Inflammation (Chronic)

Inflammation (Chronic)

1 Overview

Summary and Quick Facts

  • Unlike short-term inflammation which can be protective for the body, chronic (long-term) inflammation can have serious consequences. In fact, it can go undetected for years and contribute to the development of at least seven of the 10 leading causes of death in the United States.
  • In this protocol you will learn about risk factors for inflammation and lab tests used to identify and monitor inflammation within the body. You will also discover several natural strategies for combating the negative side effects of chronic inflammation.
  • Omega-3 fatty acids from fish oil have been shown in several cases to reduce markers of inflammation. Supplementation with omega-3 fatty acids has proven successful at improving outcomes for several inflammatory diseases.

Chronic inflammation contributes to many leading causes of death in the United States:

  • heart disease
  • cancer
  • diabetes
  • stroke
  • Alzheimer’s disease
  • kidney disease
  • chronic lower respiratory disease

Fortunately, fish oil, sesame lignans, and other integrative interventions can counteract destructive chronic inflammation.

Causes of Chronic Inflammation

Several factors contribute to chronic inflammation:

  • Mitochondrial dysfunction
  • Advanced glycation end products due to elevated blood sugar levels
  • Uric acid crystals
  • Oxidized lipoproteins (such as low-density lipoprotein)

Risk Factors Associated with Chronic Inflammation

Several risk factors promote chronic inflammation:

  • Increasing age
  • Obesity
  • High saturated fat intake
  • High sugar intake

Testing for Chronic Inflammation

Blood tests that can detect chronic inflammation include:

  • High sensitivity C-reactive protein (hs-CRP)
  • fibrinogen
  • tumor necrosis factor-alpha (TNF-α)
  • interleukin-1 beta (IL-1β)
  • interleukin-6 (IL-6)
  • interleukin-8 (IL-8)

Conventional Medical Treatments

Drugs that can help address chronic inflammation include:

  • Pentoxifylline
  • Metformin

Dietary and Lifestyle Changes

Several dietary and lifestyle changes can help reduce chronic inflammation:

  • Low-glycemic diet
  • Reduced consumption of:
    • total and saturated fat
    • cholesterol
  • Increased exercise

Integrative Interventions

  • Fish Oil: A higher intake of omega-3 fatty acids is associated with lower levels of markers of TNF-α activity, CRP, and IL-6.
  • Curcumin: Curcumin, a constituent of turmeric, has been studied in over 7000 published scientific articles and is known to modulate several important pathways including the ones involved in inflammatory processes.
  • Magnesium: In several large observational studies, greater magnesium intake was associated with lower hs-CRP, IL-6, and TNF-α activity.
  • Tea polyphenols: Tea polyphenols have been shown to produce reductions in CRP in human clinical studies.
  • DHEA: Supplementation was shown to significantly decrease TNF-α and IL-6 levels in elderly volunteers, as well as lower visceral fat mass and improve glucose tolerance.
  • Sesame lignans: Supplementation reduced the levels of a pro-inflammatory vasoconstrictor by approximately 30%.

2 Introduction

Of the 10 leading causes of mortality in the United States, chronic, low-level inflammation contributes to the pathogenesis of at least seven. These include heart disease, cancer, chronic lower respiratory disease, stroke, Alzheimer’s disease, diabetes, and nephritis.1-9

Inflammation has classically been viewed as an acute (short-term) response to tissue injury that produces characteristic symptoms and usually resolves spontaneously. More contemporary revelations show chronic inflammation to be a major factor in the development of degenerative disease and loss of youthful functions.

Chronic inflammation can be triggered by cellular stress and dysfunction, such as that caused by excessive calorie consumption, elevated blood sugar levels, and oxidative stress. It is now clear that the destructive capacity of chronic inflammation is unprecedented among physiologic processes.10

The danger of chronic, low-level inflammation is that its silent nature belies its destructive power.

In fact, stress-induced inflammation, once triggered, can persist undetected for years, or even decades, propagating cell death throughout the body. Due to the fact that it contributes so greatly to deterioration associated with the aging process, this silent state of chronic inflammation has been coined “inflammaging.”

Chronic low-level inflammation may be threatening your health at this very moment, without you realizing it. In this protocol you will learn about low-cost blood tests that can assess the inflammatory state within your body. You will also discover novel approaches that combat chronic inflammation to help avoid age-related health decline.

3 The Inflammatory Process

The Acute Inflammatory Response

Inflammation, the adaptive immune response to tissue injury or infection, plays a central role in metabolism in a variety of organisms.11

At its most basic level, an acute inflammatory response is triggered by 1) tissue injury (trauma, exposure to heat or chemicals); or 2) infection by viruses, bacteria, parasites, or fungi. The classic manifestation of acute inflammation is characterized by four cardinal signs: Redness and heat result from the increased blood flow to the site of injury. Swelling results from the accumulation of fluid at the injury site, a consequence of the increased blood flow. Finally, swelling can compress nerve endings near the injury, causing the characteristic pain associated with inflammation. Pain is also important to make the organism aware of the tissue damage. Additionally, inflammation in a joint usually results in a fifth sign (impairment of function), which has the effect of limiting movement and forcing rest of the injured joint to aid in healing.

A well-controlled acute inflammatory response has several protective roles:

  • It prevents the spread of infectious agents and damage to nearby tissues;
  • helps to remove damaged tissue and pathogens; and
  • assists the body's repair processes

However, a third type of stimuli, cellular stress and malfunction, triggers chronic inflammation, which, rather than benefiting health, contributes to disease and age-related deterioration via numerous mechanisms.

Cellular Stress and Chronic, Low-Level Inflammation

Mitochondria—cellular organelles responsible for generating biochemical energy in the form of adenosine triphosphate (ATP)—are a fundamentally necessary component of life in higher organisms. In fact, in the case of sophisticated multicellular life forms, organismal viability depends upon optimal mitochondrial function. Paradoxically, mitochondrial processes can also bring about a tissue-destroying inflammatory mediator known as the inflammasome; this phenomenon is provoked by damaged and dysfunctional mitochondria.12

Mitochondrial dysfunction arises consequent of exposure to exogenous (eg, environmental toxins, tobacco smoke) and endogenous (eg, reactive oxygen species) stressors, and as a result of the aging process itself. For example, a byproduct of mitochondrial energy generation is the creation of free radical molecules. Free radicals can damage cellular structures and initiate a cascade of proinflammatory genetic signals that ultimately results in cell death (apoptosis), or worse, uncontrolled cell growth—the hallmark of cancer.

Aging is associated with declining mitochondrial efficiency and increased production of free radical molecules. Recent research identifies this age-associated aberration of mitochondrial function as a principle actuator of chronic inflammation.13 Specifically, mitochondrial dysfunction brings about inflammation as follows:

  1. Accumulation of free radicals induces mitochondrial membrane permeability;
  2. Molecular components normally contained within the mitochondria leak into the cytoplasm (intracellular fluid in which cellular organelles are suspended);
  3. Cytoplasmic pattern recognition receptors (PRR's), which detect and initiate an immune response against intracellular pathogens, recognize the leaked mitochondrial molecules as potential threats;
  4. Upon detection of the potential threat, PRR's form a complex called the inflammasome that activates the inflammatory cytokine interleukin-1β, which then recruits components of the immune system to destroy the “infected” cell.14

These four steps represent a simplified scheme of mitochondrial dysfunction leading to cellular destruction; however, intracellular free radicals are not the only inducers of inflammatory cell death.

Circulating sugars, primarily glucose and fructose, are culprits as well. When these “blood sugars” come in contact with proteins and lipids a damaging reaction occurs forming compounds called advanced glycation end products (AGEs). AGEs bind to the cell-surface receptor called receptor for advanced glycation end products, or RAGE. Upon activation, RAGE triggers the movement of the inflammatory mediator nuclear factor kappa-B (NF-κB) to the nucleus, where it activates numerous inflammatory genes.15 AGEs are primarily formed in vivo, and glycation is exacerbated by elevated blood sugar levels. However, dietary AGEs also contribute to inflammation; they are abundant in foods cooked at high temperatures, especially red meat.16,17

Additional biochemical inducers of a chronic inflammatory response include:

  • Uric acid (urate) crystals, which can be deposited in joints during gouty arthritis; elevated levels are a risk factor for kidney disease, hypertension, and metabolic syndrome18,19;
  • Oxidized lipoproteins (such as LDL), a significant contributor to atherosclerotic plaques20; and
  • Homocysteine, a non-protein-forming amino acid that is a marker and risk factor for cardiovascular disease, and may increase bone fracture risk.21

Together, these proinflammatory instigators promote a perpetual low-level chronic inflammatory state called para-inflammation.11

Although it progresses silently, para-inflammation presents a major threat to the health and longevity of all aging humans. Chronic, low-level inflammation is associated with common diseases including cancer, type II diabetes, osteoporosis, cardiovascular diseases, and others. Thus, by targeting the myriad physiological variables that can inaugurate an inflammatory response, one can effectively temper chronic inflammation and reduce their risk for inflammatory diseases.

4 Markers and Mediators of Inflammation

Following is a list of some of the most prominent markers of inflammation used in research and diagnosis. Some can be detected by blood tests (see “Diagnosis and Conventional Treatment of Chronic Inflammation”):

Tumor Necrosis Factor-alpha

Tumor necrosis factor-alpha (TNF-α) is an intercellular signaling protein called a cytokine, which can be released by multiple types of immune cells in response to cellular damage, stress, or infection. Originally identified as an anti-tumor compound produced by macrophages (immune cells),22 TNF-α is required for proper immune surveillance and function. Acting alone or with other inflammatory mediators, TNF-α slows the growth of many pathogens. It activates the bactericidal effects of neutrophils, and is required for the replication of several other immune cell types.23 Excessive TNF-α, however, can lead to a chronic inflammatory state, can increase thrombosis (blood clotting) and decrease cardiac contractility, and may be implicated in tumor initiation and promotion.7

Nuclear Factor Kappa-B

Nuclear factor kappa-B (NF-κB)is important in the initiation of the inflammatory response. When cells are exposed to damage signals (such as TNF-α or oxidative stress), they activate NF-κB, which turns on the expression of over 400 genes involved in the inflammatory response.23 These include other inflammatory cytokines, and pro-inflammatory enzymes including cyclooxygenase-2 (COX-2) and lipoxygenase. COX-2 is the enzyme responsible for synthesizing pro-inflammatory prostaglandins, and is the target of non-steroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, aspirin) and COX-2 inhibitors (Celebrex).

Interleukins

Interleukins are cytokines that have many functions in the promotion and resolution of inflammation. Pro-inflammatory interleukins that have been the subject of most research include IL-1β, IL-6, and IL-8. IL-1β helps immune cells to move out of blood vessels and into damaged or dysfunctional tissues. IL-6 has both pro-inflammatory and anti-inflammatory roles, and coordinates the production of compounds required during the progression and resolution of acute inflammation. IL-8 is expressed by both immune and non-immune cells, and helps to attract neutrophils (immune cells that can destroy pathogens) to sites of injury.

C-reactive Protein

C-reactive protein (CRP) is an acute-phase protein, one of several proteins rapidly produced by the liver during an inflammatory response. Its primary goal in acute inflammation is to coat damaged cells to make them easier to recognize by other immune cells.24 CRP elevation above basal levels is not diagnostic on its own, as it can raise in several cancers, rheumatologic, gastrointestinal, and cardiovascular conditions, and infections.25 Elevation of CRP (as determined by a high-sensitivity CRP assay or hs-CRP) has a strong association with elevated risk of cardiovascular disease and stroke.26

Eicosanoids

The cytokine factors mentioned earlier (interleukins, TNF-α) are “long-distance messages.” They are produced by cells at the site of inflammation and released into the blood, carrying information about the inflammatory response throughout the body. In contrast, eicosanoids are “local” messages; they are produced by cells that are proximal to the site of inflammation, and are meant to travel short distances (locally within the same organ, to neighboring cells, or sometimes only to different parts of the same cell) in order to elicit immune defenses.27 There are several families of eicosanoids (including prostaglandins, prostacyclins, leukotrienes, and thromboxanes) that are created by most cell types in all major organ systems. Aside from their roles in inflammation (and anti-inflammation), prostaglandins have a variety of functions in cell growth, kidney function, digestion, and the constriction and dilation of blood vessels. Thromboxanes are important mediators of the blood clotting process. Pro-inflammatory leukotrienes are important for recruiting and activating white blood cells during inflammation, and are best studied for their role in airway constriction and anaphylaxis.

Cells produce eicosanoids using unsaturated fatty acids that are part of their cell membranes. The fatty acid starting materials for eicosanoid synthesis are the essential fatty acids linoleic acid (omega-6) and its derivative arachidonic acid (AA); and alpha-linolenic acid (an omega-3) and its derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). While generalizations about roles of these fatty acids in eicosanoid synthesis should be approached cautiously, the most potent inflammatory eicosanoids are produced from omega-6 fatty acids (linoleic and arachidonic acids). Diets high in omega-3 fatty acids are associated with lower biomarkers of inflammation and cardiovascular disease risk; proposed mechanisms include the production of less inflammatory or anti-inflammatory eicosanoids and through the cyclooxygenase and lipoxygenase enzymes.28

Cyclooxygenases and Lipoxygenases

The eicosanoids require several enzymatic steps to be synthesized from unsaturated fatty acids; the cyclooxygenase (COX) and lipoxygenase (LOX) enzymes catalyze the first steps in these reactions. Cyclooxygenases initiate the conversion of omega-3 and omega-6 derivatives into one of the many prostaglandins or thromboxanes. The interest in COX enzyme metabolism comes from the fact that its inhibition leads to decreased prostaglandin synthesis, and therefore a reduction in inflammation, fever, and pain. The analgesic and anti-inflammatory activity of aspirin and NSAIDs (like ibuprofen and naproxen) is due to their inhibition of COX enzymes. There are two COX enzymes with well-defined roles in humans (COX-1 and COX-2). COX-2 has the most relevance to the inflammatory process; it is normally inactive, but is turned on during inflammation and stimulates this process of inflammation by creating pro-inflammatory prostaglandins and thromboxanes.

