is involved in the regulation and progression of various cellular responses in the body. Cytokines that play key roles in the inflammatory process are often referred to as inflammatory cytokines. The presence of histamine and other chemical factors causes the initiation of three key inflammatory processes: vasodilatation (widening of the blood vessels) in the affected area. or even to produce more cytokines. including histamine. macrophages.Many pharmaceutical drugs for inflammation target only one mechanism of action. and are generally involved in the body’s immune response. but now this category includes a broad range of different signaling molecules involved in the immune response. instead. that is. and is part of what is called the innate or non-specific defense system. The inflammatory response is initiated as a response to trauma. Cytokines may also be inhibitory and reduce the production of proteins or other cytokines. Interleukins (abbreviated as IL) were initially described as cytokines produced by leukocytes. it does not target specific viruses or pathogens.

when should we intervene? For example. fibroblasts Tissue destruction.term inflammation The inflammation process is highly complex. For example. monocytes. the inability to move a body part like a sprained ankle. plasma cells. Finally. causing plasma to leak out of the blood vessels and into the affected area. but the main purpose of this is to supply more immune system cells and other factors to aid in healing and repair. The reason for this leakage is that the plasma contains proteins and other factors that are critical for the initiation of healing. and even obesity. disease Onset Duration Cells Involved Immediate A few days neutrophils (primarily). This chronic inflammation is not beneficial. and it continues on in a long term cycle of chronic inflammation. The injured area is warm to the touch since more blood is being delivered. Next. scientists and physicians are beginning to understand that there is a very real need to bring a stop to this long. the inflammatory response is then complete. heart disease. 4. many diseases have now been linked Table 1. Serves as a warning signal to help prevent further injury. among others! Although acute inflammation is a vital process. For example. or autoimmune reactions Delayed Up to many months or years monocytes. diabetes. Vasodilation of the blood vessels in the affected or damaged area brings more blood to the affected area. 2. the key question is: at what stage does the balance tip? When does inflammation turn from being beneficial to harmful? And most importantly. and can impede the function of joints or muscles. if one were to intervene immediately upon the onset of inflammation. white blood cells called phagocytes will move out of the blood vessels and migrate to the affected site. This causes swelling or edema. it can actually cause even more damage and can eventually contribute to the development of various diseases. for example. theoretically Advances 7 . leading to eventual healing. The same process that the body uses to defend itself during short-term inflammation backfires when it becomes chronic and ends up harming the body. The Five Key Characteristics of Inflammation 1. liver disease. Loss of Function Table 2. The above description outlines how inflammation is initiated and progresses. macrophages Healing. abscess formation or chronic inflammation Outcome The same process that the body uses to defend itself during short-term inflammation backfires when it becomes chronic and ends up harming the body to inflammation. in general. persistent foreign bodies. we can think of inflammation as being divided into short-term and long-term types. This is generally temporary and is a precautionary measure to allow the damaged part to heal quickly. and things go back to their normal state. stroke. If short-term inflammation is beneficial and long term inflammation is unhealthy. the walls of the blood vessels become more permeable. can lead to pain due to increased pressure. 3. Comparison between Acute and Chronic Inflammation Acute Inflammation Cause Pathogens. in some cases the inflammation process does not stop. basophils . lymphocytes. In most cases. Caused by increased blood flow to the area.white blood cells from the blood to the damaged area (Figure 1). This occurs as the body tries to improve its defenses at the site of injury by delivering the key cellular players and soluble factors to initiate repair. as well as cleaning up dead cells and other cellular debris during the healing process (Figure 1). macrophages. These important immune system cells will consume and destroy bacteria and pathogens in the infected area. It is much like an army that turns on the citizens and the country it was meant to defend! In fact. eosinophils. Swelling Pain Redness Caused by an accumulation of fluid and pus called edema. Also raising the temperature acts as a defensive measure by eliminating and/or preventing infection. Heat 5. the plasma contains clotting proteins and other proteins that stimulate the body’s immune system to destroy bacteria. however. However. injured tissues Chronic Inflammation Persistent acute inflammation. This causes redness and heat. although this short-term inflammatory process is essential for healing and repair.

been withdrawn from the market. meaning that they usually have only one mechanism of action. Whilst these markers do not provide a perfect solution. Fortunately. In fact some of these drugs. have 8 Advances . like Vioxx for example. that a certain checkpoint has been reached and will proceed with a specific course of action based on this information. natural products often have multiple mechanisms of action. Unfortunately. Treating Inflammation In the pharmaceutical world we have a class of drugs called non steroidal anti-inflammatory drugs (NSAID’s) that are often used to treat inflammation. biological chemistry comes to the rescue as various biomarkers or “markers of inflammation” have been identified that can be used to help us make this decision. COX. would be preventing the body from doing its job of protection! This is where the checkpoints come in. heartburn and even kidney or cardiovascular complications. These include drugs like the commonly used overthe-counter ibuprofen or the more powerful COX-2 inhibitors like Celebrex. LOX. including gastrointestinal problems or bleeding. they are a Fortunately. dealing with only one pathway will never address the situation effectively. the natural world offers powerful and effective yet safe alternatives which can meet the challenges of inflammation. Fortunately. the body’s immune system will decide. It is these check points that ultimately determine the fate of the inflammatory process. Measurement of various biomarkers like NF-KB. This is important because inflammation is a process that acts through numerous pathways. Generally. Unfortunately. natural products tend to be less potent but more “balanced” in their action because they often contain additional molecules that support the major compounds in performing their actions. the natural world offers powerful and effective yet safe alternatives which can meet the challenges of inflammation very useful aid in making the decision of how and when to intervene with treatment for an inflammatory condition. no definite signs or symptoms have been identified that could be used to indicate that a critical checkpoint has been reached and that the balance is about to tip from beneficial to harmful inflammation. Therefore. the more effective the treatment is likely to be. it is not going to put out all of the fires. This knowledge would certainly make the lives of physicians much easier as they would be better able to identify at what precise point to intervene. the more pathways that are blocked. At some stage in the inflammatory process. these drugs are associated with many unpleasant side-effects. which is the great orchestrator of the inflammatory process. IL-6 and others (which will be discussed in greater detail in a later section) as well as the presence of various cells and inflammatory gene products are useful markers that are used in the decision of when to act in the treatment of inflammation. Moreover. as of now. based on the evidence available and feedback from key cells. Unlike the pharmaceutical drugs that act solely on a “silver bullet” model. These checkpoints involve feedback and actions from the body’s immune system. Several natural solutions for inflammation and their mechanisms of action are discussed in detail in a later section of this magazine.

