What Is Nuclear Factor-Kappa Beta? (Looonnnnggg)

[Guest guest]

There has been some interest lately in this molecule - this article in July 06

Life Extension Magazine is very informative. Dr. JM

What Is Nuclear Factor-Kappa Beta?

By Julius G. Goepp, MD

From Life Extension Magazine, July 06

For the past seven years, Life Extension has published extensive articles

about chronic inflammation and the numerous diseases it causes, such as cancer,

athero-sclerosis, arthritis, dementia, and more.

In these articles, we showed how aging people over-express a molecule called

nuclear factor-kappa beta, which then ignites a lethal inflammatory cascade

throughout the body.

An abundance of new scientific studies has validated the multiple pathological

effects inflicted by nuclear factor-kappa beta. Fortunately, scientists have

discovered methods to safely suppress this insidious chronic

inflammation-inducing agent. Aging humans are thus able to protect against a

major cause of age-related disease.

In this article, we enlighten Life Extension members about what nuclear

factor-kappa beta is and what can be done to suppress it.

Understanding the relationship between nuclear factor-kappa beta (NFkB) and

inflammation is critical to maintaining your health and longevity. Over the last

several years, scientists have gained new insights into how NFkB functions in

the body. As a result, we are on the verge of finding ways to overcome our

genetic predisposition toward degenerative conditions such as cancer, heart

disease, arthritis, and even asthma.

Simply put, NFkB is a protein that acts as a switch to turn inflammation on

and off in the body. Scientists describe NFkB as a “smoke sensor” that detects

dangerous threats like free radicals and infectious agents. In response to these

threats, NFkB “turns on” the genes that produce inflammation. As we age, NFkB

expression in the body increases, provoking widespread chronic inflammation and

setting the stage for diseases ranging from atherosclerosis and diabetes to

Alzheimer’s. The knowledge of this simple fact should motivate us to counteract

NFkB’s deleterious effects and thus guard against many of the diseases commonly

associated with aging.

As we have reported over the last several years, inflammation is the key

initiating factor in major degenerative diseases. In fact, some scientists

estimate that inflammation underlies up to 98% of the diseases afflicting

humans, including a vast array of seemingly different conditions such as cancer,

heart disease, diabetes, and neurodegenerative disorders.1

NFkB is an instigating factor that unleashes inflammatory responses in chronic

disease conditions. For example, NFkB can signal our cells to continue to

multiply long past their normal life span, which can promote cancer.

Furthermore, NFkB can further spark the smoldering inflammation that damages

joint tissues, thereby provoking crippling arthritic conditions. NFkB likewise

plays a role in spurring inflammation in the nervous system, which can set the

stage for the onset of various neurological disorders. Scientists believe that

NFkB-induced inflammation in the airways may play a role in asthma.

RECENT FINDINGS ON NFkB AND DISEASE

In recent years, numerous studies have shed light on the disease-promoting

effects of NFkB and the benefits of quieting its activity in the body. For

instance, recent studies indicate that NFkB plays a role in the following

conditions:

Autoimmune joint disease: NFkB plays a crucial role in both rheumatoid

arthritis and systemic lupus erythematosus, according to Spanish researchers.2

These two autoimmune conditions are known to produce severe joint pain and

deterioration, as well as other symptoms that dramatically impair quality of

life. Effective therapies to block NFkB may positively modulate these disease

processes.

Hepatitis C: Infection with the hepatitis C virus is a growing cause of liver

disease and liver cancer, and (unlike hepatitis there is no vaccine to

protect against this deadly threat. In early 2006, Japanese scientists

determined that NFkB plays a key role in the process by which the hepatitis C

virus leads to the proliferation of human liver cancer cells.3

Inflammatory bowel disease: Crohn’s disease is an inflammatory bowel disease

associated with symptoms such as severe abdominal pain, diarrhea, weight loss,

and rectal bleeding. Recently, scientists noted that therapies that improve the

symptoms and pathological signs of Crohn’s disease may work by decreasing levels

of NFkB.4

Survival after heart attack: The death of heart muscle due to a blocked

coronary artery is known as a heart attack. If the heart cannot adequately

repair itself after such an attack, a common result is heart failure, in which

the heart muscle cannot pump enough blood to meet the body’s needs. New findings

from 2006 suggest that blocking NFkB may support cardiac muscle healing and

prevent heart failure following heart attack.5

Prostate cancer: Zinc has long been known for its role in supporting healthy

prostate function. Research from 2006 suggests that NFkB may provide the link

between zinc and protection against prostate cancer. Zinc supplementation

suppresses NFkB’s signaling effects, and researchers believe this may help

prevent the metastasis of malignant prostate cancer cells.6

Diabetes: Insulin resistance in muscle tissues is a key factor in type II

diabetes. In a recent investigation, researchers studied the muscle tissue of

people with type II diabetes and found signs of increased NFkB activity.