Lipoxygenases convert fatty acids into proinflammatory leukotrienes, important local mediators of inflammation. Several potent inflammatory leukotrienes are produced by 5-LOX in mammals. Lipoxygenase enzymes, and the pro-inflammatory factors they produce, have a fundamental role in the inflammatory process by aiding in the recruitment of white blood cells to the site of inflammation. They also stimulate local cells to produce cytokines, which amplifies the inflammatory response.27 Thus, LOX enzymes may be involved in a wide variety of inflammatory conditions, and represent an additional target for anti-inflammatory therapy.

While COX and LOX enzymes are most often associated with pro-inflammatory processes, it is important to remember that both enzymes also produce factors that inhibit or resolve inflammation and promote tissue repair (including the prostacyclins and lipoxins). The proper transition from pro- to anti-inflammatory activities of the COX and LOX enzymes is important for the progression of a healthy inflammatory response.

5 Risk Factors for Chronic Inflammation

There are several risk factors which increase the likelihood of establishing and maintaining a low-level inflammatory response.

Age

In contrast to younger individuals (whose levels of inflammatory cytokines typically increase only in response to infection or injury), older adults can have consistently elevated levels of several inflammatory molecules, especially IL-6 and TNF-α.9 These elevations are observed even in healthy older individuals. While the reasoning for this age-associated increase in inflammatory markers is not thoroughly understood, it may reflect cumulative mitochondrial dysfunction and oxidative damage, or may be the result of other risk factors associated with age (such as increases in visceral body fat or reductions in sex hormones).

Obesity

Fat tissue is an endocrine organ, storing and secreting multiple hormones and cytokines into circulation and affecting metabolism throughout the body. For example, fat cells produce and secrete both TNF-α and IL-6, and visceral (abdominal) fat can produce these inflammatory molecules at levels sufficient to induce a strong inflammatory response.29,30 Visceral fat cells can produce three times the amount of IL-6 as fats cells elsewhere,31 and in overweight individuals, may be producing up to 35% of the total IL-6 in the body.32 Fat tissue can also be infiltrated by macrophages, which secrete pro-inflammatory cytokines. This accumulation of macrophages appears to be proportional to body mass index (BMI), and appear to be a major cause of low-grade, systemic inflammation and insulin resistance in obese individuals.33,34

Diet

A diet high in saturated fat is associated with higher pro-inflammatory markers, particularly in diabetic or overweight individuals.35,36 This effect was absent in healthy individuals.37-39 Diets high in synthetic trans fats (such as those produced by hydrogenation) have been associated with increases in inflammatory markers (IL-6, TNF-α, IL-8, CRP) in some studies,40,41 but had no effect in others.42,43 The increases in markers of inflammation due to synthetic trans fats may be more pronounced in overweight individuals.42

General dietary over-consumption is a major contributor to inflammation and other detrimental age-related processes in the modern world. Therefore, eating a calorie-restricted diet is an effective means of relieving physiologic stressors. Indeed, several studies show that calorie restriction provides powerful protection against inflammation.44,45 For more information about the metabolic benefits of eating fewer calories, readers should refer to the “Caloric Restriction” protocol.

Low Sex Hormones

Amongst their many roles in biology, sex hormones also modulate the immune/inflammatory response. The cells that mediate inflammation (such as neutrophils and macrophages) have receptors for estrogens and androgens that enable them to selectively respond to sex hormone levels in many tissues.46 A notable example is that of osteoclasts, the macrophages that reside in skeletal tissue and are responsible for breaking down and recycling old bone. Estrogens turn down osteoclast activity. Following menopause, lowered estrogen levels cause these bone depleting cells to maintain their activity, breaking down bone faster than it is rebuilt. This is one of the factors in the progression of osteoporosis.

Experiments in cell culture have demonstrated that testosterone and estrogen can repress the production and secretion of several pro-inflammatory markers, including IL-1β, IL-6, TNF-α, and the activity of NF-κB.47-49 These observations have been corroborated by observational studies that have linked lower testosterone levels in elderly men to increases in inflammatory markers (IL-6 and IL-6 receptor).50,51 Several studies have shown an increase in inflammatory IL-1β, IL-6, and TNF-α following surgical or natural menopause.9,52 Conversely, the preservation of sex hormone levels is associated with reductions in the risk of several inflammatory diseases, including atherosclerosis, asthma in women, and rheumatoid arthritis in men.46 Hormone replacement therapy (HRT) may partially exert its protective effects through an attenuation of the inflammatory response. Reductions in the risks of coronary heart disease and inflammatory bowel disease in some individuals, as well as levels of some circulating inflammatory cytokines (including IL-1B, IL-8, and TNF-α) has been observed in some studies of women on HRT.53-55

Smoking

Cigarette smoke contains several inducers of inflammation, particularly reactive oxygen species. Chronic smoking increases production of several pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8), while simultaneously reducing production of anti-inflammatory molecules.56 Smoking also increases the risk of periodontal disease, an independent risk factor for increasing systemic inflammation.57

Sleep Disorders

Production of inflammatory cytokines (TNF-α and IL-1β) appears to follow a circadian rhythm and may be involved in the regulation of sleep in animals and humans.58 Disruption of normal sleep can lead to daytime elevations of these pro-inflammatory molecules. Plasma levels of TNF-α and/or IL-6 were elevated in patients with excessive daytime sleepiness, including those with sleep apnea and narcolepsy.58 These elevations in cytokines were independent of BMI or age,59,60 although persons with higher visceral body fat were more likely to have sleep disorders.61

Other Inciting Factors

Periodontal disease can produce a systemic inflammatory response that may affect several other systems, such as the heart and kidneys.62,63 It is by this mechanism that periodontal disease is thought to be a risk factor for cardiovascular diseases.64

Stress (both physical and emotional) can lead to inflammatory cytokine release (IL-6); stress is also associated with decreased sleep and increased body mass (stimulated by release of the stress hormone cortisol), both of which are independent causes of inflammation.65

The maintenance of a proper inflammatory response may also involve the central nervous system. The recently identified vagal immune reflex senses inflammatory molecules through a network of nerves (branches of the vagus nerve), and sends this information to the brain. If the brain determines that the inflammatory response is too great, it sends signals to the site(s) of inflammation to attenuate the response.66 Preliminary data suggest depressed nerve activity may be associated with exaggerated inflammatory responses seen in sepsis.67 Smoking, itself a risk factor for inflammation, also decreases activity of the vagus nerve.68

Excess Blood Glucose Fuels Inflammatory Fires

When glucose is properly utilized, our cells produce energy efficiently. As cellular sensitivity to insulin diminishes, excess glucose accumulates in our bloodstream. Like spilled gasoline, excess blood glucose creates a highly combustible environment from which oxidative and inflammatory fires chronically erupt.

Excess glucose not used for energy production converts to triglycerides that are either stored as unwanted body fat or accumulate in the blood where they contribute to the formation of atherosclerotic plaque.

As an aging human, you face a daily onslaught of excess glucose that poses a grave risk to your health and longevity. Surplus glucose relentlessly reacts with your body’s proteins, causing damaging glycation reactions while fueling the fires of chronic inflammation and inciting the production of destructive free radicals.69-71

Avert Glycation and Inflammation by Controlling Glucose Levels with Green Coffee Extract

Unroasted coffee beans, once purified and standardized, produce high levels of chlorogenic acid and other beneficial polyphenols that can suppress excess blood glucose levels. Human clinical trials support the role of chlorogenic acid-rich green coffee bean extract in promoting healthy blood sugar control and reducing disease risk.

Scientists have discovered that chlorogenic acid found abundantly in green coffee bean extract inhibits the enzyme glucose-6-phosphatase that triggers new glucose formation and glucose release by the liver.72,73 Glucose-6-phosphatase is involved in dangerous postprandial (after-meal) spikes in blood sugar.

In another significant mechanism, chlorogenic acid increases the signal protein for insulin receptors in liver cells.74 That has the effect of increasing insulin sensitivity, which in turn drives down blood sugar levels.

In a clinical trial, 56 healthy volunteers were challenged with an oral glucose tolerance test before and after a supplemental dose of green coffee extract. The oral glucose tolerance test is a standardized way of measuring a person's after-meal blood sugar response. In subjects not taking green coffee bean extract, the oral glucose tolerance test showed the expected rise of blood sugar to an average of 144 mg/dL after a 30-minute period. But in subjects who had taken 200 mg of the green coffee bean extract, that sugar spike was significantly reduced, to just 124 mg/dL—a 14% decrease.75 When a higher dose (400 mg) of green coffee bean extract was supplemented, there was an even greater average reduction in blood sugar—up to nearly 28% at one hour.

Ensuring fasting glucose levels stay between 70 and 85 mg/dL, and that two-hour post-meal glucose levels remain under 125 mg/dL, can help combat chronic inflammation.

6 Diseases Associated with Chronic Inflammation

Cardiovascular Diseases (CVD)

Inflammation is an integral part of atherosclerosis (recall that oxidized low-density lipoprotein cholesterol stimulates the inflammatory response). Circulating inflammatory cytokines are predictive of peripheral arterial disease, heart failure, atrial fibrillation, stroke, and coronary heart disease.9,26

Cancer

Several studies have established links between chronic low-level inflammation and many types of cancer, including lymphoma, prostate, ovarian, pancreatic, colorectal and lung.7,76 There are several mechanisms by which inflammation may contribute to carcinogenesis, including alterations in gene expression, DNA mutation, epigenetic alterations, promotion of tumor vascularization, and the expression of pro-inflammatory cytokines that have roles in cancer cell proliferation.7,77

Diabetes

The infiltration of macrophages into fat tissue and their subsequent release of pro-inflammatory cytokines into circulation occur at a greater rate in type II diabetics than in non-diabetics.33,35,78 Pro-inflammatory cytokines clearly decrease insulin sensitivity.2

Age-Related Macular Degeneration (AMD)

An evaluation of 11 population-based studies encompassing over 41,000 patients demonstrated a clear association between elevated serum CRP levels (> 3 mg/L) and the incidence of late onset AMD.79 The risk of AMD in these high-CRP patients was increased over 2-fold compared with patients with CRP levels < 1 mg/L.

Chronic Kidney Disease (CKD)

The chronic, low-grade inflammation in CKD can lead to the retention of several pro-inflammatory molecules in the blood (including cytokines, AGEs, and homocysteine).6 The reduced excretion of pro-inflammatory factors by the diseased kidney can accelerate the progression of chronic inflammatory disturbances elsewhere in the body, such as the cardiovascular system.

Osteoporosis

Inflammatory cytokines (TNF-α, IL-1β, IL-6) are involved in normal bone metabolism. Osteoclasts, the cells that break down (resorb) bone tissue, are a type of macrophage and can be stimulated by pro-inflammatory factors. Systemic elevations in pro-inflammatory cytokines push bone metabolism towards resorption, and have been observed to induce bone loss in persons with periodontal disease, pancreatitis, inflammatory bowel disease, and rheumatoid arthritis.3 An increase in the levels of inflammatory cytokines is also a mechanism by which menopause stimulates bone loss.

Depression

There is a small, but significant association between elevated IL-6 and CRP in depressed patients, which has been observed in many population studies.80 It is unclear whether inflammation leads to stress or vice versa, and there is data supporting both hypotheses.81,82

Cognitive Decline

Several observational studies have linked chronic low-level inflammation in older adults to cognitive decline and dementia, including vascular dementia and Alzheimer’s disease.9 One study found people with the highest CRP and IL-6 levels (> 2.4 pg/mL) had a ~30‒40% increased risk of cognitive decline compared to those with the lowest levels (< 1.4 pg/mL).83 Inflammatory markers can be elevated before the onset of cognitive dysfunction, indicating their potential relevance as a prognostic tool in high-risk individuals.9

Others

Elevations in circulating inflammatory cytokines are associated with several other conditions, both inflammatory (rheumatoid arthritis, IBD/Crohn’s disease, pancreatitis) and non-inflammatory (anemia, fibromyalgia, frailty, sarcopenia/cachexia/muscle wasting).4,5,84-86 Again, whether inflammation incites these conditions or results from them is unclear, and requires further investigation.

7 Conventional Medicine Typically Overlooks Chronic Inflammation

Chronic inflammation or para-inflammation is generally not treated on its own by mainstream physicians. Interventions in conventional medicine are usually only undertaken when the inflammation occurs in association with another medical condition (such as arthritis). Currently, conventional preventive medical approaches to inflammation are limited to the use of CRP to predict cardiovascular disease in high-risk subjects, and the prophylactic use of drugs like aspirin to inhibit the inflammatory cascade linked to thrombosis (uncontrolled blood clotting). Indeed, the potentially asymptomatic nature of low grade inflammation is such that elevations of pro-inflammatory cytokines may progress undetected for some time, only being discovered after they have had time to cause enough cellular damage to produce disease symptoms. As future studies solidify the association between inflammatory mediators and different diseases, early detection of cytokine aberrations and anti-inflammatory therapy to reduce disease risk may gain more mainstream acceptance.