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Since then over 200 billion dollars have been spent.000 versus 193. cardiovascular disease and Alzheimer’s disease. however. colon (colitis). infections. diabetes. in the 1860’s this link between inflammation and cancer was considered too bold and largely went ignored. studies conducted in large groups of people have reinforced Virchow’s original observation suggesting a strong relationship between stimulators of inflammation and cancer. These epidemiological studies have identified stimulators of inflammation in the form of chronic irritants like tobacco smoke. inflammation of the bronchus (bronchitis) due to the constant irritation from tobacco smoke can lead to cancer of the lung. together with long standing tissue injury invoked inflammation that ultimately led to cancer. a diet high in fats or sugar. Research has now identified chronic inflammation as a factor in the progression of cancer. red meat. various heavy metals. Unfortunately. He based his hypothesis on the fact that certain irritants. A summary of the cancers linked to chronic inflammation is listed in Table 3. Additionally. This appropriation led to the creation of the National Cancer Institute (NCI). For example. and we and liver (hepatitis) leads to cancers of these tissues. all of the damaging stimuli listed above could contribute to chronic inflammation. hormonal insult like excess estrogen exposure post menopause.9 per 100.855 studies in mice reported. Similarly. Let us make a total national commitment to conquer this dread disease.000)! Hopefully. other stronger NSAID’s have been shown to prevent the metastases or spread of certain forms of cancer. grilled food. however. radiation and many more.56 million papers published. There is a significant body of evidence demonstrating that chronic inflammation over a long period of time (20-30 years) can lead to cancer. along with many others! The link between inflammation and these diseases is discussed in the following sections. but has also been strongly linked to the development of stomach cancer. cancers are a chronic disease caused by the prolonged exposure to a long list of damaging stimuli. alcohol. For example.Inflammation and Disease More and more studies are showing the potentially damaging effects of chronic inflammation and its link to the development of various serious chronic diseases. These stimuli can include: infections or toxins like aflatoxin. Similarly. research will continue. UV light. Now it is time we become the healthiest nation in the world”. the bacteria Helicobacter pylori which is widely present in the stomach of most people world-wide and has a propensity to burrow its way into the lining of the stomach wall. Other chronic infections and/or inflammation like inflammatory bowel disease (IBD) also increase the risk of cancer of the colon. solvents and trauma as major risk factors in various types of cancer. Recently. 1. and 150. stress. is not only a primary contributor to the development of ulcers. chronic irritation from tobacco smoke. fried foods. will move closer to finding the key to this deadly disease. alcohol. inflammation of the bladder (cystitis). the human papilloma virus has been linked to cervical cancer and chronic viral hepatitis B and C (HBV and HBC) infections have been identified as major risk factors for a specific liver cancer called hepatocellular carcinoma. In fact. In the early 1860’s the renowned German pathologist Rudolf Virchow mentioned that certain cancers seemed to occur at sites of chronic inflammation. In spite of this. 10 Advances . There is evidence that chronic inflammation is an important contributing factor. carcinogens or asbestos exposure. esophagus (esophagitis) Inflammation and Cancer In his 1971 State of the Union address President Richard Nixon pledged “I will ask for an appropriation of an extra $100 million to launch an extensive campaign to find a cure to cancer. esophagus and stomach cancers. In general. In fact it is estimated that approximately 15-20% of all human cancers are linked to infection and/or inflammation! Perhaps the best evidence for the significance of inflammation during cancerous growth comes from long term users of aspirin and non-steroidal anti-inflammatory drugs. Recent data indicates that these drug users reduce colon cancer risk by 40-50% and they also may be preventive for other cancers including lung.4 per 100. America has long been the wealthiest nation in the world. the US cancer death rate was the same in 2002 as it was in 1950 (193.

overlap considerably and involve various players like initiating compounds. Cancers Linked to Chronic Inflammation (Adapted from Maeda and Omata. angiogenesis (formation of blood vessels so that the tumour can be continually fed and grow). Cancer is a multistage process defined by at least three main stages: initiation. how is inflammation linked to cancer? What is the mechanism of action? Which cellular processes are involved? If we can understand these things then perhaps we can use specific nutrients to target the key molecules or mechanisms that are involved in the development of cancer. while distinct. it has been shown that certain antiinflammatory agents like the nonsteroidal anti-inflammatory drugs (NSAID’s) reduce chronic inflammation and thus reduce the incidence of various cancers. For example. growth factors and hormones. radiation. signaling molecules. Table 3. However. A malignant tumor forms.Inflammation is rightly regarded as a “secret killer” in diseases such as cancer. and their actions in the body and their contribution to inflammation and cancer initiation are shown in Figure 3. A list of these various signaling molecules. some of these NSAID’s are themselves harmful. producing more mutated cells PROGRESSION Mutation and rapid division continue. it has been noted that NF-κB is raised in every Advances 11 . and metastasis (spreading of cancer to distant sites). viruses) causes DNA damage and mutation PROMOTION The mutated cell is stimulated to proliferate rapidly . These molecular players are legitimate targets for the anti-cancer effects of various nutrients. growth factors and other key players linking inflammation and cancer are described in Table 4. invasion. including cellular transformation (where cells change their look and behaviour). The Stages of Tumour Development Inflammation can work both ways with short term inflammation being protective and having anti-cancer effects. chemokines. Eventually can spread to other parts of the body by metastasis Figure 2. Mesothelioma Esophageal Cancer Pancreatic Cancer Colon Cancer Melanoma Infection Related Conditions Tuberculosis Chronic Gastritis Chronic Hepatitis Mononucleosis Chronic Cervitis Non-Infection Related Conditions Asbestosis Reflux Esophagitis Chronic Pancreatitis Inflammatory Bowel Disease Skin Inflammation Causative Agent Mycobacterium tuberculosis Helicobacter pylori Hepatitis B or C virus Epstein-Barr virus Papilloma virus Causative Agent Asbestos Gastric Acid Alcohol Ulcerative Colitis Crohn’s Disease UV light NORMAL CELL MUTATED CELL MALIGNANT TUMOR INITIATION A Carcinogenic Agent (chemicals. These stages can then be further subdivided into various steps. this begs the question. and progression (Figure 2). and cause side-effects like gastric irritation and liver and kidney toxicity. However. For example. which plays an enormous role in inflammation and is discussed in greater detail in the next article. Unfortunately. promotion. survival. as well as various cytokines. it is possible that certain natural compounds could target such pathways without having the associated sideeffects and thus could be used to help prevent or reduce the incidence of cancer. It is clear that there is a link between the two. These stages. growth factors and numerous other mediators in a complex role play that links chronic inflammation to all of these stages. promotion. 2008) Tumour Type Lung Cancer Gastric Cancer Hepatocellular Carcinoma Lymphoma Cervical Cancer Tumour Type Lung Cancer. proliferation (multiplication of cells). The intent of many natural products is to reduce chronic inflammation by targeting one or more of the above pathways that involve numerous inflammatory players including NF-κB. while long term inflammation can cause cancer.

protect transformed cells from apoptosis. Bharat Aggarwal of The University of Texas M. angiogenesis.. Promote tumour growth. vitamin C and many others. induced by proinflammatory cytokines. In fact. early physicians remarked that the high sugar content of the urine produced by diabetic patients could be used as a diagnostic marker of the disease. Those most critical to the development of type-2 diabetes are shown in Table 5. kidneys and blindness. The insulin producing cells are called Beta cells and they are located in the islets of Langerhans in the pancreas.D. NF-κB has been associated with every known carcinogen and has also been linked Inflammation and Diabetes The association between a reduced production of insulin and type-2 diabetes has been considered the hallmark of this condition. and metastasis Activated by pro-inflammatory cytokines. According to Aggarwal all roads to cancer go through this single molecule! Several lines of evidence points to the key role NF-κB plays in inflammation and cancer. kidneys and the central nervous system. Facilitate invasion and metastasis by directing tumour cell migration and promoting basement membrane degradation Mediate inflammation. regulate angiogenesis and metastasis Produce inflammation mediators. protect against DNA damage Regulate pro-inflammatory cytokine expression. Furthermore. feedback loop between proinflammatory cytokines Downstream of NF-κB and pro-inflammatory cytokines. Several theories have been proposed to help explain why some individuals develop inadequate insulin production and insulin resistance. anti-apoptotic activity. There are several factors that may induce chronic inflammation in the body. Aggarwal is convinced that NF-κB is the key culprit in cancer. After thirty years of research. apoptosis resistance. tumour invasion. 2006) Molecule IL-6 (cytokine) TNF-α (cytokine) Chemokines Function linking Inflammation to Cancer Promote tumour growth Induce DNA damage and inhibit DNA repair. Texas is one of the foremost researchers on NF-κB and its association with cancer. nephropathy and neuropathy which results in damage to the nerves. One of the most credible of these theories is inflammation. like those in the eyes. Induce angiogenic factors Promote tumour cell growth. Insulin resistance is a condition in which insulin becomes less effective at lowering glucose levels in the body even when it is present at normal levels. required in cell transformation with other inflammatory mediators like COX-2 and 5-LOX enzymes. and immune tolerance Anti-inflammatory activity.Table 4. induce DNA damage. Furthermore. Type-2 diabetes is associated with a number of long term consequences including atherosclerosis or hardening of the blood vessels which leads to poor circulation and a loss of vessel elasticity as well as eventual heart disease and high blood pressure. promote cell proliferation. vitamin E. The net result of this is that glucose is excreted into the urine. and metastasis Promote chronic inflammation. Anderson Cancer Center in Houston. In diabetic patients. type-2 diabetes is not only associated with a decreased production of insulin but also with a more recently discovered phenomenon called insulin resistance. However. with especially strong links to cancer. flavonoids. 12 Advances . All these findings provide compelling evidence that NFκB is likely a major mediator of cancer. promote proliferation. these Beta cells are either destroyed during the course of the disease and/or are unable to be regenerated quickly to produce sufficient quantities of insulin to handle the body’s requirements. promote production of mutagenic reactive oxygen species. tumour necrosis factor (TNF) and others. causing retinopathy. promote tumour invasion and metastasis. This reduction in insulin production causes an inability of insulin to transport sufficient quantities of glucose from the blood and into the tissues. The link between inflammation and type-2 diabetes has become increasingly strengthened by the results of numerous scientific studies in both animals and humans. promote chronic inflammation. NF-κB levels are dramatically reduced by anticancer agents like natural polyphenols. contribute to angiogenesis. Key Molecular Players Linking Inflammation to Cancer (Adapted from Lu et al. diabetes can also affect smaller vessels. lycopene. NF-κB iNOS COX-2 HIF-1α STAT3 Nrf2 NFAT inflammatory condition.