Reducing NFkB through exercise training in these individuals led to improvements

in blood sugar metabolism.7

The identification of NFkB as a critical “switch” that “turns on” inflammation

has profound impli-cations for both preventing and treating some of today’s

deadliest diseases. Clearly, NFkB is something we need to control if our goal is

to lead a long and healthy life.

Fortunately, ongoing research continues to uncover a wealth of natural

remedies that suppress NFkB’s activity in the body. These remedies provide the

foundation for safe, effective nutritional strategies to quell NFkB and

disease-provoking inflammation, thus providing a formidable defense against a

vast array of deadly diseases and against aging itself.

Interacting with DNA: How NFkB Works

Present in the interior portion (cytoplasm) of every cell, NFkB is normally

bound to inhibitory proteins that keep it in an inactive state. When cells are

exposed to infectious invaders or stressors such as free radicals or

environmental toxins (like cigarette smoke), NFkB is activated. NFkB then

travels to the cells’ command center, known as the nucleus, where it binds with

DNA to turn certain genes on or off. By interacting with more than 400 different

genes, NFkB can thus activate the body’s blueprints for inflammation.1 These

gene products are used to coordinate further inflammatory and immune responses

in the body.

NFkB and Cancer Development

One of NFkB’s most lethal functions is inducing cancer in our bodies.

Scientists are finding that, in addition to its central role in producing

inflammation, NFkB plays an equally prominent and related role in the

development of cancer.

THREE STAGES OF CANCER DEVELOPMENT

Initiation: Cells become cancerous when their DNA is damaged by any of a

host of factors, including various forms of radiation, oxidative stress, and

specific toxins. Such DNA damage occurs over 3 million times per cell per day.

Fortunately, because of cellular repair mechanisms, few of these mutations go on

to produce cancer. Cells that survive with enough unrepaired DNA to potentially

become cancerous are said to have become initiated.

Promotion: Even initiated cells rarely go on to become cancerous, because

cells in most tissues have lost the ability to replicate themselves. The process

of programmed cell death, or apoptosis, prevents potentially cancerous cells

from passing damaged DNA along to future generations of cells. Unfortunately,

under certain circumstances, cells regain the ability to replicate. Such

“immortalized” cells are said to have undergone promotion, the second stage in

cancer development.

Progression: Even at this late stage, our bodies’ defenses normally maintain

control even over collections of initiated cells that have undergone promotion.

The immune system constantly patrols the body looking for potentially cancerous

cells. When it finds them, it destroys these trouble-making cells and mounts an

offensive against similar cells found in other body areas. Cancerous tissue that

has overcome these defenses is said to be in the final stage of cancer

development, known as progression.

Since NFkB plays a role in all three stages of cancer development,

understanding its actions as well as strategies to control its activity is

crucial to both the prevention and adjuvant treatment of various cancers.

NFkB acts in each of the main phases of cancer development, which are known as

initiation, promotion, and progression. NFkB “switches on” genes that allow

cells to become initiated, and once initiated, to have their growth promoted,

and once promoted, to progress and invade healthy tissue.8 Successful cancers

evade powerful repair and control mechanisms at each of the three distinct

stages of cancer development.8 Since NFkB is involved in each of the three

stages, it is critically important that we understand NFkB’s actions in our

bodies and what we can do to better control them.

The NFkB system has emerged as the central actor in the link between

inflammation and cancer. NFkB affects both malignant and non-malignant tumor

cells. In malignant cells, it turns on genes that create resistance to apoptotic

cell death and DNA damage, in effect promoting cancer development by rendering

cells capable of reproducing, even when they are exposed to pharmaceutical

anti-cancer agents. In non-malignant tumor cells, NFkB turns on genes that

produce factors to stimulate blood vessel formation, in support of rapid tumor

enlargement and progression. Finally, byproducts produced by NFkB stimulation

can also damage DNA, thereby contributing to the very earliest stages of tumor

initiation.8

How Inhibiting NFkB

Helps Fight Cancer Recent discoveries about NFkB confirm the deadly link

between inflammation and cancer. It is well known that nutrients and drugs that

reduce inflammation also help fight cancer.8,9 Some anti-inflammatory drugs,

however, carry cardiovascular risk.10,11 Scientists hope that therapies that

block NFkB may provide safe, effective action against both inflammation and

cancer.