Testing Blood for Inflammatory Factors

The following two blood tests are inexpensive and are good markers of systemic inflammation. They can be used to detect the presence of chronic inflammation and monitor the success or failure of various anti-inflammatory regimens:

Pro-Inflammatory Marker Optimal Ranges
High-sensitivity C-reactive protein (CRP) Under 0.55 mg/L in men
Under 1.0 mg/L in women
Fibrinogen 200‒300 mg/dL

The following blood tests are expensive and help identify specific factors that are causing systemic inflammation:

Cytokine Testing Normal Ranges (LabCorp)
Tumor necrosis factor-alpha (TNF-α) <8.1 pg/mL
Interleukin-1 beta (IL-1β) <15.0 pg/mL
Interleukin-6 (IL-6) 2‒29 pg/mL
Interleukin-8 (IL-8) <32.0 pg/mL

8 Drug Strategies to Combat Chronic Inflammation

Pentoxifylline

Pentoxifylline is a drug used to treat conditions involving poor circulation to the brain, limbs, and other areas perfused by small blood vessels. The drug effectively modulates properties of both blood vessels and red blood cells thanks to its action as a non-selective phosphodiesterase inhibitor. Phosphodiesterase inhibition is a clinically important mechanism in many additional aspects of human physiology as well, so pentoxifylline has been studied in a wide range of applications ranging from diabetic complications and non-alcoholic liver disease, to endometriosis and cardiac surgery.87-90

The potent anti-inflammatory properties of pentoxifylline were a secondary discovery, and still not fully understood. Studies have revealed, though, that pentoxifylline modulates TNF-α signaling, which probably contributes to the considerable suppression of inflammation it has evoked in several human trials.91 In a recent trial, 400 mg of pentoxifylline taken twice daily significantly suppressed hs-CRP, fibrinogen, and TNF-α levels in patients with chronic kidney disease; subjects’ renal function improved with treatment as well.92 In patients with HIV-related vascular dysfunction, pentoxifylline lessened leukocyte adhesion—a process that contributes to cardiovascular disease by allowing inflammatory cells to infiltrate the endothelial lining of blood vessels.93 Given by IV-infusion, pentoxifylline lowered TNF-α levels and pain intensity following surgical removal of kidney stones.94

Pentoxifylline dosage varies depending on individual circumstances and clinical application. However, 400 mg taken twice daily has consistently tempered inflammation in diverse human trials. For example, administered at this dose for one month to 30 diabetic individuals with high blood pressure, not only did pentoxifylline quell inflammation (20% reduction in CRP levels and an 11% improvement in erythrocyte sedimentation rate [measure of inflammatory tendency of a blood sample]), but it also bolstered plasma antioxidant status, as evidenced by a 20% reduction in malondialdehyde levels (measure of oxidative stress) and a nearly 5% increase in glutathione levels, a powerful antioxidant.95

Metformin

The regulation of energy metabolism and inflammation are closely associated; this is evidenced by the co-incidence of metabolic disorders (obesity, diabetes) and low-grade inflammation.96 Metformin may reduce the activity of inflammatory cytokines by increasing the production of IL-1βreceptor antagonist (IL1Rn), a protein factor which interferes with pro-inflammatory signaling of IL-1β.97 It may also promote favorable CRP levels, although not to the same extent as weight loss.96,98 A randomized controlled trial of hypertensive and dyslipidemia patients taking 1,700 mg/day of metformin for 12 weeks demonstrated a 26.7% reduction in IL-6 and 8.3% reduction in TNF-α from baseline levels, a degree of reduction similar to that of the potent statin drug rosuvastatin (Crestor).99 The anti-inflammatory effects of metformin appear to be rapid; reductions in circulating TNF-α, IL-1β, CRP, and fibrinogen were observed after only 30 days in a larger study of 128 type II diabetic patients with dyslipidemia.100

Aspirin

Aspirin has been used as an anti-inflammatory therapy long before the molecular mechanics of inflammation had been discovered; it is now well characterized as an inhibitor of cyclooxygenase enzymes. The modification of COX molecules by aspirin has important implications for cardiovascular health. Blood platelets use cyclooxygenase to produce thromboxane A2, a pro-inflammatory molecule that is an important signal during the initial stages of the clotting process. The inhibitory effect of aspirin on COX enzymes in platelets can partially explain its protective effects against the complications of several disorders, including hypertension, heart attack, and stroke.101 Aspirin's inhibition of cyclooxygenase also helps explain its potential effect on cancer risk reduction as observed in several studies,102-105 as COX-2 also appears to have roles in increasing the proliferation of mutated cells, tumor formation, tumor invasion, and metastasis, and may contribute to drug resistance in some cancers.106 Aspirin has also been shown to reduce the activity of NF-kB in vitro,107 and lower levels of multiple inflammatory markers (TNF-α, CRP, IL-6) in patients with cardiovascular disease.108-111

Unlike many other NSAIDs, the effects of aspirin on COX enzymes are permanent for the life of the COX enzyme. Interestingly, it appears that rather than rendering the enzyme inactive, aspirin modifies the function of COX. Aspirin stops the enzyme from producing pro-inflammatory prostaglandins, and enables it to begin producing anti-inflammatory molecules called resolvins.112

Low-Dose Statin Drugs

Statins are thought to reduce inflammation by a mechanism distinct from their effects on cholesterol metabolism; they interfere with the function of cytokine receptors on the surface of white blood cells. Therefore, pro-inflammatory signals in the blood are unable to provoke a response from white blood cells, and they are prevented from further stimulating inflammation.113,114 Results of the JUPITER trial presented the strongest evidence for statins as anti-inflammatory therapy. In this study of over 17,000 healthy middle-aged men and women with elevated levels of the inflammatory marker CRP but normal levels of blood lipids, 20 mg/day of rosuvastatin reduced CRP levels by over half, in addition to reducing heart attack and stroke incidence.115 Smaller studies have looked at the effect of statins on other inflammatory markers as well. A randomized controlled trial of hypertensive and dyslipidemia patients taking a lower dose (10 mg/day) of rosuvastatin for 12 weeks demonstrated a ~22% reduction in IL-6 and 13% reduction in TNF-α from baseline levels.99 A second uncontrolled study of simvastatin demonstrated more modest reductions in IL-6, but no changes in TNF-α from the statin treatment.116 To generate a substantial anti-inflammatory effect using statin drugs alone requires a high dose that is more likely to induce side effects than lower dose statin therapy.

9 Dietary and Lifestyle Approaches to Reduce Chronic Inflammation

Inflammation itself is not a disease, but is featured, to varying degrees, in adverse health conditions. Information on strategies and research regarding the reduction of inflammation characteristic to specific health conditions are featured in their respective Life Extension protocols: "Allergies," "Macular Degeneration," "Cancer Adjuvant Therapy," "Atherosclerosis and Cardiovascular Disease," "Gout and Hyperuricemia," "Inflammatory Bowel Disease (Crohn’s and Ulcerative Colitis)," "Osteoarthritis," "Arthritis–Rheumatoid," and "Osteoporosis." What follows is a summary of dietary and supplemental approaches to addressing general chronic inflammation and para-inflammation. As many types of general inflammation often occur without additional symptoms, most of the strategies listed below are based on their ability to reduce circulating inflammatory cytokines, the hallmark of the para-inflammatory state.

Macronutrients and Energy Balance

Macronutrient content (particularly the types and levels of carbohydrates and fats) can have a significant effect on the progression of inflammation (as measured by increases in pro-inflammatory markers). Diets with relatively high glycemic index (GI) and glycemic load (GL) have been associated with elevated risk of coronary heart disease, stroke, and type 2 diabetes mellitus, particularly among overweight individuals, and have been associated with modest increases in proinflammatory markers in multiple studies.117 In a study of over 18,000 healthy women ≥45 years old without diagnosed diabetes, high GI and GL diets resulted in a small but significant increase in hs-CRP (+12% for high GI) over low GI diets.118 In the Danish Hoorne study,119 for every 10 unit increase in dietary glycemic index, circulating CRP was increased by 29%. As discussed previously, some dietary fats (particularly saturated and synthetic trans fats) increase inflammation occurrence, while omega-3 polyunsaturated fats appear to be anti-inflammatory.40

Since fat tissue (especially abdominal fat) expresses inflammatory cytokines, obesity can be a major cause of low-grade, systemic inflammation.33,34 Thus, it is important that total energy intake be proportional to energy expenditure, to avoid the deposition of abdominal fat. Obesity-induced increases in inflammatory cytokines appear to be reversible with fat loss.120 In a dramatic example, weight loss (by adjustable gastric banding) in a group of 20 severely obese individuals reduced IL-6 by 22% and CRP by almost half.121

An inflammatory index, developed by a group from the Arnold School of Public Health at the University of South Carolina, scored 42 common dietary constituents based on their ability to raise serum CRP.122 Constituents (such as saturated fat, tea polyphenols, or vitamin D) were given either a positive (anti-inflammatory) or negative (pro-inflammatory) score, the magnitude of which was weighted based on the volume of inflammation research on the isolated ingredient. Human clinical data was weighted more than animal data, and clinical trials more than observational studies. The scores were then verified by comparing them to nutrient intakes and CRP levels from a group of 494 volunteers over the course of one year. Amongst the most anti-inflammatory nutrients (based on the model and study data) are magnesium, beta-carotene, turmeric (curcumin), genistein, and tea; the most pro-inflammatory included carbohydrates, total- and saturated fat, and cholesterol. The index may provide a useful metric for accessing the overall inflammatory potential of an individual diet.

Exercise

Energy expenditure through exercise lowers multiple cytokines and pro-inflammatory molecules independently of weight loss. While muscle contraction initially results in a pro-inflammatory state, it paradoxically lowers systemic inflammation. This effect has been observed in dozens of human trials of exercise training in both healthy and unhealthy individuals across many age groups.123

Fiber

In an analysis of seven studies on the relationship between weight loss and hs-CRP, increased fiber consumption correlated with significantly greater reductions in hs-CRP concentrations. In these studies, daily fiber intakes ranging from 3.3 to 7.8 grams/MJ (equivalent to about 27 to 64 grams/day for a standard 2,000 kcal diet) reduced CRP from 25%‒54% in a dose-dependent fashion. These results should be interpreted carefully, as only two of the seven studies were specifically designed to examine the effects of fiber independently.120 The Women’s Health Initiative failed to detect an effect of fiber consumption on hs-CRP, but found that greater intake of dietary soluble and insoluble fiber (over 24 grams/day) was associated with lower levels of IL-6 and TNF-α.124

Micronutrients

Magnesium. In two large observation studies (the Women’s Health Initiative and Harvard Nurses Study), greater magnesium intake was associated with lower hs-CRP, IL-6, and TNF-α receptor, a measure of TNF-α activity.117,125 Data from the Multi-Ethnic Study of Atherosclerosis failed to find significant differences in IL-6 or CRP levels between individuals with the highest and lowest magnesium intakes, but did find a significant association between greater dietary magnesium and the lower levels of the inflammation-associated proteins homocysteine and fibrinogen.126 Magnesium was rated as the most anti-inflammatory dietary factor in the Dietary Inflammatory index, which rated 42 common dietary constituents on their ability to reduce CRP levels based on human and animal experimental and observation data.122

Vitamin D. Vitamin D appears to exert anti-inflammatory activity by the suppression of pro-inflammatory prostaglandins, and inhibition of the inflammatory mediator NF-κB.127 Although intervention studies of its anti-inflammatory activity in humans are lacking, several observational studies suggest vitamin D deficiency may promote inflammation. Vitamin D deficiencies are more common amongst patients with inflammatory diseases (including rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, and diabetes) than in healthy individuals.128 They also occur more frequently in populations that are prone to low-level inflammation, such as obese individuals and the elderly.129 Vitamin D levels can drop following surgery (a condition associated with acute inflammation), with a concomitant rise in CRP.130 Low vitamin D status was associated with elevated CRP in a study of 548 heart failure patients,131 and with increases in IL-6 and NF-κB in a group of 46 middle-aged men with endothelial dysfunction.132

Vitamin E. Vitamin E functions as an antioxidant in the body. Specifically, vitamin E is incorporated into low-density lipoprotein (LDL) particles and protects them against oxidative damage; it seems to guard against atherosclerosis via other mechanisms as well.133 The gamma-tocopherol form of vitamin E appears to complement the anti-inflammatory action of alpha-tocopherol. Gamma-tocopherol has been shown to inhibit COX-2 and attenuate IL-1β signaling.134,135 In a small clinical trial on subjects with metabolic syndrome, the combination of gamma-tocopherol and alpha-tocopherol effectively suppressed C-reactive protein and TNF-α levels compared to placebo.136 In this study, the combination of both tocopherols performed better than either alone, prompting the investigators to remark "the combination of [alpha-tocopherol] and [gamma-tocopherol] supplementation appears to be superior to either supplementation alone on biomarkers of oxidative stress and inflammation and needs to be tested in prospective clinical trials..."

Zinc and selenium. Zinc- and selenium-containing antioxidant proteins (such as superoxide dismutase and glutathione peroxidase) reduce reactive oxygen species (free radicals), which indirectly inhibits NF-κB activity and prevents the production of several inflammatory enzymes and cytokines. Zinc can also inhibit NF-κB in a more direct manner.137,138 Zinc supplementation is associated with decreases in inflammation in populations that are prone to zinc deficiency, such as children and the elderly.139,140 Low level inflammation and circulating pro-inflammatory factors (CRP, TNF-α, IL-6, and IL-8) were reduced in elderly subjects by moderate zinc supplementation in several studies.141-143 Like zinc, selenium deficiencies are common in chronic inflammatory states associated with disease (such as sepsis),144 where selenium supplementation has been associated with reductions in inflammation and better patient outcomes.138

Other Dietary Factors

Resveratrol and pterostilbene. The exact mechanism by which resveratrol exerts anti-inflammatory activity has not been established, although it inhibits a variety of pro-inflammatory compounds (cyclooxygenase, TNF-α, IL-1β, IL-6, NF-κB) in animal models and human cell culture.145,146 The related compound pterostilbene has demonstrated similar inhibition of inflammatory markers in cell culture.147 Modulation of the inflammatory immune response likely contributes to resveratrol’s protective role in animal models of heart disease, cancer, acute pancreatitis and inflammatory bowel disease.148 Resveratrol may be protective against general, low-level para-inflammation as well: when taken with a single high-fat, high-carbohydrate meal (930 kcal), resveratrol (100 mg) prevented the sharp post-meal increases in markers of oxidation and inflammation in a small crossover study of 10 healthy volunteers. For example, synthesis of IL-1β increased by 91% over five hours following the test meal; with resveratrol, this increase was significantly less (29%).149

Curcumin. Extensive in vitro and animal studies have examined the effects of curcumin on experimentally-induced inflammatory diseases (atherosclerosis, arthritis, diabetes, liver disease, gastrointestinal disorders, and cancers) and disease markers (lipoxygenase, cyclooxygenase, TNF-α, IL-1β, NF-κB, and others).150,151 Fewer human studies have examined curcumin’s effects on patient-oriented outcomes in inflammatory diseases, but most of the small randomized controlled trials of curcumin have consistently shown patient improvements in several inflammatory diseases, including psoriasis, irritable bowel syndrome, rheumatoid arthritis, and inflammatory eye disease.152,153

Tea polyphenols. The anti-inflammatory effects of green and black tea polyphenols have been substantiated by dozens of in vitro and animal studies.154 The polyphenols EGCG and theaflavin exert their anti-inflammatory effects through the inhibition of the NF-κB signaling pathway, which decreases expression of several inflammatory proteins (lipoxygenase, cyclooxygenase, TNF-α, IL-1β, IL-6, and IL-8) in cell culture experiments.155 EGCG also inhibits the production and release of histamine, a key mediator of allergic and inflammatory response, in vitro.156 In observational studies of tea consumption, >2 cups of tea/day (black or green) was associated with a nearly 20% reduction in CRP compared to non-tea drinkers, and significantly lower levels of two other inflammatory markers (serum amyloid A and haptogen, which are elevated in coronary heart disease).157 In clinical interventions, black tea appears to be more successful in reducing inflammatory markers than green.117 A 25% reduction in CRP was also observed in a small trial of healthy, non-smoking men consuming a black tea extract (equivalent to four cups of tea/day) for six weeks.158 A similar average reduction was observed in a larger study of healthy, individuals at high risk for coronary heart disease, but revealed a more dramatic 40‒50% reduction in CRP amongst individuals with the highest starting CRP values (>3 mg/L).159

Carotenoids. In the Women’s Health and Aging Study, participants with the highest blood levels of α-carotene and total carotenoids were significantly more likely to have the lower IL-6 levels than participants with low carotenoid levels at the onset of the study.160 Participants with the lowest blood levels of α- and β-carotene, lutein/zeaxanthin, or total carotenoids were more likely to experience increases in IL-6 over a period of two years.