(Adapted from Lu et al.IL-6) Chemokines Hypoxia (Low Oxygen) Other Inflammatory Mediators (e.Microbial Infection. and is thought to play a major role in the development of cancer. NF-κB. Summary of mechanisms for the involvement of inflammation in cancer development. For more information see Table 4. 2009) Advances 13 .g. NF-kB.. (Adapted from Ralhan et al. IL-1. a key inflammation inducing molecule is activated by a large number of carcinogens. Chemical Irritation. NFAT. STAT3) HIF-1α Resolution of Inflammation DNA Damage & Mutation iNOS and COX-2 Inflammatory Environment in the Body Tumour Initiation Tumour Promotion Tumour Progression Tumour Invasion & Metastasis Figure 3. Injury Acute Inflammation Chronic Inflammation Reactive Oxygen Species Inflammatory Cells Pro-Inflammatory Cytokine (e. TNF-a. 2006) Carcinogens that Activate NF-κB Infectious Agents Helicobacter pylori UV Diesel Ozone Papilloma virus Hepatitis B or C virus Epstein-Barr Virus Obesity Stress Drug Use NF-κB Heavy Metals DBMA Radiation Cigarette Smoke Alcohol Poor Diet TNF IL-1 IL-17 IL-18 H2O2 PMA Inflammatory Agents Figure 4.g..

Toxic effects of excess glucose in the body. leading to cellular death. The second strong evidence of a link between inflammation and type2 diabetes comes from biopsies of various tissues that show clear evidence of inflammatory cell involvement. These deposits cause both destruction of the insulin producing Beta cells and also prevent regeneration of the pancreatic tissue. Glucotoxicity Lipotoxicity Despite the overwhelming evidence of the involvement of inflammation in diabetes. Can cause tissue damage and disrupt the uptake of glucose by the cells. these studies have shown that the higher the levels of these inflammatory markers. it has been argued that raised levels of these inflammatory biomarkers indicated that inflammation also results in the activation of the immune system. the difference is that the primary cause of an autoinflammatory disease is inflammation. If inflammation is in fact a cause of diabetes. it remains uncertain whether inflammation is a cause of the disease or whether it is a resulting symptom. as with cancer. In particular. Treatments to Reduce Inflammation in Type-2 Diabetes Evidence for the role of inflammation in type-2 diabetes is quite strong and new treatments that block the activation of various inflammatory markers like NF-κB or interleukin are actively being developed. which may then actually attack various tissues of the body. much like the plaque that get deposited in the arteries. which are so common in biological science. Moreover. then we must examine the mechanisms by which this occurs. The strongest is data from both animal and human studies that shows raised levels of key inflammatory markers like C-reactive protein (CRP) or certain interleukins like IL-1B or IL-6 in patients or animals with Type-2 diabetes. 2. Diabetes specialists call this auto-inflammatory disease which is similar to an auto-immune disease in that it results in the body attacking its own tissues. inflammation may be initiated by excessive nutrients like glucose or free fatty acids that can activate the immune system (see Table 5). Multiple mechanisms may contribute to increased inflammation in type-2 diabetes.Table 5. Causes of Inflammation Linked to Diabetes 1. how can inflammation cause type2 diabetes? Research in this area has suggested that inflammation may lead to diabetes by causing cell death and by creating hypoxic conditions. this means that inflammation causes an environment in which the tissues are literally starved for oxygen. the most extensively studied of these in diabetes is the NF-κB pathway. some of which are quite general and others that are highly specific. It is a classic case of a chicken or the egg scenario. Toxic effects of excess fats and increased concentrations of free fatty acids that may cause cell death. Research is beginning to show that an antiinflammatory approach to treatment of the disease seems to lower blood glucose levels and improve insulin release as well as helping to limit the damaging effects that ensue. 14 Advances . 4. the greater the chance the individual has diabetes. There are a large number of biochemical pathways and molecules that are implicated in the inflammatory process. In the pancreas. anti-inflammatory treatments appear to be very helpful for reducing the glycation of hemoglobin (also referred to as HbAC1) which is a commonly used marker for diagnosing diabetes. Plaque-like deposits can form in the pancreas. Oxidative Stress Oxidative stress in the pancreas and/or cellular organelles like the endoplasmic reticulum (ER) results in highly reactive oxygen and nitrogen free radicals which damage the tissue in a chain reaction or domino effect process. however. Glycation is a major factor There are several lines of evidence that implicate inflammation in the development of diabetes. Plaque 3. In fact. That is.

In the case of blood vessels. This may be maintained if diet and lifestyle factors are improved. which can eventually rupture. and a large number of cardiovascular complications including high blood pressure and heart attacks. This narrowing can greatly restrict blood flow. Conditions included under the umbrella of Cardiovascular Disease include: heart failure. or large blood clots. the lipid core can grow. The resulting effect is that glucose molecules bind to various proteins in the body like hemoglobin or other proteins in the plasma. This plaque can then lead to further damage to the vessels. Libby was studying atherosclerosis. In the Advances 15 . resulting in a thinning of the fibrous cap. Inflammation and Cardiovascular Disease Cardiovascular disease includes a spectrum of closely related conditions associated with the heart and circulation and is the leading cause of death in the western world. fibrous wall and a narrowed blood vessel. At this point. heart attacks. Initially the artery enlarges in an outward direction to accommodate the increasing fat build-up. These effects can lead to increased blood pressure and an increased incidence of vessel rupturing. Glycation is a chronic condition brought upon by consistently high levels of glucose in the blood. glycation may result in a weakening of the blood vessel walls or a reduction in elasticity. which changes the structure and therefore the function of the protein. Many of these studies validate the potential of targeting inflammation as a therapeutic approach to treating type-2 diabetes and support a causative role of inflammation in this disease. high blood pressure and the formation thrombi. When the plaque ruptures. resulting in conditions like angina (Adapted from Libby. resulting in a thickened. blood flow is largely maintained (stabilized plaque). Obviously more work is needed to test the effects of either single antiinflammatory compounds or cocktails that will target the various pathways of inflammation involved in diabetes to achieve improved results. Nevertheless. there is ample evidence of a significant role of inflammation in type-2 diabetes as either the underlying cause or a resulting symptom that needs to be addressed. The thrombus may also be resorbed into the blood vessel wall. which are the primary cause of stroke. blood that contact it will start to clot. When a protein is glycated it becomes warped. tissues or blood vessels. in the development of diabetic complications. If the thrombus blocks the flow of blood through the vessel a heart attack can occur. angina. for example. 2002). Peter Libby of Harvard Medical School was among the first researchers to uncover a connection between inflammation and cardiovascular disease (CVD). resulting in the formation of large blood clot or thrombus. The glycation of hemoglobin can be a major problem in diabetes. In early plaque formation the recruitment of inflammatory cells and the accumulation of fat leads to formation of a lipid core in the artery. if inflammatory conditions persist. However. The use of anti-inflammatory compounds in the treatment of diabetes has also been shown to improve the release of insulin by the Beta cells.Normal Artery Blood vessel lining (endothelium) Smooth muscle cells Healed Ruptured Plaque Reduced blood flow Fibrous vessel wall Early Plaque Formation Stabilized Plaque Thick fibrous cap Small lipid core Blood flow normal Vulnerable Plaque Thin fibrous cap Large lipid core Many inflammatory cells Heart Attack occurs Fibrous Cap Plaque Ruptures Blood clot (thrombus) forms Figure 5. a condition that results in hardening of the arteries due to the accumulation of plaque in the blood vessels.