DHEA. Low levels of sex hormones are associated with systemic increases in inflammatory markers9; DHEA (dehydroepiandrosterone), an adrenal steroid hormone, is the precursor to the sex steroids testosterone and estrogen. DHEA is abundant in youth, but steady declines with advancing age and may be partially responsible for age-related decreases sex steroids.161 In cell culture and animal models, DHEA can suppress inflammatory cytokine activity, in some cases more effectively than either testosterone or estrogen.162 Chronic inflammation may itself reduce DHEA levels.163 DHEA supplementation in elderly volunteers (50 mg/day for two years) significantly decreased TNF-α and IL-6 levels, as well as lowered visceral fat mass and improved glucose tolerance (both associated with inflammation) in a small study.164

Fish oil. Fish oil is the best source of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which can only be synthesized to a limited extent in humans. Omega-3 fatty acids have been well studied for their prevention of cardiovascular disease and mortality in tens of thousands of patients; the anti-inflammatory effects of omega-3’s contribute to this activity.165 They have also proven successful at improving patient outcomes in scores of studies of other inflammatory diseases, particularly asthma, inflammatory bowel disease, and rheumatoid arthritis.166,167

The association between greater fish oil/omega-3 consumption and reduced systemic inflammation is substantiated by data from several large observational trials. In 855 healthy participants from the Health Professionals Follow-Up Study, omega-3 fatty acid intake was associated with lower plasma levels of markers of TNF-α activity; interestingly, high intake of both omega-3 and omega-6 fatty acids (which are usually assumed to be pro-inflammatory) was associated with the lowest level of inflammation.168 The Nurses’ Health Study I cohort of 727 women revealed lower concentrations of inflammatory markers (including CRP and IL-6) amongst those in the top 20% of omega-3 consumption, when compared to those who consumed least amount.169 In the ATTICA study of over 3,000 Greek men and women without any evidence of cardiovascular disease, participants who consumed over 300 grams of fish per week had, on average, 33% lower CRP, 33% lower IL-6, and 21% lower TNF-α than participants who did not consume fish.170 In a sample of 5,677 men and women without cardiovascular disease from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, long-chain omega-3 intake (from fish or supplements) was associated with reduced plasma concentrations of multiple inflammatory markers (including CRP, IL-6, and TNF-α receptor, a measure of TNF-α activity).171

N-acetyl cysteine. Activation of the NF-κB pathway plays a central role in the activation of inflammatory cytokine genes; N-acetyl cysteine (NAC) inhibits NF-κB in cell culture, lowering expression of cytokines such as IL-6 and IL-8.172,173 Data establishing the effects of NAC on lowering chronic inflammation in humans is limited, but shows promise. NAC supplementation for eight weeks demonstrated modest, but statistically significant decreases in circulating IL-6 levels in patients with chronic kidney disease.174 The effects were more pronounced in persons with significant inflammation at the start of the study (as measured by hs-CRP). NAC also reduced markers of systemic inflammation in a small study of patients with burn injuries.175

Boswellia. Boswellia serrata (frankincense) is a traditional anti-arthritic in Ayurvedic medicine; its anti-inflammatory properties have been attributed to the specific inhibition of 5-LOX and reduction in the production of pro-inflammatory leukotrienes by boswellic acids, a constituent of the Boswellia gum resin.176 In cell culture, both crude and highly purified Boswellia extracts inhibited the production of pro-inflammatory TNF-α and IL-1β.177 One of the boswellic acids, Acetyl-11-keto-beta-boswellic acid (AKBA), was an inhibitor of NF-κB activity in mice,178 while a topical mixture of the four most abundant boswellic acids decreased inflammation in a rodent inflammation model.179 A recent systematic review of human trials of Boswellia for inflammatory conditions revealed that the small number of randomized controlled trials on the extract have produced encouraging results for its use for asthma and osteoarthritis,180 warranting larger studies to confirm the extract as an effective therapy. Standardized Boswellia extracts (30% AKBA) have been effective in mitigating pain in osteoarthritis patients181; when combined with non-volatile Boswellia oil, the standardized extract (called AprèsFlex, or Aflapin) demonstrated improved activity at a lower concentration.182 The use of Boswellia extracts for inflammatory bowel diseases has been investigated in multiple clinical trials, although results have been mixed.183-185

Sesame lignans. The observation that sesame oil could decrease the production of arachidonic acid in fungi and rat liver cells led to the identification of the sesame lignans (sesamin, sesamolin, sesaminol) as specific inhibitors of Δ5 desaturase (delta-5-desaturase), one of the enzymes used in the synthesis of arachidonic acid.186 By inhibiting Δ5 desaturase, sesame lignans may reduce the synthesis of pro-inflammatory prostaglandin, leukotrienes, and thromboxanes, each of which require arachidonic acid as a starting material.187 In animal models, diets high in sesame seed oil reduced production of the pro-inflammatory prostaglandins PGE-1 and -2, as well as thromboxane B2.188 In humans, five weeks of sesamin supplementation (39 mg/day) reduced the production of the pro-inflammatory vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE; a product of the enzyme 5-LOX) by 30%.189 This potential anti-inflammatory property of sesame lignans may partially explain its observed hypotensive (blood pressure-lowering) activity.190

Bromelain. The anti-inflammatory activity of the proteolytic enzyme preparation bromelain has been attributed to its ability to reduce COX-2 activity, decrease prostaglandin and thromboxane synthesis, lower circulating fibrinogen levels, and reduce cellular adhesion of pro-inflammatory white blood cells to the sites of inflammation.191 Human trials of bromelain for inflammatory conditions have yielded promising results.192 In a blinded study from Germany, researchers divided 90 patients with painful osteoarthritis of the hip into two groups: one half receiving an oral enzyme preparation containing bromelain for six weeks, while the other half received the anti-inflammatory drug diclofenac (sold under the brand name Voltaren and generic names). They found that the bromelain preparation was as effective as diclofenac in standard scales of pain, stiffness and physical function, and better tolerated than the drug comparator. The researchers concluded, "[the bromelain preparation] may well be recommended for the treatment of patients with osteoarthritis of the hip with signs of inflammation as indicated by a high pain level."193

Another study comparing a standardized commercial enzyme preparation containing bromelain with diclofenac reached the same conclusion. The study reported that the supplement containing bromelain (90 mg, three times daily) to be as effective as diclofenac (50 mg, twice daily) in improving the symptoms of osteoarthritis of the knee. Patients reported comparable reductions in joint tenderness, pain and swelling, and improvement in range of motion at the end of the study. The investigators found bromelain to be as good as diclofenac on a standard pain assessment scale and to be better than the drug in reducing pain at rest (by 41% for bromelain vs. 23% for the drug), improving restricted function (by 10% for bromelain vs. 0% for the drug), being rated by more patients in improving symptoms (24% for bromelain vs. 19% for the drug), and being evaluated by more physicians as having good efficacy (51% for bromelain vs. 37% for the drug). In summary, the investigators determined bromelain to be an effective and safe alternative to NSAIDs such as diclofenac for painful osteoarthritis.194

In further research from the United Kingdom, a three-month study looked at the dose-dependent effects of bromelain, either 200 mg or 400 mg a day in volunteers with mild acute knee pain. Pain evaluation was based on patient symptom scores, which were reduced by 41% in the 200 mg bromelain group and by 59% in those receiving 400 mg of bromelain, indicating a dose-response relationship. This was also observed for scores of stiffness and physical function, which decreased significantly in the higher-dose bromelain group compared with those receiving 200 mg. The researchers also noted that overall psychological well-being was significantly improved in both bromelain groups, leading to their conclusion that this natural therapy may be effective in improving general well-being as well as symptoms in otherwise healthy adults suffering from mild knee pain.195

In animal models and cell culture experiments, bromelain has consistently demonstrated a variety of anti-inflammatory properties.196-199

Mung bean extract. Mung bean (Vigna radiata) has been used for centuries in Asia as a traditional food and herbal medicine for inflammatory conditions, and modern research is supporting its anti-inflammatory effects.200 Two flavonoids in particular, vitexin and isovitexin, appear to be major contributors to mung bean’s beneficial properties. In one study, mung bean seed coat was found to contain 96% of the vitexin and isovitexin in mung bean, and accounted for 87% of the free radical-neutralizing potential of the bean.201 In preclinical studies, vitexin inhibited the production of inflammatory cytokines and maintained levels of defenses against oxidative stress.202,203 In an animal model of lung injury, isovitexin demonstrated anti-inflammatory effects related to inhibition of cytokines and reduction in oxidative tissue damage.204 Laboratory research has found additional compounds called mung bean seed coat saponins also inhibit cytokine expression.205 One laboratory trial found mung bean coat extract powerfully inhibited both a herpes and respiratory virus to a similar degree as the antiviral drug acyclovir, while in this case inducing antiviral cytokines including TNF-α and IL-6.206

In a trial in obese mice, mung bean seed coat extract significantly reduced inflammatory cytokine levels.207 Mung bean sprout extract demonstrated anti-arthritic activity in arthritic rats,208 and both mung bean seed coat and sprout extracts markedly improved glucose tolerance and metabolic health in diabetic mice.209

In one trial, mice that received mung bean seed coat extract were protected from lethal bacterial infection; the survival rate was 70% in treated mice versus 29.4% in untreated mice. In a laboratory component of the study, mung bean seed coat extract was found to inhibit a protein that mediates lethal systemic inflammation, and the inflammatory cytokine IL-6, while also demonstrating possible direct antibacterial activity.200 In a mouse study, treatment with a fermented mung bean preparation protected mice from cancer while inhibiting inflammation and stimulating immunity.210

Mitochondrial Support

Reactive oxygen species generated during mitochondrial respiration contribute to inflammation, as outlined earlier in the protocol. Aging individuals are especially susceptible to mitochondria-related oxidative stress since mitochondria become increasingly dysfunctional with age. Taking steps to support mitochondrial integrity and efficiency can help alleviate some of the systemic oxidative and inflammatory burden caused by poorly functioning mitochondria. Two nutrients, coenzyme Q10 and pyrroloquinoline quinoneare powerful mitochondrial protectants,211,212 and studies support an anti-inflammatory role for these compounds.

Pyrroloquinoline quinone. Pyrroloquinoline quinone (PQQ) is a cofactor for enzymes critically important for cellular energy homeostasis and redox balance.213 Several studies have shown that PQQ exerts a protective effective during circumstantial mitochondrial stress and increased oxidative load.212,214 In one study, rats given a diet supplemented with PQQ displayed greater energy expenditure and, remarkably, increased mitochondrial density in liver tissue. PQQ supplemented rats also had lower triglycerides and their hearts were more protected against lack of oxygen than rats that had not been given PQQ.215 During periods of limited oxygen supply to cardiac tissue, a dramatic spike in oxidative stress and subsequent inflammation damages cells; the findings from this animal model indicate that PQQ can stave off this inflammatory cell destruction by preserving mitochondrial efficiency in adverse conditions.

Coenzyme Q10. Coenzyme Q10 (CoQ10) is an indispensable intermediary in mitochondrial ATP production. Studies have shown that CoQ10 levels are low during inflammatory conditions. In one investigation, patients with septic shock were found to have CoQ10 levels substantially lower than healthy individuals, and, among patients, lower CoQ10 levels correlated with higher levels of an inflammatory mediator called VCAM.216 In an animal model in which rats were given drinking water with added fructose, an experiment that leads to obesity, diabetes, and other inflammatory complications, CoQ10 supplementation attenuated the inflammatory response by decreasing hepatic expression of CRP and other inflammatory mediators.217 Laboratory experiments indicate that CoQ10 modulates the expression of several hundred genes, many involved in inflammatory signaling.218 Of particular significance, one experiment showed that CoQ10, at physiologically relevant concentrations, was able to blunt induced TNF-α by more than 25% via modulation of the NF-κB signaling pathway.218

Guarding Against Inflammatory Glycation Reactions

The role of elevated blood sugar and glycation end products in initiating an inflammatory storm has been discussed. Fortunately, in addition to reducing caloric intake to suppress both fasting and post-meal glucose concentrations, some natural compounds ameliorate the glycation process and may help rein in the sugar-induced inflammatory cascade. Chief among these anti-glycation nutrients are benfotiamine, a member of the B-vitamin family, and carnosine, an amino acid.

Benfotiamine. Benfotiamine has been used to target diabetic complications since the mid 1990’s.219 More recent evidence continues to support its use as a powerful protector against blood sugar-induced tissue damage. In a clinical trial, 165 subjects with diabetes were randomized to receive benfotiamine at either 300 or 600 mg per day, or a placebo for six weeks. After the intervention period, those taking benfotiamine exhibited improvements in neuropathic pain in a dose-dependent fashion.220 An animal model found that benfotiamine relieved neuropathic pain by powerfully suppressing inflammation.221 Moreover, laboratory experiments have shown that, in addition to blocking glycation reactions, benfotiamine may regulate inflammation more directly by modulating COX and LOX enzyme activity.222

Carnosine. Carnosine exerts a range of favorable biochemical effects within the body; it powerfully blunts glycation reactions and eases oxidative stress.223 In addition, several experiments have revealed a marked ability of carnosine to suppress inflammation in various cell types.224-226 Unfortunately, carnosine levels decline as much as 63% between ages 10 and 70.227 Furthermore, in patients with type II diabetes, skeletal muscle carnosine content is markedly lower than in healthy control subjects.228 When carnosine is administered as a supplement to animals with chemically-induced diabetes, it is able to protect delicate retinal cells from inflammatory complications related to high blood sugar.229

Gynostemma pentaphyllum. Gynostemma pentaphyllum (G. pentaphyllum) is used in Asian medicine to treat several health conditions, including dyslipidemia, type 2 diabetes, and inflammation.230 Its effects are due, at least in part, to its ability to activate a critical enzyme called adenosine monophosphate-activated protein kinase (AMPK). This enzyme, which affects glucose metabolism and fat storage, has been called a "metabolic master switch" because it controls numerous pathways related to extracting energy from food and storing and distributing that energy throughout the body.231

Being overweight has a significant effect on AMPK activation and chronic inflammation; it suppresses AMPK activation, leading to abdominal fat deposits which, in turn, activate systemic inflammation. At the same time, inflammation itself suppresses AMPK activation, creating a viscous circle.232

Yet greater AMPK activation contributes to weight loss and can suppress inflammation.233-235 In addition, increased AMPK activation is associated with reduced liver fat accumulation, another source of inflammatory chemicals.236

Evidence demonstrate the anti-inflammatory effects of G. pentaphyllum. In one laboratory study, researchers found extracts of the herb significantly inhibited several inflammatory chemicals, including TNF-α, interleukin-6, and COX-2 mRNA.237 Another study in 24 patients with type 2 diabetes found drinking a tea made with the herb for 12 weeks significantly reduced insulin resistance, which is a key contributor to systemic inflammation.2,238

Hesperidin. Hesperidin and related flavonoids are found in a variety of plants, but especially in citrus fruits, particularly their peels.239,240 Digestion of hesperidin produces a compound called hesperetin along with other metabolites. These compounds are powerful free radical scavengers and have demonstrated anti-inflammatory, insulin-sensitizing, and lipid-lowering activity.241,242 Findings from animal and in vitro research suggest hesperidin’s positive effects on blood glucose and lipid levels may be related in part to activation of the AMP-activated protein kinase (AMPK) pathway.243-245 Accumulating evidence suggest hesperidin may help prevent and treat a number of chronic diseases associated with aging.241

Hesperidin may protect against diabetes and its complications, partly through activation of the AMPK signaling pathway. Coincidentally, metformin, a leading diabetes medication, also activates the AMPK pathway. In a six-week randomized controlled trial on 24 diabetic participants, supplementation with 500 mg of hesperidin per day improved glycemic control, increased total antioxidant capacity, and reduced oxidative stress and DNA injury.246 Using urinary hesperetin as a marker of dietary hesperidin, another group of researchers found those with the highest level of hesperidin intake had 32% lower risk of developing diabetes over 4.6 years compared to those with the lowest intake level.247

In a randomized controlled trial, 24 adults with metabolic syndrome were treated with 500 mg of hesperidin per day or placebo for three weeks. After a washout period, the trial was repeated with hesperidin and placebo assignments reversed. Hesperidin treatment improved endothelial function, suggesting this may be one important mechanism behind its benefit to the cardiovascular system. Hesperidin supplementation also led to a 33% reduction in median levels of the inflammatory marker hs-CRP, as well as significant decreases in levels of total cholesterol, apolipoprotein B (apoB), and markers of vascular inflammation, relative to placebo.244 In another randomized controlled trial in overweight adults with evidence of pre-existing vascular dysfunction, 450 mg per day of a hesperidin supplement for six weeks resulted in lower blood pressure and a decrease in markers of vascular inflammation.248 Another controlled clinical trial included 75 heart attack patients who were randomly assigned to receive 600 mg hesperidin per day or placebo for four weeks. Those taking hesperidin had significant improvements in levels of high-density lipoprotein (HDL) cholesterol and markers of vascular inflammation and fatty acid and glucose metabolism.249