is largely responsible for the development of atherosclerosis. For example. researchers still lacked a clear understanding of the sequence of events involved in the initiation of atherosclerosis. a key component of atherosclerotic plaque Cytokines stimulate proliferation of blood vessel muscle cells. which is a large molecule that in and of itself is not harmful. becoming foam cells. were the first cells to arrive at the scene of blood vessel damage. Libby then pieced together the events of atherosclerosis. For example. In piecing together this sequence of events. Based on this initial observation. which enter the vessel wall and become macrophages Macrophages induce inflammation. most researchers had accepted that there is a connection between high fat intake and atherosclerosis. expanding the artery around the growing plaque A fibrous cap forms. The first step of atherosclerosis involves cholesterol. They Produce inflammatory cytokines and attract more immune cells. it was found that the type of fat intake is also important. like macrophages. leading to clot formation and heart attack Figure 6. However. Libby noted that immune system cells associated with inflammation. and has an important role in the healthy functioning of the body. Inflammation continues. testosterone and stress hormones) 16 Advances . the plaque may rupture. Eventually.Blood Vessel Interior of the Blood Vessel Endothelium (blood vessel lining) Monocyte Fibrous Cap Oxidized Cholesterol Macrophage Foam Cell Lipid core of plaque INFLAMMATION Cytokines Muscle Cells Cholesterol is oxidized and activates the immune system. They consume cholesterol. Later. much like a forensic scientist solving a crime. the consumption of saturated fats and especially trans fats. The cellular basis of inflammation in the development of atherosclerosis 1970’s. attracting monocytes. cholesterol plays an important role in the synthesis of various hormones (like estrogen.

unstable structure that can rupture. In the midst of this battle. These cholesterol filled macrophages are called “foam cells” and form the fatty lipid core of the plaque. The muscle cells in this layer respond to the aggressive expansionist behaviour by multiplying further. Libby’s major contribution was to link high levels of various inflammatory markers like C-reactive protein (CRP) with the extent of inflammation and the extent of vascular damage. where they are a component of the cap covering the lipid core of the plaque. These cells then migrate into the walls of the vessel. Overall. consisting of a collection of fat laden inflammatory immune cells like macrophages. and transform into macrophages which initiate the body’s inflammatory response and begin to devour cholesterol molecules. Inflammation plays a role at every stage in the progression of atherosclerosis. When plaque rupture occurs. there are usually many affected areas. like the blood vessels. When the immune system detects this aberrant and “nonself ” form of cholesterol building up in the blood vessels it acts quickly to send the various immune cells into action. These free radicals include reactive oxygen and nitrogen species that commonly lurk in areas of the body that experience high levels of stress. leading to the formation of a blood clot. this happens at areas where the cap is thinnest. even more immune cells infiltrate the region of plaque formation. which results in these capsules being formed in many areas along the walls of the blood vessels. and also release various inflammatory cytokines. This process transforms the stable plaque into a vulnerable. This connection between inflammatory markers and cardiovascular disease progression provides a series of predictive markers that may be able to be used to help identify patients with plaque build-up and the beginning stages of atherosclerosis earlier. Unfortunately. This series of events suggests a connection between a chronic state of inflammation and the progression of atherosclerosis.and is an important component the membranes lining the cells of the body. The details of plaque formation in the arteries are shown in Figure 5. Immune cells also act to cordon off the foreign cholesterol molecules by forming a fibrous capsule around the lipid core to help prevent it from spreading to other areas. resulting in a continuing loop of increasing inflammation. Unfortunately. These immune cells exhibit signs of activation and release various inflammatory cytokines. the cholesterol filled foam cells begin to burrow deeper into the vessel wall and into the muscle layer around the blood vessel. very early atherosclerotic lesions are almost purely inflammatory in nature. At this point. It is this damaged cholesterol that is the “bad” cholesterol that gets deposited on the walls of the blood vessels as a fatty build-up. which in turn can cause a heart attack and possible death. These areas tend to be highly abundant in activated immune cells which produce high levels of inflammatory molecules and various enzymes that can weaken the cap and activate cells in the core. Eventually. When it is attacked by free radicals cholesterol becomes oxidized or nitrated. the plaque can rupture. As atherosclerosis progresses. other immune players send out signals to recruit more cells and immune system factors to the site of damage. called monocytes to latch onto the walls of the blood vessels. The damaged or oxidized cholesterol causes immune system cells. meaning that an oxygen or nitrogen atom is added to the molecule. the cholesterol molecule has a number of protruding arms called hydroxyl groups that are especially susceptible to damage by highly reactive molecules called free radicals. In fact. allowing treatment to give at a an earlier stage Advances 17 . leading to thrombosis or clot formation.

Lindahl and colleagues found that in patients with unstable coronary artery disease. especially in patients with very high levels to start with. The other possible contributing cause of AD are specific ‘tau’ proteins called neurofibrillary tangles (NFT) which also form around nerve cells. Research has clearly shown that elevated inflammatory markers are associated with increased cardiovascular risk among healthy individuals as well as those at higher risk. The value of these predictive. one of which is called amyloid beta peptide (Aβ). inflammatory markers has been shown in a variety of studies. Once formed. various prescription drugs that are used to treat various aspects of cardiovascular disease. in the blood (Adapted from Lindahl et al. For example. This small. levels of the inflammatory marker CRP was directly and strongly related to the long-term risk of death from cardiac causes (see Figure 7). between a quarter and one third of all individuals will develop AD. aspirin. Inflammation and Alzheimer’s Disease Alzheimer’s Disease (AD) is a devastating and a progressive degenerative disease of the central nervous system that dramatically affects both the patient and their caregivers. Proponents of the Aβ theory are jokingly referred to as “Baptists” while 18 Advances . like statins. Furthermore. An enzyme called BACE1 breaks down APP into smaller subunits. These Aβ aggregates produce a plaque-like deposit around the nerve cells in the brain. How does Alzheimer’s disease Develop? Amyloid-beta precursor protein (APP) is a protein molecule composed of around 700 amino acids and is located in within the membrane of nerve cells. It is estimated that by the age of 85. Over two thirds of all cases of dementia (memory decay.Figure 7.. diminished reasoning and personality changes affecting all areas of daily living) are associated with AD. multiple Aβ join together to form large aggregates that are even more aggressive and damaging. a marker of inflammation. 42 amino acid subunit is thought to be one of the major contributors of to the development and progression of Alzheimer’s disease. much like a cholesterol laden plaque in the blood vessels forms and causes atherosclerosis or damage of blood vessels. fibrates and ACE inhibitors have also been shown to have the effect of reducing levels of various markers of inflammation. 2000) of the disease. Probability of death from cardiac causes in relation to the level of C-reactive protein (CRP).