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

  1. Centers for Disease Control and Prevention. FASTSTATS - Leading Causes of Death. cdc.gov. 2011; Available at: http://www.cdc.gov/NCHS/fastats/Default.htm [Accessed December 23, 2011].
  2. Bastard, J.-P., Maachi, M., Lagathu, C., et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur. Cytokine Netw. 2006;17(1):4–12
  3. Cao, J. J. Effects of obesity on bone metabolism. J Orthop Surg Res. 2011;6:30
  4. Jha, R. K., Ma, Q., Sha, H., and Palikhe, M. Acute pancreatitis: a literature review. Med Sci Monit. 2009;15(7):RA147–56
  5. Ferrucci, L., Semba, R. D., Guralnik, J. M., et al. Proinflammatory state, hepcidin, and anemia in older persons. Blood. 2010;115(18):3810–3816
  6. Glorieux, G., Cohen, G., Jankowski, J., and Vanholder, R. Platelet/Leukocyte activation, inflammation, and uremia. Semin Dial. 2009;22(4):423–427
  7. Kundu, J. K., and Surh, Y.-J. Inflammation: gearing the journey to cancer. Mutat Res. 2008;659(1-2):15–30
  8. Murphy SL. et al. Deaths: Preliminary Data for 2010. National Vital Statistics Report 60:4; 1/11/2012.
  9. Singh, T., and Newman, A. B. Inflammatory markers in population studies of aging. Ageing Res Rev. 2011;10(3):319–329
  10. Karin, M., Lawrence, T., and Nizet, V. Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell. 2006;124(4):823–835
  11. Medzhitov, R. Origin and physiological roles of inflammation. Nature. 2008;454(7203):428–435
  12. Green DR et al. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science. 2011 Aug 26;333(6046):1109-12.
  13. Dinarello CA et al. A clinical perspective of IL-1β as the gatekeeper of inflammation. Eur J Immunol. 2011 May;41(5):1203-17. doi: 10.1002/eji.201141550.
  14. Tschopp J. Mitochondria: Sovereign of inflammation? Eur J Immunol. 2011 May;41(5):1196-202. doi: 10.1002/eji.201141436.
  15. Mosquera JA. [Role of the receptor for advanced glycation end products (RAGE) in inflammation]. Invest Clin. 2010 Jun;51(2):257-68.
  16. Witko-Sarsat, V., Friedlander, M., Nguyen Khoa, T., et al. Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure. J Immunol. 1998;161(5):2524–2532
  17. Vlassara, H., Cai, W., Crandall, J., et al. Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy. Proc Natl Acad Sci USA. 2002;99(24):15596–15601
  18. Martinon, F., Pétrilli, V., Mayor, A., Tardivel, A., and Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440(7081):237–241
  19. Alvarez-Lario, B., and Macarrón-Vicente, J. Is there anything good in uric acid? QJM. 2011;
  20. Nguyen Khoa, T., Massy, Z. A., Witko-Sarsat, V., et al. Oxidized low-density lipoprotein induces macrophage respiratory burst via its protein moiety: A novel pathway in atherogenesis? Biochem Biophys Res Commun. 1999;263(3):804–809
  21. Au-Yeung, K. K. W., Yip, J. C. W., Siow, Y. L., and O, K. Folic acid inhibits homocysteine-induced superoxide anion production and nuclear factor kappa B activation in macrophages. Can. J. Physiol. Pharmacol. 2006;84(1):141–147
  22. Green, S., Dobrjansky, A., Carswell, E. A., et al. Partial purification of a serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA. 1976;73(2):381–385
  23. Sethi, G., Sung, B., and Aggarwal, B. B. TNF: a master switch for inflammation to cancer. Front Biosci. 2008;13:5094–5107
  24. Meyer, O. Anti-CRP antibodies in systemic lupus erythematosus. Joint Bone Spine. 2010;77(5):384–389
  25. Windgassen, E. B., Funtowicz, L., Lunsford, T. N., Harris, L. A., and Mulvagh, S. L. C-reactive protein and high-sensitivity C-reactive protein: an update for clinicians. Postgrad Med. 2011;123(1):114–119
  26. Emerging Risk Factors Collaboration, Kaptoge, S., Di Angelantonio, E., et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010;375(9709):132–140
  27. Luo, P., and Wang, M.-H. Eicosanoids, β-cell function, and diabetes. Prostaglandins Other Lipid Mediat. 2011;95(1-4):1–10
  28. Serhan, C. N., and Oliw, E. Unorthodox routes to prostanoid formation: new twists in cyclooxygenase-initiated pathways. J Clin Invest. 2001;107(12):1481–1489
  29. Trayhurn, P., and Wood, I. S. Signalling role of adipose tissue: adipokines and inflammation in obesity. Biochem. Soc. Trans. 2005;33(Pt 5):1078–1081
  30. Schrager, M. A., Metter, E. J., Simonsick, E., et al. Sarcopenic obesity and inflammation in the InCHIANTI study. J Appl Physiol. 2007;102(3):919–925
  31. Fried, S. K., Bunkin, D. A., and Greenberg, A. S. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab. 1998;83(3):847–850
  32. Mohamed-Ali, V., Goodrick, S., Rawesh, A., et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab. 1997;82(12):4196–4200
  33. Ortega Martinez de Victoria, E., Xu, X., Koska, J., et al. Macrophage content in subcutaneous adipose tissue: associations with adiposity, age, inflammatory markers, and whole-body insulin action in healthy Pima Indians. Diabetes. 2009;58(2):385–393
  34. Weisberg, S. P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R. L., and Ferrante, A. W. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796–1808
  35. Nappo, F., Esposito, K., Cioffi, M., et al. Postprandial endothelial activation in healthy subjects and in type 2 diabetic patients: role of fat and carbohydrate meals. J Am Coll Cardiol. 2002;39(7):1145–1150
  36. Peairs, A. D., Rankin, J. W., and Lee, Y. W. Effects of acute ingestion of different fats on oxidative stress and inflammation in overweight and obese adults. Nutr J. 2011;10:122
  37. Myhrstad, M. C. W., Narverud, I., Telle-Hansen, V. H., et al. Effect of the fat composition of a single high-fat meal on inflammatory markers in healthy young women. Br J Nutr. 2011;106(12):1826–1835
  38. Poppitt, S. D., Keogh, G. F., Lithander, F. E., et al. Postprandial response of adiponectin, interleukin-6, tumor necrosis factor-alpha, and C-reactive protein to a high-fat dietary load. Nutrition. 2008;24(4):322–329
  39. Payette, C., Blackburn, P., Lamarche, B., et al. Sex differences in postprandial plasma tumor necrosis factor-alpha, interleukin-6, and C-reactive protein concentrations. Metab. Clin. Exp. 2009;58(11):1593–1601
  40. Mozaffarian, D., and Pischon, T. Dietary intake of trans fatty acids and systemic inflammation in women. American Journal of …. 2004;
  41. Lopez-Garcia, E., Schulze, M. B., Meigs, J. B., et al. Consumption of trans fatty acids is related to plasma biomarkers of inflammation and endothelial dysfunction. J Nutr. 2005;135(3):562–566
  42. Nielsen, B. M., Nielsen, M. M., Jakobsen, M. U., et al. A cross-sectional study on trans-fatty acids and risk markers of CHD among middle-aged men representing a broad range of BMI. Br J Nutr. 2011;106(8):1245–1252
  43. Bendsen, N. T., Stender, S., Szecsi, P. B., et al. Effect of industrially produced trans fat on markers of systemic inflammation: evidence from a randomized trial in women. The Journal of Lipid Research. 2011;52(10):1821–1828
  44. Ahmadi N, Eshaghian S, Huizenga R, et al. Effects of intense exercise and moderate caloric restriction on cardiovascular risk factors and inflammation. Am J Med. 2011;124(10):978-82.
  45. González O, Tobia C, Ebersole J, et al. Caloric restriction and chronic inflammatory diseases. Oral Dis. 2012;18(1):16-31.
  46. Gilliver, S. C. Sex steroids as inflammatory regulators. J. Steroid Biochem. Mol. Biol. 2010;120(2-3):105–115
  47. Keller, E. T., Chang, C., and Ershler, W. B. Inhibition of NFkappaB activity through maintenance of IkappaBalpha levels contributes to dihydrotestosterone-mediated repression of the interleukin-6 promoter. J Biol Chem. 1996;271(42):26267–26275
  48. Ray, P., Ghosh, S. K., Zhang, D. H., and Ray, A. Repression of interleukin-6 gene expression by 17 beta-estradiol: inhibition of the DNA-binding activity of the transcription factors NF-IL6 and NF-kappa B by the estrogen receptor. FEBS letters. 1997;409(1):79–85
  49. Deshpande, R., Khalili, H., Pergolizzi, R. G., Michael, S. D., and Chang, M. D. Estradiol down-regulates LPS-induced cytokine production and NFkB activation in murine macrophages. Am. J. Reprod. Immunol. 1997;38(1):46–54
  50. Maggio, M., Basaria, S., Ble, A., et al. Correlation between testosterone and the inflammatory marker soluble interleukin-6 receptor in older men. J Clin Endocrinol Metab. 2006;91(1):345–347
  51. Khosla, S., Atkinson, E. J., Dunstan, C. R., and O'Fallon, W. M. Effect of estrogen versus testosterone on circulating osteoprotegerin and other cytokine levels in normal elderly men. J Clin Endocrinol Metab. 2002;87(4):1550–1554
  52. Gameiro, C., and Romao, F. Changes in the immune system during menopause and aging. Front Biosci (Elite Ed). 2010;2:1299–1303
  53. Kane, S. V., and Reddy, D. Hormonal replacement therapy after menopause is protective of disease activity in women with inflammatory bowel disease. Am J Gastroenterol. 2008;103(5):1193–1196
  54. Vural, P., Akgul, C., and Canbaz, M. Effects of hormone replacement therapy on plasma pro-inflammatory and anti-inflammatory cytokines and some bone turnover markers in postmenopausal women. Pharmacol. Res. 2006;54(4):298–302
  55. Anderson, G. L., Limacher, M., Assaf, A. R., et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701–1712
  56. Arnson, Y., Shoenfeld, Y., and Amital, H. Effects of tobacco smoke on immunity, inflammation and autoimmunity. J. Autoimmun. 2010;34(3):J258–65
  57. Lee J, Taneja V, Vassallo R. Cigarette smoking and inflammation: cellular and molecular mechanisms. J Dent Res. 2012;91(2):142-9.
  58. Vgontzas, A. N., Papanicolaou, D. A., Bixler, E. O., Kales, A., Tyson, K., and Chrousos, G. P. Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. J Clin Endocrinol Metab. 1997;82(5):1313–1316
  59. Vgontzas, A. N., Papanicolaou, D. A., Bixler, E. O., et al. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab. 2000;85(3):1151–1158
  60. Vgontzas, A. N., Zoumakis, M., Bixler, E. O., et al. Impaired nighttime sleep in healthy old versus young adults is associated with elevated plasma interleukin-6 and cortisol levels: physiologic and therapeutic implications. J Clin Endocrinol Metab. 2003;88(5):2087–2095
  61. Trakada, G., Chrousos, G., Pejovic, S., and Vgontzas, A. Sleep Apnea and its association with the Stress System, Inflammation, Insulin Resistance and Visceral Obesity. Sleep Med Clin. 2007;2(2):251–261
  62. Slade, G. D., Ghezzi, E. M., Heiss, G., Beck, J. D., Riche, E., and Offenbacher, S. Relationship between periodontal disease and C-reactive protein among adults in the Atherosclerosis Risk in Communities study. Arch Intern Med. 2003;163(10):1172–1179
  63. Pradeep, A. R., Kathariya, R., Arjun Raju, P., Sushma Rani, R., Sharma, A., and Raghavendra, N. M. Risk factors for chronic kidney diseases may include periodontal diseases, as estimated by the correlations of plasma pentraxin-3 levels: a case-control study. Int Urol Nephrol. 2011;
  64. Vaishnava, P., Narayan, R., and Fuster, V. Understanding systemic inflammation, oral hygiene, and cardiovascular disease. Am. J. Med. 2011;124(11):997–999
  65. Pervanidou, P., and Chrousos, G. P. Metabolic consequences of stress during childhood and adolescence. Metab. Clin. Exp. 2011;
  66. van Westerloo, D. J. The vagal immune reflex: a blessing from above. Wien Med Wochenschr. 2010;160(5-6):112–117
  67. Pontet, J., Contreras, P., Curbelo, A., et al. Heart rate variability as early marker of multiple organ dysfunction syndrome in septic patients. J Crit Care. 2003;18(3):156–163
  68. Taylor, L., Loerbroks, A., Herr, R. M., Lane, R. D., Fischer, J. E., and Thayer, J. F. Depression and smoking: mediating role of vagal tone and inflammation. Ann Behav Med. 2011;42(3):334–340
  69. Basta G, Schmidt AM, De Caterina R. Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovasc Res. 2004 Sep 1;63(4):582-92.
  70. Uribarri J, Cai W, Sandu O, Peppa M, Goldberg T, Vlassara H. Diet-derived advanced glycation end products are major contributors to the body’s AGE pool and induce inflammation in healthy subjects. Ann N Y Acad Sci. 2005 Jun;1043:461-6.
  71. Toma L, Stancu CS, Botez GM, Sima AV, Simionescu M. Irreversibly glycated LDL induce oxidative and inflammatory state in human endothelial cells; added effect of high glucose. Biochem Biophys Res Commun. 2009 Dec 18;390(3):877-82.
  72. Henry-Vitrac C, Ibarra A, Roller M, Merillon JM, Vitrac X. Contribution of chlorogenic acids to the inhibition of human hepatic glucose-6-phosphatase activity in vitro by Svetol, a standardized decaffeinated green coffee extract. J Agric Food Chem. 2010 Apr 14;58(7):4141-4.
  73. Andrade-Cetto A, Vazquez RC. Gluconeogenesis inhibition and phytochemical composition of two Cecropia species. J Ethnopharmacol. 2010 Jul 6;130(1):93-7.
  74. Rodriguez de Sotillo DV, Hadley M, Sotillo JE. Insulin receptor exon 11+/- is expressed in Zucker (fa/fa) rats, and chlorogenic acid modifies their plasma insulin and liver protein and DNA. J Nutr Biochem. 2006 Jan;17(1):63-71.
  75. Nagendran MV. Effect of green coffee bean extract (GCE), High in Chlorogenic Acids, on Glucose Metabolism. Poster presentation number: 45-LB-P. Obesity 2011, the 29th Annual Scientific Meeting of the Obesity Society. Orlando, Florida. October 1-5, 2011.
  76. Aggarwal, B. B., Shishodia, S., Sandur, S. K., Pandey, M. K., and Sethi, G. Inflammation and cancer: how hot is the link? Biochem. Pharmacol. 2006;72(11):1605–1621
  77. Balkwill, F. Tumour necrosis factor and cancer. Nat. Rev. Cancer. 2009;9(5):361–371
  78. Pickup, J. C., Chusney, G. D., Thomas, S. M., and Burt, D. Plasma interleukin-6, tumour necrosis factor alpha and blood cytokine production in type 2 diabetes. Life Sci. 2000;67(3):291–300
  79. Hong, T., Tan, A. G., Mitchell, P., and Wang, J. J. A review and meta-analysis of the association between C-reactive protein and age-related macular degeneration. Surv Ophthalmol. 2011;56(3):184–194
  80. Dantzer, R. Depression and inflammation: an intricate relationship. Biol. Psychiatry. 2012;71(1):4–5
  81. Gimeno, D., Kivimäki, M., Brunner, E. J., et al. Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study. Psychol Med. 2009;39(3):413–423
  82. Copeland, W. E., Shanahan, L., Worthman, C., Angold, A., and Costello, E. J. Cumulative depression episodes predict later C-reactive protein levels: a prospective analysis. Biol. Psychiatry. 2012;71(1):15–21
  83. Yaffe, K., Lindquist, K., Penninx, B. W., et al. Inflammatory markers and cognition in well-functioning African-American and white elders. Neurology. 2003;61(1):76–80
  84. Kaser, A., and Tilg, H. “Metabolic aspects” in inflammatory bowel diseases. Curr Drug Deliv. 2011;
  85. Kadetoff, D., Lampa, J., Westman, M., Andersson, M., and Kosek, E. Evidence of central inflammation in fibromyalgia - Increased cerebrospinal fluid interleukin-8 levels. J. Neuroimmunol. 2011;
  86. Rolland, Y., Abellan van Kan, G., Gillette-Guyonnet, S., and Vellas, B. Cachexia versus sarcopenia. Current Opinion in Clinical Nutrition and Metabolic Care. 2011;14(1):15–21
  87. Groesdonk HV et al. [Anti-inflammatory effects of pentoxifylline: importance in cardiac surgery]. Anaesthesist. 2009 Nov;58(11):1136-43. Review. German.
  88. Li W et al. Systematic review on the treatment of pentoxifylline in patients with non-alcoholic fatty liver disease. Lipids Health Dis. 2011 Apr 8;10:49. Review.
  89. Lopes de Jesus CC et al. lline for diabetic retinopathy. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD006693. Review.
  90. Lv D et al. Pentoxifylline versus medical therapies for subfertile women with endometriosis. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD007677. Review.
  91. Hepgul G et al. Preventive effect of pentoxifylline on acute radiation damage via antioxidant and anti-inflammatory pathways. Dig Dis Sci. 2010 Mar;55(3):617-25. Epub 2009 Mar 18.
  92. Goicoechea M et al. Effects of pentoxifylline on inflammatory parameters in chronic kidney disease patients: a randomized trial. J Nephrol. 2012 Jan 11:0. doi: 10.5301/jn.5000077. [Epub ahead of print]
  93. Gupta SK et al. Anti-inflammatory treatment with pentoxifylline improves HIV-related endothelial dysfunction: a pilot study. AIDS. 2010 Jun 1;24(9):1377-80.
  94. Izadpanah F et al. Effect of intravenous pentoxifylline in inflammatory response in patients undergoing nephrolithotomy. J Endourol. 2009 Feb;23(2):323-8.
  95. Maiti R et al. Effect of Pentoxifylline on inflammatory burden, oxidative stress and platelet aggregability in hypertensive type 2 diabetes mellitus patients. Vascul Pharmacol. 2007 Aug-Sep;47(2-3):118-24. Epub 2007 Jun 2.
  96. Molavi, B., Rassouli, N., Bagwe, S., and Rasouli, N. A review of thiazolidinediones and metformin in the treatment of type 2 diabetes with focus on cardiovascular complications. Vasc Health Risk Manag. 2007;3(6):967–973
  97. Buler, M., Aatsinki, S.-M., Skoumal, R., et al. Energy-sensing Factors Coactivator Peroxisome Proliferator-activated Receptor γ Coactivator 1-α (PGC-1α) and AMP-activated Protein Kinase Control Expression of Inflammatory Mediators in Liver: INDUCTION OF INTERLEUKIN 1 RECEPTOR ANTAGONIST. J Biol Chem. 2012;287(3):1847–1860
  98. Sobel, B. E., Hardison, R. M., Genuth, S., et al. Profibrinolytic, antithrombotic, and antiinflammatory effects of an insulin-sensitizing strategy in patients in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Circulation. 2011;124(6):695–703
  99. Gómez-García, A., Martínez Torres, G., Ortega-Pierres, L. E., Rodríguez-Ayala, E., and Alvarez-Aguilar, C. [Rosuvastatin and metformin decrease inflammation and oxidative stress in patients with hypertension and dyslipidemia]. Rev Esp Cardiol. 2007;60(12):1242–1249
  100. Pruski, M., Krysiak, R., and Okopien, B. Pleiotropic action of short-term metformin and fenofibrate treatment, combined with lifestyle intervention, in type 2 diabetic patients with mixed dyslipidemia. Diabetes Care. 2009;32(8):1421–1424
  101. Patrono C, Rocca B. Aspirin: promise and resistance in the new millennium. Arterioscler Thromb Vasc Biol. 2008;28(3):s25-32.
  102. Rothwell PM, Fowkes FG, Belch JF, et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011;377(9759):31-41.
  103. Rothwell PM, Wilson M, Elwin CE, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010;376(9754):1741-50.
  104. Salinas CA, Kwon EM, FitzGerald LM, et al. Use of aspirin and other nonsteroidal antiinflammatory medications in relation to prostate cancer risk. Am J Epidemiol. 2010;172(5):578-90.
  105. Flossmann E, Rothwell PM, British Doctors Aspirin Trial and the UK-TIA Aspirin Trial. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet. 2007;369(9573):1603-13.
  106. Sobolewski, C., Cerella, C., Dicato, M., Ghibelli, L., and Diederich, M. The role of cyclooxygenase-2 in cell proliferation and cell death in human malignancies. Int J Cell Biol. 2010;2010:215158
  107. Weber, C., Erl, W., Pietsch, A., and Weber, P. C. Aspirin inhibits nuclear factor-kappa B mobilization and monocyte adhesion in stimulated human endothelial cells. Circulation. 1995;91(7):1914–1917
  108. Ikonomidis, I., Andreotti, F., Economou, E., Stefanadis, C., Toutouzas, P., and Nihoyannopoulos, P. Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. Circulation. 1999;100(8):793–798
  109. Chen, Y.-G., Xu, F., Zhang, Y., et al. Effect of aspirin plus clopidogrel on inflammatory markers in patients with non-ST-segment elevation acute coronary syndrome. Chin. Med. J. 2006;119(1):32–36
  110. Solheim, S., Arnesen, H., Eikvar, L., Hurlen, M., and Seljeflot, I. Influence of aspirin on inflammatory markers in patients after acute myocardial infarction. Am J Cardiol. 2003;92(7):843–845
  111. Solheim, S., Pettersen, A. A., Arnesen, H., and Seljeflot, I. No difference in the effects of clopidogrel and aspirin on inflammatory markers in patients with coronary heart disease. Thromb. Haemost. 2006;96(5):660–664
  112. Serhan, C. N., Hong, S., Gronert, K., et al. Resolvins: A Family of Bioactive Products of Omega-3 Fatty Acid Transformation Circuits Initiated by Aspirin Treatment that Counter Proinflammation Signals. Journal of Experimental Medicine. 2002;196(8):1025–1037
  113. Stancu, C., and Sima, A. Statins: mechanism of action and effects. J. Cell. Mol. Med. 2001;5(4):378–387
  114. Bu, D.-X., Griffin, G., and Lichtman, A. H. Mechanisms for the anti-inflammatory effects of statins. Curr. Opin. Lipidol. 2011;22(3):165–170
  115. Ridker, P. M., Danielson, E., Fonseca, F. A. H., et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–2207
  116. Bulcão, C., Giuffrida, F. M. A., Ribeiro-Filho, F. F., and Ferreira, S. R. G. Are the beneficial cardiovascular effects of simvastatin and metformin also associated with a hormone-dependent mechanism improving insulin sensitivity? Braz. J. Med. Biol. Res. 2007;40(2):229–235
  117. Galland, L. Diet and inflammation. Nutr Clin Pract. 2010;25(6):634–640
  118. Levitan, E. B., Cook, N. R., Stampfer, M. J., et al. Dietary glycemic index, dietary glycemic load, blood lipids, and C-reactive protein. Metabolism. 2008;57(3):437–443
  119. Du, H., van der A, D. L., van Bakel, M. M. E., et al. Glycemic index and glycemic load in relation to food and nutrient intake and metabolic risk factors in a Dutch population. American Journal of Clinical Nutrition. 2008;87(3):655–661
  120. North, C. J., Venter, C. S., and Jerling, J. C. The effects of dietary fibre on C-reactive protein, an inflammation marker predicting cardiovascular disease. Eur J Clin Nutr. 2009;63(8):921–933
  121. Moschen, A. R., Molnar, C., Geiger, S., et al. Anti-inflammatory effects of excessive weight loss: potent suppression of adipose interleukin 6 and tumour necrosis factor alpha expression. Gut. 2010;59(9):1259–1264
  122. Cavicchia, P. P., Steck, S. E., Hurley, T. G., et al. A new dietary inflammatory index predicts interval changes in serum high-sensitivity C-reactive protein. Journal of Nutrition. 2009;139(12):2365–2372
  123. Bruunsgaard, H. Physical activity and modulation of systemic low-level inflammation. J Leukoc Biol. 2005;78(4):819–835
  124. Ma, Y., Hébert, J., Li, W., and Bertone-Johnson, E. Association between dietary fiber and markers of systemic inflammation in the Women's Health Initiative Observational Study. Nutrition. 2008;
  125. Chacko, S., Song, Y., Nathan, L., and Tinker, L. Relations of dietary magnesium intake to biomarkers of inflammation and endothelial dysfunction in an ethnically diverse cohort of postmenopausal women. Diabetes. 2010;
  126. de Oliveira Otto, M. C. C., Alonso, A., Lee, D.-H., et al. Dietary micronutrient intakes are associated with markers of inflammation but not with markers of subclinical atherosclerosis. Journal of Nutrition. 2011;141(8):1508–1515
  127. Krishnan, A. V., Trump, D. L., Johnson, C. S., and Feldman, D. The role of vitamin D in cancer prevention and treatment. Endocrinol. Metab. Clin. North Am. 2010;39(2):401–18, table of contents
  128. Guillot, X., Semerano, L., Saidenberg-Kermanac'h, N., Falgarone, G., and Boissier, M.-C. Vitamin D and inflammation. Joint Bone Spine. 2010;77(6):552–557
  129. Awad, A. B., Alappat, L., and Valerio, M. Vitamin d and metabolic syndrome risk factors: evidence and mechanisms. Crit Rev Food Sci Nutr. 2012;52(2):103–112
  130. Reid, D., Toole, B. J., Knox, S., et al. The relation between acute changes in the systemic inflammatory response and plasma 25-hydroxyvitamin D concentrations after elective knee arthroplasty. American Journal of Clinical Nutrition. 2011;93(5):1006–1011
  131. Liu, L. C. Y., Voors, A. A., van Veldhuisen, D. J., et al. Vitamin D status and outcomes in heart failure patients. Eur. J. Heart Fail. 2011;13(6):619–625
  132. Jablonski, K. L., Chonchol, M., Pierce, G. L., Walker, A. E., and Seals, D. R. 25-Hydroxyvitamin D deficiency is associated with inflammation-linked vascular endothelial dysfunction in middle-aged and older adults. Hypertension. 2011;57(1):63–69
  133. Meydani M. Vitamin E and atherosclerosis: beyond prevention of LDL oxidation. J Nutr. 2001Feb;131(2):366S-8S.
  134. Jiang Q, Elson-Schwab I, Courtemanche C, Ames BN. gamma-tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells. Proc Natl Acad Sci USA. 2000 Oct 10;97(21):11494-9.
  135. Sjoholm A, Berggren PO, Cooney RV. gamma-tocopherol partially protects insulin-secreting cells against functional inhibition by nitric oxide. Biochem Biophys Res Commun. 2000 Oct 22;277(2):334-40.
  136. Devaraj S, Leonard S, Traber MG, et al. Gamma-tocopherol supplementation alone and in combination with alpha-tocopherol alters biomarkers of oxidative stress and inflammation in subjects with metabolic syndrome. Free Radic Biol Med. 2008;44(6):1203-8.
  137. Prasad, A. S. Zinc: role in immunity, oxidative stress and chronic inflammation. Current Opinion in Clinical Nutrition and Metabolic Care. 2009;12(6):646–652
  138. Duntas, L. H. Selenium and inflammation: underlying anti-inflammatory mechanisms. Horm. Metab. Res. 2009;41(6):443–447
  139. Kelishadi, R., Hashemipour, M., Adeli, K., et al. Effect of zinc supplementation on markers of insulin resistance, oxidative stress, and inflammation among prepubescent children with metabolic syndrome. Metab Syndr Relat Disord. 2010;8(6):505–510
  140. Wong, C. P., and Ho, E. Zinc and its role in age-related inflammation and immune dysfunction. Mol. Nutr. Food Res. 2011;
  141. Bao, B., Prasad, A. S., Beck, F. W. J., et al. Zinc decreases C-reactive protein, lipid peroxidation, and inflammatory cytokines in elderly subjects: a potential implication of zinc as an atheroprotective agent. American Journal of Clinical Nutrition. 2010;91(6):1634–1641
  142. Kahmann, L., Uciechowski, P., Warmuth, S., et al. Zinc supplementation in the elderly reduces spontaneous inflammatory cytokine release and restores T cell functions. Rejuvenation Res. 2008;11(1):227–237
  143. Mariani, E., Cattini, L., Neri, S., et al. Simultaneous evaluation of circulating chemokine and cytokine profiles in elderly subjects by multiplex technology: relationship with zinc status. Biogerontology. 2006;7(5-6):449–459
  144. Maehira, F., Luyo, G. A., Miyagi, I., et al. Alterations of serum selenium concentrations in the acutephase of pathological conditions. Clin. Chim. Acta. 2002;316(1-2):137–146
  145. Jha, R. K., Ma, Q., Sha, H., and Palikhe, M. Emerging role of resveratrol in the treatment of severe acute pancreatitis. Front Biosci (Schol Ed). 2010;2:168–175
  146. Khanduja, K. L., Bhardwaj, A., and Kaushik, G. Resveratrol inhibits N-nitrosodiethylamine-induced ornithine decarboxylase and cyclooxygenase in mice. J. Nutr. Sci. Vitaminol. 2004;50(1):61–65
  147. Pan, Z., Agarwal, A. K., Xu, T., et al. Identification of molecular pathways affected by pterostilbene, a natural dimethylether analog of resveratrol. BMC Med Genomics. 2008;1:7
  148. Clarke, J. O., and Mullin, G. E. A review of complementary and alternative approaches to immunomodulation. Nutrition in Clinical Practice. 2008;23(1):49–62
  149. Ghanim, H., Sia, C. L., Korzeniewski, K., et al. A resveratrol and polyphenol preparation suppresses oxidative and inflammatory stress response to a high-fat, high-carbohydrate meal. J Clin Endocrinol Metab. 2011;96(5):1409–1414
  150. Chainani-Wu, N. Safety and anti-inflammatory activity of curcumin: a component of turmeric (Curcuma longa). J Altern Complement Med. 2003;9(1):161–168
  151. Bengmark, S. Curcumin, an atoxic antioxidant and natural NFkappaB, cyclooxygenase-2, lipooxygenase, and inducible nitric oxide synthase inhibitor: a shield against acute and chronic diseases. JPEN J Parenter Enteral Nutr. 2006;30(1):45–51
  152. Epstein, J., Docena, G., Macdonald, T. T., and Sanderson, I. R. Curcumin suppresses p38 mitogen-activated protein kinase activation, reduces IL-1beta and matrix metalloproteinase-3 and enhances IL-10 in the mucosa of children and adults with inflammatory bowel disease. Br J Nutr. 2010;103(6):824–832
  153. White, B., and Judkins, D. Z. Clinical Inquiry. Does turmeric relieve inflammatory conditions? J Fam Pract. 2011;60(3):155–156
  154. Singh, R., Akhtar, N., and Haqqi, T. M. Green tea polyphenol epigallocatechin-3-gallate: inflammation and arthritis. [corrected]. Life Sci. 2010;86(25-26):907–918
  155. de Mejia, E. G., Ramirez-Mares, M. V., and Puangpraphant, S. Bioactive components of tea: cancer, inflammation and behavior. Brain Behav. Immun. 2009;23(6):721–731
  156. Melgarejo, E., Medina, M. A., Sánchez-Jiménez, F., and Urdiales, J. L. Targeting of histamine producing cells by EGCG: a green dart against inflammation? J. Physiol. Biochem. 2010;66(3):265–270
  157. De Bacquer, D., Clays, E., Delanghe, J., and De Backer, G. Epidemiological evidence for an association between habitual tea consumption and markers of chronic inflammation. Atherosclerosis. 2006;189(2):428–435
  158. Steptoe, A., Gibson, E. L., Vuononvirta, R., et al. The effects of chronic tea intake on platelet activation and inflammation: a double-blind placebo controlled trial. Atherosclerosis. 2007;193(2):277–282
  159. Bahorun, T., Luximon-Ramma, A., Gunness, T. K., et al. Black tea reduces uric acid and C-reactive protein levels in humans susceptible to cardiovascular diseases. Toxicology. 2010;278(1):68–74
  160. Walston, J., Xue, Q., Semba, R. D., et al. Serum antioxidants, inflammation, and total mortality in older women. Am. J. Epidemiol. 2006;163(1):18–26
  161. Heffner, K. L. Neuroendocrine effects of stress on immunity in the elderly: implications for inflammatory disease. Immunol Allergy Clin North Am. 2011;31(1):95–108
  162. Gordon, C. M., LeBoff, M. S., and Glowacki, J. Adrenal and gonadal steroids inhibit IL-6 secretion by human marrow cells. Cytokine. 2001;16(5):178–186
  163. Ernestam, S., Hafström, I., Werner, S., Carlström, K., and Tengstrand, B. Increased DHEAS levels in patients with rheumatoid arthritis after treatment with tumor necrosis factor antagonists: evidence for improved adrenal function. The Journal of Rheumatology. 2007;34(7):1451–1458
  164. Weiss, E. P., Villareal, D. T., Fontana, L., Han, D.-H., and Holloszy, J. O. Dehydroepiandrosterone (DHEA) replacement decreases insulin resistance and lowers inflammatory cytokines in aging humans. Aging. 2011;3(5):533–542
  165. Marik, P. E., and Varon, J. Omega-3 dietary supplements and the risk of cardiovascular events: a systematic review. Clin Cardiol. 2009;32(7):365–372
  166. Calder, P. C. n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr. 2006;83(6 Suppl):1505S–1519S
  167. Giugliano, D., Ceriello, A., and Esposito, K. The Effects of Diet on Inflammation. J Am Coll Cardiol. 2006;48(4):677–685
  168. Pischon, T., Hankinson, S. E., Hotamisligil, G. S., Rifai, N., Willett, W. C., and Rimm, E. B. Habitual dietary intake of n-3 and n-6 fatty acids in relation to inflammatory markers among US men and women. Circulation. 2003;108(2):155–160
  169. Lopez-Garcia, E., Schulze, M. B., Manson, J. E., et al. Consumption of (n-3) fatty acids is related to plasma biomarkers of inflammation and endothelial activation in women. J Nutr. 2004;134(7):1806–1811
  170. Zampelas, A., Panagiotakos, D. B., Pitsavos, C., et al. Fish consumption among healthy adults is associated with decreased levels of inflammatory markers related to cardiovascular disease: the ATTICA study. J Am Coll Cardiol. 2005;46(1):120–124.
  171. He, K., Liu, K., Daviglus, M. L., et al. Associations of dietary long-chain n-3 polyunsaturated fatty acids and fish with biomarkers of inflammation and endothelial activation (from the Multi-Ethnic Study of Atherosclerosis [MESA]). Am J Cardiol. 2009;103(9):1238–1243