This provides an explanation for a variety of epidemiological studies Amyloid β Accumulation and Plaque Formation Oxidative Damage Inflammation Failure of Phagocytic clearance Dysfunctional signal transduction NFT Accumulation Neuron Loss Synapse Loss Glutamate Accumulation Cognitive Decline (memory loss. Whether the main cause is Aβ or NFT. In the end. The role on inflammation in Alzheimer’s may be even more nefarious than initially thought. one significant problem encountered in AD is that the Aβ is not cleared rapidly enough by the body’s phagocytes. as previously discussed. cognitive deficits. cells or other debris. 2010) in humans that have shown that individuals using NSAID’s over a long period of time have a reduced risk of developing Alzheimer’s disease. the net result is the destruction of the nerve cells. chronic inflammation combined with the generation of damaging free radical species and the destruction of synapses or “connections” between the nerve cells ultimately leads to the degeneration of the neural circuitry. Advances 19 . They also found that it revved up an entrance transporter that actually transported more Aβ into the brain! When the mice were given the NSAID indomethacin. depression) Figure 8. The role and actions of curcumin and other natural anti-inflammatory agents are discussed in detail in the next article in this magazine. they found that the key was inflammation! When they induced inflammation in healthy mice they found that it turned off the transporter that lets Aβ exit the brain into the bloodstream. this chronic inflammation is likely to significantly exacerbate the pathogenesis of the disease. When this transporter malfunctions. when the researchers looked further into what actually caused the transporter to malfunction. the chronic use of NSAID’s comes with its own risks and side-effects. A theoretical progression of events involved in this process is shown in Figure 8. Both Aβ plaque formation and the formation of NFT are thought to stimulate localized and chronic inflammation around the affected nerve cells. and a loss of neurons and functional neural synapses. leading to AD. the transporters went back to their normal functioning. However. For example. A recent study in humans has shown that the combination of curcumin and vitamin D was able to enhance the clearance of the Aβ by phagocytes. A hypothesized sequence of events in the development of Alzheimer’s disease (Adapted from Frautschy and Cole. New research shows that not only is inflammation a contributor to the progression of the disease. Over many years. the result is that Aβ accumulates in the brain. However. These specialized white blood cells have the ability of engulf and eliminate foreign molecules.those in the NFT camp are referred to as “Taoists”. it may actually be one of the main causes! Two studies conducted at the Saint Louis University School of Medicine have suggested that AD occurs due to a malfunction in a transporter protein that is supposed to clear Aβ across the blood brain barrier and out of the brain. agitation. An interesting aspect of the study is that the two nutrients were synergetic. The good news is that some natural products are also beginning to show considerable promise for reducing inflammation and other symptoms associated with AD. 2009). meaning that the effect t together was greater than the sum of their individual effects on Aβ clearance (Masoumi et al. The progression of Alzheimer’s disease is also accompanied by the eventual loss of brain volume or atrophy.

which means that the control of inflammation presents a huge challenge to scientists and physicians. chemokines. Molecular Targets for Anti-inflammatory Action Natural Solutions for Inflammation As a primary defense system of the body. Much debate rages. This results in chronic inflammation. With this subunit (called IKK) disabled. microbial infections. which is associated with a whole range of diseases from Alzheimer’s disease to Systemic Lupus Erythematosus and even obesity (see Figure 10). tobacco. and cyclooxygenase (COX enzymes). dietary factors like foods with a high glycemic index foods or high in saturated fats. the failure of this usually carefully controlled process to stop when it should. certain foods or cosmetics. The inflammatory process is highly complex and proceeds in a manner that can be described as a dominolike process. Enzymes in general act to speed up or modify the function of their target. alcohol. NF-κB is free to initiate inflammation by reading 20 Advances . or a combination of these two factors. however. It must be remembered. It is unclear at this stage whether inflammation is the cause or the consequence. The way in which each of these can be targeted to control inflammation is discussed below. research has revealed that there are a number of cracks in the inflammatory armour that can be targeted for therapeutic purposes. The interplay between these players is not completely understood. Short term inflammation is selflimiting and stops as quickly as it starts once healing and repair is under control. Typically PKs achieve their action through a process called phosphorylation. burns and many more (See Figure 9). swelling and pain. tumour necrosis factor (TNF). stress. which means that they add a molecule called a phosphate group to their target. but the end result is the classical signs of inflammation. growth factors. This can occur due to continuous provocation or exposure to inflammation-inducing stimuli (like those shown in Figure 9). These stimuli can include UV radiation from excessive sun exposure. cuts. Protein Kinases (PK) Protein Kinases are a very large family of enzymes including several hundred different but related enzymes. The inflammatory response consists of a series of events that involve many players including various cells (mainly white blood cells). it is PKs that are responsible for de-activating a particular subunit of a key mediator of inflammation called NF-κB. However. various allergens like pollen. namely heat. hormones and the nervous system. the association is very strong. there are many more possible targets and the whole process is a biochemist’s nightmare with intricate and often seemingly conflicting interactions and roles between a huge number of molecular factors and chemical signals. Nevertheless. harmful chemicals. some well-known inflammatory targets include: protein kinases (PK).plus the (usually temporary) loss of function of the tissue in question. Generally these include certain molecules that play key roles in the progression of inflammation. and PK enzymes are no different. free radicals or radical oxygen species (ROS). leading some researchers to state that “All roads to chronic diseases lead through inflammation”. For example. Currently the intricate and complex process of inflammation is far from being completely understood. The process of phosphorylation changes the structure and thus the function of the enzyme’s target. inflammation is critical in both healing and repair following exposure to a wide array of diverse stimuli. that these represent only a few players in the inflammatory cycle. adhesion molecules. For example. serious problems arise when inflammation continues and becomes a long-term condition. redness. nevertheless. animal dander. and chemicals called cytokines. NFκB.

NF- κB consists of three subunits. angiogenesis. which means that they are not the ideal target for intervention to treat and control inflammation. once stimulated by any of a multitude of provocative stimuli (see Figure 9) enzymes called protein kinases (PKs) inactivate the inhibitor protein IKK. Present in every cell from the fruit fly to man. These products then instigate and sustain the inflammatory process. because there are so many different PKs. Infections Fungi Bacteria Viral Injury Cuts Burns Sprains Figure 9. Once read. IL-2 and others. despite the potential for fine control over inflammation. The active subunits then move from the cell towards the nucleus where they act to read hundreds of different genes associated with inflammation. NF-κB NF-κB is complex four protein molecule that acts as a nuclear transcription factor. responsible for hundreds of different activities in the body.Harmful Solevents Solvents Gasoline Pesticides. the genes become active. COX.000 that we humans have) that will produce specific protein products that play a major role in inflammation and cancer-associated pathologies like invasion. PKs are fairly high up in the inflammatory cascade and as one of the early players in the process their job is to fine tune the carefully controlled inflammatory process. This process is discussed in more detail below. proliferation and others. two of which activate genes and a third. Stimuli for Inflammation and activating key inflammatory genes. etc. Unfortunately. The major role of NF-κB is to read (or transcribe) the DNA code and turn on or regulate over 400 genes (out of the 30. producing a series of downstream products including proteins. Foods Pet Dander Cosmetics etc. receptors. called IKK. and at the moment researchers haven’t figured out which PK acts where. NF-κB levels are raised in every inflammatory condition including Advances 21 . PKs are a huge family of enzymes. many natural products do have some influence on various PKs. Additionally. LOX. Nevertheless. which does contribute to their anti-inflammatory actions. Essentially. meaning that it plays a role in controlling whether certain genes are activated or inhibited. Stress Unhealthy Diet High Sugar High Saturated or Trans Fats Tobacco Smoke & Alcohol Inflammation UV Radiation Allergens Pollen. NF-κB was discovered in 1986 and is one of the most researched proteins of the inflammation process. which is an inhibitor that keeps the other two in check. enzymes and other factors like TNF. which frees the two active subunits. It is incredibly difficult to modulate the function of one specific PK.

High Cholesterol. Heart Attack Cancer Breast. which allows it to be manipulated without significantly affecting other pathways. Lung. second. multiple sclerosis. like many of the inflammatory players. at other times the reverse can happen. Stomach. allergies. Myeloma Kidney etc Skin Diseases Psoriasis. however. Multiple Sclerosis. Measles. Scleroderma Lung Diseases Bronchitis. is a molecule that is positioned on the outside of cellular membranes. TNF-α leaves the membrane and “docks” on receptors at distant sites to promote an inflammatory reaction. Diabetes Figure 10. Epilepsy Heart Disease Atherosclerosis. Cystic Fibrosis Diseases Linked to Inflammation Liver Diseases Alcohol induced. NF-κB is farther down in the process and is thus “closer” to the scene of action. These adhesion molecules are akin to the cholesterol plaque that builds up in blood vessels. Alzheimer’s disease. and through a positive feedback loop TNF-α can further activate NF-κB! TNF-α also acts to activate specific downstream inflammatory products like adhesion molecules. Prostate. Skin. NF-κB is very well researched and has shown a strong correlation with virtually all inflammatory diseases and third. various forms of arthritis (osteo and rheumatoid). asthma. diabetes. or Tumour Necrosis Factor alpha. Cirrhosis. Diseases Associated with Inflammation (adapted from Aggarwal and Harikumar. unlike PKs. 2009) heart disease. Regulation of TNF-α is complex and. muscle sprains or dysfunction Other Diseases Ulcers. Fatigue. Fibrosis Infectious Diseases Malaria. NF- κB. Crohn’s disease. Eczema. and they 22 Advances .Neurodegenerative Diseases Parkinson’s. it is a key molecule that can read the inflammatory script allowing expression of various inflammatory genes. Arthritis. Colorectal. Unlike PKs. at other times acts as an agent provocateur causing damage itself! In many cases NF-κB will activate TNF-α. Once activated by the various provocative stimuli. TNF-alpha TNF-α. Asthma. Allergy. The advantage of targeting NF-κB is three-fold: first. Wounds. however. Small Pox. Gall Stones. Alzheimer’s. osteoporosis and many more (See Figure 10). Fevers Bone or Muscle Disorders Osteoporosis. is a single molecule. Depression Endocrine Disorders Hypothyroidism. it is a double-agent. At times it can be a beneficial anti-inflammatory agent that helps to destroy tumours and improves healing of damaged tissues. IBD.

UV light. referred to as COX-1 and COX-2. Free Radicals – ROS and RNS There is a constant battle between the forces of good and evil within the body and in every cell. 2010) short term ROS and RNS are beneficial and have the effect of neutralizing the offending stimuli and causing acute inflammation. these are called COX-2 selective drugs. The ensuing dysfunction of the endothelial cells is one of the major causes of cardiovascular problems. hydroxyl radical OH. COX-2 generates a series of products called prostaglandins (specifically PGE2) that are highly well as nitrogen species collectively termed reactive nitrogen species (RNS) including 4-hydroxynonenal and various other reactive aldehydes. membranes. on the other hand. Celebrex® and Vioxx® are examples Advances 23 . Antioxidants are a collection of protective agents that can be produced by the body or derived from the diet. Tumours can use enzymes like MMP’s to eat away the surrounding tissue. There are two major types of COX enzymes. the continued production of these free radicals begins to cause damage to the healthy tissue.. Several pharmaceutical drugs target COX-2 without affecting COX-1. including cancer (from Reuter et al. catalase. certain defensive cells like mast cells and white blood cells (leukocytes) are quickly recruited to the site of damage which leads to a “respiratory burst” releasing both ROS and RNS into the area. Under normal conditions. which is one of the main mechanisms that tumours use to spread to distant sites. which is a component of the cell membrane. toxins etc.oxidants Anti . antioxidants outbalance pro-oxidants. Oxidants are a motley group of reactive oxygen species (ROS) including superoxide anion O2-.cause damage to the delicate endothelial cells that line the blood vessels and which are vital for the health of the vessels. The net effect of all of these antioxidants is to act as scavengers of oxygen and nitrogen free radicals. D and E to name a few. superoxide dismutase as well as vitamins C. It is an essential enzyme without which cells would be unable to maintain a healthy state. These include glutathione. DNA and other targets. but under oxidative conditions. COX-2. A therapeutic strategy involves neutralizing both ROS and RNS after the initial acute inflammatory process. These molecules or “free radicals” cause much damage to proteins. hydrogen peroxide H2O2. Certain chemicals or molecules (like cytokines) promote the production of free radicals. the stressors persist. In other cases TNF-α activates proteolytic enzymes like matrix metalloproteins (MMP’s). In the Cytokines SOD Catalase Growth Factors Glutathione Chemotherapy Heme Oxygenase Radiation Peroxidase Pro .oxidants Figure 11. is an enzyme that is induced by many of the factors responsible for inflammation: stress. The former is a housekeeping enzyme that works on maintaining homeostasis or status-quo of the cells. If however. and therefore they can be referred to as “pro-oxidants”. radiation or toxic chemicals for example. allowing them to spread into these areas. When oxidative stress occurs as a result of exposure to allergens. pro-oxidants prevail over antioxidants. Biochemists refer to these competing forces as antioxidants and oxidants or pro-oxidants (See Figure 11). which can lead to many inflammatory diseases. COX Enzymes Cyclooxygenase is a family of enzymes that work on arachidonic acid.

24 Advances . this multi-targeted approach to inflammation makes more sense. All of this was without the side effects associated with COX-2 inhibitors. Moreover. at least for now since singletargeted therapy has shown little promise. amazingly. researchers have conducted animal and human studies to verify these anti-inflammatory effects. Unlike pharmaceuticals that only address one specific pathway. how does one put out all of these inflammatory fires within? Although this is a huge challenge. unlike pharmaceuticals that have a single target.Boswellia serrata of this type of anti-inflammatory pharmaceutical. the numerous pathways allow an opportunity to tackle a multitude of mechanisms simultaneously. More recently. Boswellia serrata The herb Boswellia serrata or Indian frankincense has been used in Ayurveda for thousands of years for a multitude of diseases. like the classic silver bullet mechanism of action of COXinhibitors. and as result they have had to be withdrawn from the market. the reduction of inflammation in those taking Boswellia was maintained even Natural Anti-inflammatory Agents With so many factors at work. The empirical evidence for its anti-inflammatory benefits is strong. Nature is full of anti-inflammatory agents that target many of the pathways associated with inflammation. and. An incredibly important aspect of Boswellia is that it does not have a significant immediate effect on inflammation. from the second month onward. One study found that while Boswellia showed no significant effect on inflammation in the first month of use. an added advantage is that multi-targeted natural products are generally safer since a lower dose is required than for pharmaceuticals. liver and gastrointestinal damage. some of these drugs can cause harmful side-effects like kidney. Unfortunately. Because we do not yet know which pathways are most critical. with several human studies showing very positive results for Boswellia’s anti-inflammatory benefits. In fact. natural products tend to have much more widespread activity. symptoms were reduced to the same degree as with powerful COX-2 inhibitor pharmaceuticals. natural products often have multiple mechanisms.