  172. Araki, S., Dobashi, K., Kubo, K., Kawagoe, R., Yamamoto, Y., and Shirahata, A. N-acetylcysteine inhibits induction of nitric oxide synthase in 3T3-L1 adipocytes. J. UOEH. 2007;29(4):417–429
  173. Radomska-Leśniewska, D. M., Sadowska, A. M., Van Overveld, F. J., Demkow, U., Zieliński, J., and De Backer, W. A. Influence of N-acetylcysteine on ICAM-1 expression and IL-8 release from endothelial and epithelial cells. J. Physiol. Pharmacol. 2006;57 Suppl 4:325–334
  174. Nascimento, M. M., Suliman, M. E., Silva, M., et al. Effect of oral N-acetylcysteine treatment on plasma inflammatory and oxidative stress markers in peritoneal dialysis patients: a placebo-controlled study. Perit Dial Int. 2010;30(3):336–342
  175. Csontos, C., Rezman, B., Foldi, V., et al. Effect of N-acetylcysteine treatment on the expression of leukocyte surface markers after burn injury. Burns. 2011;37(3):453–464
  176. Boswellia serrata. Altern Med Rev. 2008;13(2):165–167
  177. Gayathri, B., Manjula, N., Vinaykumar, K. S., Lakshmi, B. S., and Balakrishnan, A. Pure compound from Boswellia serrata extract exhibits anti-inflammatory property in human PBMCs and mouse macrophages through inhibition of TNFalpha, IL-1beta, NO and MAP kinases. International Immunopharmacology. 2007;7(4):473–482
  178. Cuaz-Pérolin, C., Billiet, L., Baugé, E., et al. Antiinflammatory and antiatherogenic effects of the NF-kappaB inhibitor acetyl-11-keto-beta-boswellic acid in LPS-challenged ApoE-/- mice. Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28(2):272–277
  179. Singh, S., Khajuria, A., Taneja, S. C., Johri, R. K., Singh, J., and Qazi, G. N. Boswellic acids: A leukotriene inhibitor also effective through topical application in inflammatory disorders. Phytomedicine. 2008;15(6-7):400–407
  180. Ernst, E. Frankincense: systematic review. BMJ. 2008;337:a2813
  181. Sengupta, K., Alluri, K. V., Satish, A. R., et al. A double blind, randomized, placebo controlled study of the efficacy and safety of 5-Loxin for treatment of osteoarthritis of the knee. Arthritis Res. Ther. 2008;10(4):R85
  182. Sengupta, K., Krishnaraju, A. V., Vishal, A. A., et al. Comparative efficacy and tolerability of 5-Loxin and AflapinAgainst osteoarthritis of the knee: a double blind, randomized, placebo controlled clinical study. Int J Med Sci. 2010;7(6):366–377
  183. Gupta, I., Parihar, A., Malhotra, P., et al. Effects of Boswellia serrata gum resin in patients with ulcerative colitis. Eur. J. Med. Res. 1997;2(1):37–43
  184. Gupta, I., Parihar, A., Malhotra, P., et al. Effects of gum resin of Boswellia serrata in patients with chronic colitis. Planta Med. 2001;67(5):391–395
  185. Holtmeier, W., Zeuzem, S., Preiss, J., et al. Randomized, placebo-controlled, double-blind trial of Boswellia serrata in maintaining remission of Crohn's disease: good safety profile but lack of efficacy. Inflamm. Bowel Dis. 2011;17(2):573–582
  186. Shimizu, S., Akimoto, K., Shinmen, Y., Kawashima, H., Sugano, M., and Yamada, H. Sesamin is a potent and specific inhibitor of delta 5 desaturase in polyunsaturated fatty acid biosynthesis. Lipids. 1991;26(7):512–516
  187. Harikumar, K. B., Sung, B., Tharakan, S. T., et al. Sesamin manifests chemopreventive effects through the suppression of NF-kappa B-regulated cell survival, proliferation, invasion, and angiogenic gene products. Mol. Cancer Res. 2010;8(5):751–761
  188. Chavali, S. R., Zhong, W. W., Utsunomiya, T., and Forse, R. A. Decreased production of interleukin-1-beta, prostaglandin-E2 and thromboxane-B2, and elevated levels of interleukin-6 and -10 are associated with increased survival during endotoxic shock in mice consuming diets enriched with sesame seed oil supplemented with Quil-A saponin. Int. Arch. Allergy Immunol. 1997;114(2):153–160
  189. Wu, J. H. Y., Hodgson, J. M., Clarke, M. W., et al. Inhibition of 20-hydroxyeicosatetraenoic acid synthesis using specific plant lignans: in vitro and human studies. Hypertension. 2009;54(5):1151–1158
  190. Miyawaki, T., Aono, H., Toyoda-Ono, Y., Maeda, H., Kiso, Y., and Moriyama, K. Antihypertensive effects of sesamin in humans. J. Nutr. Sci. Vitaminol. 2009;55(1):87–91
  191. Yuan, G., Wahlqvist, M. L., He, G., Yang, M., and Li, D. Natural products and anti-inflammatory activity. Asia Pac J Clin Nutr. 2006;15(2):143–152.
  192. Bromelain. Monograph. Altern Med Rev. 2010;15(4):361–368
  193. Klein G, Kullich W, Schnitker J, Schwann H. Efficacy and tolerance of an oral enzyme combination in painful osteoarthritis of the hip. A double-blind, randomised study comparing oral enzymes with non-steroidal anti-inflammatory drugs. Clin Exp Rheumatol. 2006 Jan-Feb;24(1):25-30.
  194. Akhtar NM, Naseer R, Farooqi AZ, Aziz W, Nazir M. Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee—a double-blind prospective randomized study. Clin Rheumatol. 2004 Oct;23(5):410-5
  195. Walker AF, Bundy R, Hicks SM, Middleton RW. Bromelain reduces mild acute knee pain and improves well-being in a dose-dependent fashion in an open study of otherwise healthy adults. Phytomedicine. 2002 Dec;9(8):681-6.
  196. Fitzhugh DJ et al. Bromelain treatment decreases neutrophil migration to sites of inflammation. Clin Immunol. 2008 Jul;128(1):66-74. Epub 2008 May 14.
  197. Secor ER et al. Oral Bromelain Attenuates Inflammation in an Ovalbumin-induced Murine Model of Asthma. Evid Based Complement Alternat Med. 2008 Mar;5(1):61-9.
  198. Onken JE et al. Bromelain treatment decreases secretion of pro-inflammatory cytokines and chemokines by colon biopsies in vitro. Clin Immunol. 2008 Mar;126(3):345-52. Epub 2007 Dec 21.
  199. Secor ER et al. Bromelain exerts anti-inflammatory effects in an ovalbumin-induced murine model of allergic airway disease. Cell Immunol. 2005 Sep;237(1):68-75. Epub 2005 Dec 6.
  200. Zhu S, Li W, Li J, Jundoria A, Sama AE, Wang H. It Is Not Just Folklore: The Aqueous Extract of Mung Bean Coat Is Protective against Sepsis. Evidence-based complementary and alternative medicine: eCAM. 2012;2012:498467.
  201. Cao D, Li H, Yi J, et al. Antioxidant properties of the mung bean flavonoids on alleviating heat stress. PloS one. 2011;6(6):e21071.
  202. Borghi SM, Carvalho TT, Staurengo-Ferrari L, Hohmann MS, Pinge-Filho P, Casagrande R, Verri WA, Jr. Vitexin inhibits inflammatory pain in mice by targeting TRPV1, oxidative stress, and cytokines. Journal of natural products. Jun 28 2013;76(6):1141-1149.
  203. Dong LY, Li S, Zhen YL, Wang YN, Shao X, Luo ZG. Cardioprotection of vitexin on myocardial ischemia/reperfusion injury in rat via regulating inflammatory cytokines and MAPK pathway. The American journal of Chinese medicine. 2013;41(6):1251-1266.
  204. Lv H, Yu Z, Zheng Y, Wang L, Qin X, Cheng G, Ci X. Isovitexin Exerts Anti-Inflammatory and Anti-Oxidant Activities on Lipopolysaccharide-Induced Acute Lung Injury by Inhibiting MAPK and NF-kappaB and Activating HO-1/Nrf2 Pathways. International journal of biological sciences. 2016;12(1):72-86.
  205. Lee SJ, Bae J, Kim S, et al. Saponins from soy bean and mung bean inhibit the antigen specific activation of helper T cells by blocking cell cycle progression. Biotechnol Lett. Feb 2013;35(2):165-173.
  206. Hafidh RR, Abdulamir AS, Abu Bakar F, Sekawi Z, Jahansheri F, Jalilian FA. Novel antiviral activity of mung bean sprouts against respiratory syncytial virus and herpes simplex virus -1: an in vitro study on virally infected Vero and MRC-5 cell lines. BMC complementary and alternative medicine. 2015;15:179.
  207. Kang I, Choi S, Ha TJ, Choi M, Wi HR, Lee BW, Lee M. Effects of Mung Bean (Vigna radiata L.) Ethanol Extracts Decrease Proinflammatory Cytokine-Induced Lipogenesis in the KK-Ay Diabese Mouse Model. Journal of medicinal food. Aug 2015;18(8):841-849.
  208. Venkateshwarlu E, Reddy KP, Dilip D. Potential of Vigna radiata (L.) sprouts in the management of inflammation and arthritis in rats: Possible biochemical alterations. Indian journal of experimental biology. Jan 2016;54(1):37-43.
  209. Yao Y, Chen F, Wang M, Wang J, Ren G. Antidiabetic activity of Mung bean extracts in diabetic KK-Ay mice. Journal of agricultural and food chemistry. Oct 8 2008;56(19):8869-8873.
  210. Yeap SK, Mohd Yusof H, Mohamad NE, et al. In Vivo Immunomodulation and Lipid Peroxidation Activities Contributed to Chemoprevention Effects of Fermented Mung Bean against Breast Cancer. Evidence-based complementary and alternative medicine: eCAM. 2013;2013:708464.
  211. Sourris KC et al. Ubiquinone (coenzyme Q10) prevents renal mitochondrial dysfunction in an experimental model of type 2 diabetes. Free Radic Biol Med. 2012 Feb 1;52(3):716-23. Epub 2011 Nov 21.
  212. Tao r et al. Pyrroloquinoline quinone preserves mitochondrial function and prevents oxidative injury in adult rat cardiac myocytes. Biochem Biophys Res Commun. 2007 Nov 16;363(2):257-62. Epub 2007 Aug 14.
  213. Rucker R et al. Potential physiological importance of pyrroloquinoline quinone. Altern Med Rev. 2009 Sep;14(3):268-77.
  214. Xiong XH et al. Production and radioprotective effects of pyrroloquinoline quinone. Int J Mol Sci. 2011;12(12):8913-23. Epub 2011 Dec 5.
  215. Bauerly K et al. Altering pyrroloquinoline quinone nutritional status modulates mitochondrial, lipid, and energy metabolism in rats. PLoS One. 2011;6(7):e21779. Epub 2011 Jul 21.
  216. Donnino MW et al. Coenzyme Q10 levels are low and may be associated with the inflammatory cascade in septic shock. Crit Care. 2011 Aug 9;15(4):R189.
  217. Sohet FM et al. Coenzyme Q10 supplementation lowers hepatic oxidative stress and inflammation associated with diet-induced obesity in mice. Biochem Pharmacol. 2009 Dec 1;78(11):1391-400. Epub 2009 Jul 23.
  218. Schmelzer C et al. Functions of coenzyme Q10 in inflammation and gene expression. Biofactors. 2008;32(1-4):179-83.
  219. Stracke H et al. A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy. Exp Clin Endocrinol Diabetes. 1996;104(4):311-6.
  220. Stracke H et al. Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study. Exp Clin Endocrinol Diabetes. 2008 Nov;116(10):600-5. Epub 2008 May 13.
  221. Sanchez-Ramirez GM et al. Benfotiamine relieves inflammatory and neuropathic pain in rats. Eur J Pharmacol. 2006 Jan 13;530(1-2):48-53. Epub 2005 Dec 15.
  222. 2hoeb M et al. Anti-inflammatory effects of benfotiamine are mediated through the regulation of the arachidonic acid pathway in macrophages. Free Radic Biol Med. 2012 Jan 1;52(1):182-90. Epub 2011 Oct 24.
  223. Vistoli G et al. Transforming dietary peptides in promising lead compounds: the case of bioavailable carnosine analogs. Amino Acids. 2012 Jan 28. [Epub ahead of print]
  224. Fleisher-Berkovich S et al. Inhibitory effect of carnosine and N-acetyl carnosine on LPS-induced microglial oxidative stress and inflammation. Peptides. 2009 Jul;30(7):1306-12. Epub 2009 Apr 10.
  225. Tsai SJ Antioxidative and Anti-Inflammatory Protection from Carnosine in the Striatum of MPTP-Treated Mice. J Agric Food Chem. 2010 Oct 6. [Epub ahead of print]
  226. Boldyrev AA et al. [Carnosine: endogenous physiological corrector of antioxidative system activity]. Usp Fiziol Nauk. 2007 Jul-Sep;38(3):57-71.
  227. Hipkiss AR. On the enigma of carnosine’s anti-ageing actions. Exp Gerontol. 2009 Apr;44(4):237-42.
  228. Gualano B et al. Reduced muscle carnosine content in type 2, but not in type 1 diabetic patients. Amino Acids. 2011 Nov 27. [Epub ahead of print]
  229. Pfister F et al. Oral carnosine supplementation prevents vascular damage in experimental diabetic retinopathy. Cell Physiol Biochem. 2011;28(1):125-36. Epub 2011 Aug 16.
  230. Gauhar R, Hwang SL, Jeong SS, et al. Heat-processed Gynostemma pentaphyllum extract improves obesity in ob/ob mice by activating AMP-activated protein kinase. Biotechnology letters. 2012;34(9):1607-1616.
  231. Winder WW, Ukropcova B, Deutsch WA, et al. AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am J Physiol. 1999 Jul;277(1 Pt 1):E1-10.
  232. Ruderman NB, Carling D, Prentki M, Cacicedo JM. AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest. 2013 Jul 1;123(7):2764-72.
  233. Park SH, Huh TL, Kim SY, et al. Antiobesity effect of Gynostemma pentaphyllum extract (actiponin): a randomized, double-blind, placebo-controlled trial. Obesity (Silver Spring). 2014 Jan;22(1):63-71.
  234. Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res. 2007 Feb 16;100(3):328-41.
  235. Salminen A, Hyttinen JM, Kaarniranta K. AMP-activated protein kinase inhibits NF-kappaB signaling and inflammation: impact on healthspan and life span. J Mol Med (Berl). 2011 Jul;89(7):667-76.
  236. Bijland S, Mancini SJ, Salt IP. Role of AMP-activated protein kinase in adipose tissue metabolism and inflammation. Clin Sci (Lond). 2013 Apr;124(8):491-507.
  237. Xie Z, Huang H, Zhao Y, et al. Chemical composition and anti-proliferative and anti-inflammatory effects of the leaf and whole-plant samples of diploid and tetraploid Gynostemma pentaphyllum (Thunb.) Makino. Food chemistry. 2012;132(1):125-133.
  238. Huyen VT, Phan DV, Thang P, Hoa NK, Ostenson CG. Antidiabetic effect of Gynostemma pentaphyllum tea in randomly assigned type 2 diabetic patients. Horm Metab Res. 2010 May;42(5):353-7.
  239. Umeno A, Horie M, Murotomi K, Nakajima Y, Yoshida Y. Antioxidative and Antidiabetic Effects of Natural Polyphenols and Isoflavones. Molecules. May 30 2016;21(6).
  240. Devi KP, Rajavel T, Nabavi SF, Setzer WN, Ahmadi A, Mansouri K, Nabavi SM. Hesperidin: A promising anticancer agent from nature. Industrial Crops and Products. 2015;76:582-589.
  241. Li C, Schluesener H. Health-promoting effects of the citrus flavanone hesperidin. Critical reviews in food science and nutrition. Feb 11 2017;57(3):613-631.
  242. Roohbakhsh A, Parhiz H, Soltani F, Rezaee R, Iranshahi M. Neuropharmacological properties and pharmacokinetics of the citrus flavonoids hesperidin and hesperetin--a mini-review. Life sciences. Sep 15 2014;113(1-2):1-6.
  243. Jia S, Hu Y, Zhang W, Zhao X, Chen Y, Sun C, . . . Chen K. Hypoglycemic and hypolipidemic effects of neohesperidin derived from Citrus aurantium L. in diabetic KK-A(y) mice. Food Funct. Mar 2015;6(3):878-886.
  244. Rizza S, Muniyappa R, Iantorno M, Kim JA, Chen H, Pullikotil P, . . . Quon MJ. Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndrome. The Journal of clinical endocrinology and metabolism. May 2011;96(5):E782-792.
  245. Zhang J, Sun C, Yan Y, Chen Q, Luo F, Zhu X, . . . Chen K. Purification of naringin and neohesperidin from Huyou (Citrus changshanensis) fruit and their effects on glucose consumption in human HepG2 cells. Food chemistry. Dec 01 2012;135(3):1471-1478.
  246. Homayouni F, Haidari F, Hedayati M, Zakerkish M, Ahmadi K. Hesperidin Supplementation Alleviates Oxidative DNA Damage and Lipid Peroxidation in Type 2 Diabetes: A Randomized Double-Blind Placebo-Controlled Clinical Trial. Phytotherapy research : PTR. Aug 14 2017.
  247. Sun Q, Wedick NM, Tworoger SS, Pan A, Townsend MK, Cassidy A, . . . van Dam RM. Urinary Excretion of Select Dietary Polyphenol Metabolites Is Associated with a Lower Risk of Type 2 Diabetes in Proximate but Not Remote Follow-Up in a Prospective Investigation in 2 Cohorts of US Women. The Journal of nutrition. Jun 2015;145(6):1280-1288.
  248. Salden BN, Troost FJ, de Groot E, Stevens YR, Garces-Rimon M, Possemiers S, . . . Masclee AA. Randomized clinical trial on the efficacy of hesperidin 2S on validated cardiovascular biomarkers in healthy overweight individuals. The American journal of clinical nutrition. Dec 2016;104(6):1523-1533.
  249. Haidari F, Heybar H, Jalali MT, Ahmadi Engali K, Helli B, Shirbeigi E. Hesperidin supplementation modulates inflammatory responses following myocardial infarction. Journal of the American College of Nutrition. 2015;34(3):205-211.