up to 8 grams of pure curcumin can be consumed without gaining ANY detectable levels in the blood. especially when it is something outside of the normal regime of carbohydrates. Simply put. Unlike the overly complicated nano-technology used by the pharmaceutical and biotechnology industries. has incredibly poor bioavailability. something like curcumin. like nanotubes or other structures. so many of these end up passing straight through the GI system with little medicinal effect. Three of the best ways to increase bioavailability are by improving the solubility. 4. bioavailability is the percentage of an ingested ingredient that makes it into your bloodstream. many ingredients that have shown incredibly promising results in early in vitro studies end up having their benefits significantly reduced or even completely eliminated when the ingredient is taken by humans! This has led scientists to look into the causes of poor bioavailability and also to develop a variety of technologies and strategies that can be used to help enhance the bioavailability of molecules. The process of digestion. because. Metabolism – Poorly bioavailable molecules and extracts are also often degraded by the body. The latter technology is safe and uses ingredients that are safe for use in foods. There are several factors that can cause a substance to be poorly bioavailable: 1. because the body is very selective. If altering the metabolism of a compound can have negative effects. This molecule inhibits the degradation of all foreign molecules. where it can exert a physiological effect. Much of digestion is based on solubility in water. This is more difficult than one might think. meaning they do not dissolve in water. it still needs to be absorbed. while it may frustrate us by causing low bioavailability of supplements that we want to absorb. but is that the only concern? One very common method to increase bioavailability is the inclusion of piperine. 2. even if they have helpful medicinal properties. proteins and fats that the GI system is designed to absorb. stability and absorption of compounds. is this wise? Tests on the ingredients in supplements have shown that most can be safely taken at higher doses. carcinogens and chemicals retained by the body. and it is a strategy that can also be safely and effectively applied to natural health supplements. vitamins and cofactors are what scientists call ‘hydrophobic’. This system is highly important.What’s the Deal with Bioavailability? Poor bioavailability is a problem that has plagued many natural supplements over the years. combining the low pH of the stomach and the higher pH of the intestines. it also results in the detoxification of molecules that are dangerous. Advances 25 . are there ways to safely increase bioavailability? Definitely. the active medicinal antioxidant found in turmeric root. by improving each of the above limiting factors. allowing their benefits to be better harnessed in medications and natural supplements. Many approaches aim to increase all of these factors. For example. break down many molecules that could be beneficial. because they are recognized as ‘foreign’. the nano-technology used by the food industry makes use of particle size reduction and various methods to prevent particle clumping. How can Bioavailability be increased? There are many ways to get around the bioavailability problem. Poor solubility – Many medicinal herb extracts. This works very well to increase bioavailability. but has the unintended effect of increasing the amounts of toxins. but the real question is. which indicates that increasing bioavailability is safe. both full of powerful enzymes. a component of black pepper extract. Because of these bioavailability issues. Low stability – Many molecules have low stability in the digestive system. Absorption – If a molecule survives the harsh conditions of the digestive tract and is successfully solubilized by the body. 3.

like ibuprofen. In terms of its effects on inflammation in humans. and in particular the boswellic acids (BA). It is conceivable that studies that did not report any effect could have used products that were poorly bioavailable. like many natural products. Recall earlier in this issue of Advances we discussed that the German pathologist Virchow made a unique observation that the site of inflammation was often accompanied by cancers at the same site. Moreover. with some reporting good results and others reporting no effect. the results of have been mixed. Boswellia has been shown to exert anti-cancer effects in-vitro and in animal studies. where it has been shown to reduce both tumour burden and frequency. So far. Food science nano-technology is a safe and effective way of improving the 26 Advances .It is a common theme that virtually all natural anti-inflammatory ingredients also have an anti-cancer effect after patients stopped taking it for a month! A large family of compounds called saponins. Boswellia extract showed fewer gastrointestinal and kidney side effects than ibuprofen. Furthermore. a recent German clinical study showed that inflammation of the brain could be significantly reduced by bioavailable Boswellia extracts which prevented edema. One possible reason for this discrepancy is that Boswellia. has a huge bioavailability issue (see Note: What’s the Deal with Bioavailability?). have been confirmed as the principal active compounds in this plant. Boswellia has been shown in clinical trials to be more effective than conventional NSAID’s. Boswellic acids likely have the most powerful anti-inflammatory effect of all natural products! It is a common theme that virtually all natural anti-inflammatory ingredients also have an anti-cancer effect. Boswellia’s anti-inflammatory action has also resulted in several human trials looking at its potential use in the treatment of inflammatory conditions of the bowel including ulcerative colitis and Crohn’s disease. one of the hallmark signs of inflammation. for the treatment of symptoms associated with osteoarthritis.

Curcumin accounts for approximately two thirds of all curcuminoids in the root. Advances 27 . gastric problems. kidney and cardiovascular side effects of pharmaceutical NSAID’s and COX-2 inhibitors. a spice widely used by many cultures for culinary. fever. • Chelates heavy metals like copper and iron which are known to cause inflammation via enzymatic reactions that produce free radicals.inflammatory properties. • Inhibits other inflammatory mediators like TNF-α. catalase. Curcumin is possibly the most widely researched natural product available. • Directly quenches both oxygen and nitrogen free radicals. • Benefits Alzheimer’s disease by reducing the formation and aggregation of amyloid beta peptide (Aβ) and preventing formation of neurofibrillary tangles (NFT). liver and gall bladder ailments. Boswellia extracts have been shown to prevent or reduce gastric ulcers. the various interleukins and others. As a result. all without the gastric. More recently. which are primary sources of inflammation. In Ayurveda and the traditional Chinese system of medicine. superoxide dismutase and others. • Stimulates the proliferation of nerve cells. Finally. Boswellia has been shown to exert a powerful protective effect on the stomach. The key anti-inflammatory actions of curcumin • Potently reduces NF-κB by both preventing the activation of PKs so the inhibitor IKK remains active and keeps NF-κB in check and by directly breaking down excess NF-κB. diarrhea. curcumin stimulates phagocytes so that Aβ is rapidly cleared. infections. colouring and healing purposes. skin conditions. with the other two (demethoxycurcumin and bisdemethoxycurcumin) making up the remaining third. Curcumin Curcumin is one of the three active components called curcuminoids that are present in turmeric root. • Limits arachidonic acid release from cellular membranes by inhibiting an enzyme called phospholipase A2. heart conditions. with several dozen human studies being conducted using curcumin every year! The results of this immense body of research have repeatedly confirmed that curcumin possesses not only powerful anti. • Stimulates the body’s own defensive enzymes like glutathione. yet another action that can be linked to its anti-inflammatory effects. there is less substrate for COX and LOX enzymes to work on. This effect is enhanced in the presence of vitamin D. diabetes. • In the central nervous system.bioavailability of many products like Boswellia. cancers and many more. memory. • Reduces the COX-2 enzyme selectively without significantly affecting the housekeeping enzyme COX1. further support for the Curcumin benefits of this spice has come from a large number of studies in humans. but also antioxidant. curcumin has been used for a wide range of conditions including. reducing the production of inflammatory molecules. anticancer and neuroprotective effects. with thousands of in vitro mechanistic and animal studies to back up its effects.

and especially in Camellia sinensis Recent research suggests that green tea polyphenols act through over two dozen different mechanisms As an anti-inflammatory molecule. Numerous approaches have been utilized to improve the bioavailability of curcumin. the curcumin molecule isn’t very soluble in the digestive tract. Fermented black tea leaves generally have little or no catechin content. In the case of curcumin. Clinical research also suggests that EGCG has a powerful anti-cancer effect. These anti-cancer effects could be closely linked to EGCG’s role in inhibiting inflammation. it is too big to be easily absorbed by the gastrointestinal tract and finally. it is rapidly broken down by the detoxification enzymes that protect the body. For example. and include a variety of different mechanisms and targets. More recent research suggests that green tea polyphenols act through over two dozen different mechanisms. inhibit COX-2 enzymes. prostate. liver. For example. much like the curcumin molecule. this would be the amount that reaches the nerve cells in the brain or the joints. For more information about improving bioavailability. see the Note in this article: “What’s the Deal with Bioavailability?” Green Tea Polyphenols Green tea is another widely studied natural product. Aggarwal has published hundreds of reviews and original research on this fascinating molecule. There are many possible reasons for the poor bioavailability of curcumin. which have different physiological actions. and prevent the IKK from being inactivated. kidneys or other target tissues. It must be pointed out that curcumin has a huge bioavailability issue. thus preventing NFκB from becoming activated. especially the very important NF-κB. his research has concluded that curcumin’s anti-inflammatory properties are wide ranging. Aggarwal is a strong proponent of reduction of NFκB as a means of reducing the effects of chronic inflammation. using smaller particles of curcumin can have a significant effect on improving the bioavailability of this beneficial molecule. Green tea also prevents TNF and other signaling molecules from being activated. Omega 3 fatty acids rich in EPA and DHA Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are two of the many omega-3 fatty acids found in nature. These catechins are typically found in unfermented green tea leaves. The active components in green tea are a group of polyphenols called is unstable due to pH conditions. including epigallocatechin gallate (EGCG). Bioavailability refers to the amount of the active compound that reaches the target site. especially for breast. curcumin significantly reduces a huge number of inflammatory biomarkers. Bharat Aggarwal at Texas A&M University is a world leader in curcumin and inflammation research. for example. Catechins and other polyphenols have been shown to act at multiple sites in the inflammatory cascade. 28 Advances . they act to quench oxygen and nitrogen free radicals. for example. Overall. but instead are high in theaflavins. skin and colon cancers.

in animals fed DHA and then provoked with an inflammatory stimulus. like alpha linolenic acid. As a result. but instead of forming the highly inflammatory PGE2 or LTB4 that come from AA. in humans a high intake of EPA and/or DHA significantly reduces key inflammatory markers like TNF and NF-κB. and nowadays algae can be commercially harvested under controlled conditions. EPA and DHA are important because they can actually take the place of AA in cell membranes. an enzyme called phospholipase is released that causes AA to leave the membrane and move into the interior of the cell. For example. the amount of resulting inflammation is considerably reduced. New research is starting to look at the potential to extract EPA from algae sources as well. Additionally. In individuals with a high intake of EPA/DHA the cell membranes contain more EPA and DHA and less AA. When a cell is exposed to an inflammatory stimulus. ashwagandha is a powerful anti-inflammatory agent with a strong action against NF-κB. DHA intake is also associated with a reduced risk of Alzheimer’s disease. Most other plant sources contain predominately other omega-3 fatty acids. algae are an excellent source of DHA. Arachidonic acid (AA) is abundantly present in the membranes of cells. Inside the cell. Ashwagandha has been shown to accelerate the breakdown of NF-κB. Similarly. omega-3 fatty acid intake has been shown to reduce the intake of NSAIDs by arthritis patients. As such. they also act directly as antioxidants by quenching free radicals of oxygen and nitrogen species and indirectly by boosting the body’s own antioxidant defense system through the stimulation of antioxidant enzymes like catalase. For example. which are not converted very efficiently into EPA/DHA. both EPA and DHA have been shown to possess potent anti-inflammatory properties in their own right. when provoked by inflammatory signals. which is different than other natural agents that act to prevent its activation in the first place. superoxide dismutase and glutathione peroxidase. Similarly. Ashwagandha Ashwagandha is another Ayurvedic herb that has been used for centuries.fatty fish like salmon and anchovies. they form fairly innocuous and noninflammatory molecules. EPA or DHA leaves the cell membrane instead of AA. Furthermore. research has shown that restricting DHA in laboratory animals increases their risk of Alzheimer’s disease while the addition of DHA to the diet reduces the pathology of the disease. two sets of enzymes called COX and LOX utilize AA breaking it down to two highly inflammatory molecules called prostaglandin E2 (PGE2) and leukotriene B4 (LTB4). For example. ashwagandha provides a unique alternative pathway Advances 29 . Plant sources of omega-3 fatty acids are also becoming more common. EPA has been shown to powerfully reduce inflammation of the blood vessels. and part of this health benefit comes from the role they play in reducing inflammation. Many of us have heard that omega-3 fatty acids are important for good health. COX and LOX enzymes then act on these fatty acids. Often but erroneously called the Indian ginseng. Not only do omega-3 fatty acids act as anti-inflammatory molecules.

2007. 41: 40–59 Fox JG and Wang TC. Anticancer Res. S1: 45-60. Aggarwal B and Harikumar K.for reducing NF-κB levels. and its active components the sitoindosides. These natural agents are safe and effective. 54: 139-150 30 Advances . 2006: 4(4) Madea S and Omata M. Nuclear Factor-Kappa B links carcinogenesis and chemopreventive agents. 99: 836–842 Nathan C. metabolic. Nature. it Key References may be possible to reduce the risk and progression of many serious diseases that have been linked to inflammation. against neurodegenerative. From traditional Ayurvedic medicine to modern medicine: identification of therapeutic targets for suppression of inflammation and cancer. It can therefore be speculated that since ashwagandha acts to stimulate the immune system (particularly the action of macrophages). Points of Control in Inflammation. Inflammation. ashwagandha has been shown to have other physiological effects. Helicobacter pylori and gastric inflammation. Inflammation: A key role in Cancer. 2002. pulmonary. 1998. 72: 1605-1621. the full extent of the benefits of these natural anti-inflammatory agents can be realized. Putting it all Together In the end. 117:60-69 Frautschy S and Cole B. Nevertheless. 2006. 420: 846-852 Ralhan R et al. 41: 392-409 Karin M and Lin A. The advantage of these natural antiinflammatory agents is that they act through a variety of mechanisms Aggarwal B et al. Nat Immunol. the anti-inflammatory agent. 2004. Liu H et al. 2002. anxiety reducing properties and a powerful immune system stimulating effect. and can be used in combination to help control and prevent chronic inflammation throughout the body. Aggarwal B et al. autoimmune and neoplastic diseases. Expert Opin Ther Targets. Unfortunately. Int J Biochem Cell Biology. Mol Neurobiol. and gastric cancer. Potential therapeutic effects of curcumin. Ashwagandha and influence a wide range of targets and molecules involved in the body’s inflammatory response. Nature. 2002. By preventing and treating chronic inflammation. animal studies confirm that ashwagandha. through the use of various novel techniques to improve bioavailability. Cancer Sci 2008. 2010. its use in conjunction with more traditional and well known anti-inflammatory herbs like curcumin and Boswellia could result in the exertion of a more powerful anti-inflammatory effect. 2006. J Clin Invest. and thus inflammation. 420: 19/26. 2009. 3: 221-227 Libby P. Aggarwal B et al. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Rodger K and Crabtree JF. Why pleiotropic interventions are needed for Alzheimer ’s disease. Inflammation: A key event in Cancer development. cardiovascular. Finally. 24: 2783-840. there are a wide variety of powerful natural herbs and molecules that have shown very promising results for the reduction and prevention of inflammation. Atherosclerosis and Inflammation. Front Biosciences. Br Med Bull. are powerful anti-inflammatory agents. Mol Cancer Res. NF-kappa B at the crossroads of life and death. In addition to this. 10: 87-118. atrophy. Inflammation and Cancer: How hot is the link? Biochem Pharmacol. 2009. while ashwagandha has excellent supporting empirical data. including anti-cancer actions. there are few well controlled human studies that have examined its anti-inflammatory action.

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