How NFkB activation affects gene expression.

The ubiquitous presence of NFkB throughout the inflammation-cancer cycle

suggests that the next breakthroughs in cancer treatment will likely center on

the inhibition of NFkB and its actions. As scientists learn more about NFkB and

the complex systems that regulate it, they also learn more about the wide array

of substances that can inhibit its dangerous actions. For example, the

anti-inflammatory drug ibuprofen inhibits not only the COX-2 enzyme but also

NFkB,12 and has a well-established safety record. This drug, as well as many

natural inhibitors of NFkB, will therefore play an important role in controlling

the inflammatory components of tumor formation and growth.

Because the NFkB factors are active in both the cancerous cells and

inflammatory cells in tumors, nutrients or drugs that can inhibit NFkB show

tremendous promise as anti-cancer or cancer-preventive agents.8 Scientists

believe that the combination of NFkB inhibition with drugs or cytokines that

induce cancer cell death has great promise in fighting cancer.13

Because the NFkB system is also involved in producing healthy immune

responses, there are concerns about its long-term inhibition. While NFkB seems

to be most profoundly involved in cancer at the stages of promotion and

progression,8,14 it may be possible to use inhibitors for relatively short

periods. Another potential use for such inhibitors would be in combination with

chemotherapy or radiation treatments, as a means of controlling the associated

inflammation and enhancing the effects of those treatments.8

NFkB: LINKING INFLAMMATION AND CANCER NFkB and Cancer Promotion

The impact of NFkB on inflammation and cancer is most prominent in the second

stage of cancer development, in which cells with newly mutated DNA are promoted

into “immortalized” cancer cells.8 Scientists have identified two general

mechanisms by which NFkB acts to promote tumors.

In tissue cells that have become initiated because of DNA damage from toxins,

radiation, or free radical attack, activated NFkB “switches on” genes that

reduce apoptosis (programmed cell death). These “immortalized” cells can now

reproduce in the unregulated fashion characteristic of cancer; that is, they

have been promoted.15-17

On the other hand, NFkB activation in inflammatory cells results in increased

production of cytokines and other growth factors that support the growth,

replication, and invasion of the transformed cancerous cells.8,18.19 Such

activated inflammatory cells also provide growing cancers with factors essential

to new blood vessel formation, producing a life-sustaining environment for the

deranged cancer tissue and further promoting its growth.8

Scientists now think of NFkB as the agent that links the processes of toxic

damage and inflammation during the promotion phase of cancer development.

Because of NFkB’s actions on DNA-damaged cancer cells, these cells are able to

outlive their normal counterparts and multiply. Through its action on healthy

(non-cancerous) inflammatory cells, NFkB creates an environment that favors

cancerous tissue over healthy tissue, providing yet another “advantage” for the

growing cancer.

NFkB and Tumor Progression

Inflammation is linked to cancer not only through tumor promotion, but also

through supporting the similarly complex mechanisms of tumor progression.8 Once

cancer cells have been promoted, NFkB stimulates production of inflammatory

signals that support the cancer’s spread to other tissues, both locally (a

process known as invasion) and at a distance (known as metastasis).8

Practically since the science of human cancer biology began, scientists have

known that at the core of most solid tumors is a mass of dead, or necrotic,

tissue. It is now clear that this necrotic tissue contributes to aggressive

tumor growth, and once again, the connection is NFkB.8 Dying tumor cells rupture

and release inflammatory mediators, leading to the activation of NFkB, which

then “turns on” genes involved in rapid tumor growth and invasion. Once kindled

by a small amount of necrosis, a tumor can roar to life like a forest fire from

a smoldering ember. NFkB is the strong wind that fans the cancer’s destructive

growth.

Nutrients That Inhibit NFkB The search is on for safe, effective inhibitors

of NFkB. One of the most exciting features of the explosion of NFkB research is

that it sheds new light on the mechanisms of many familiar nutrients.

Health-conscious people are quite familiar with how antioxidants, vitamins,

minerals, and essential nutrients such as omega-3 fatty acids can maintain

health and prevent disease. It is becoming increasingly clear that many such

compounds exert some of their beneficial effects through interactions with the

NFkB system. Although the precise mechanisms vary, all of these agents work by

inhibiting NFkB activation, thus preventing the expression of genes involved in

inflammation and cancer development. Here we summarize familiar nutrients whose

NFkB-related actions are now coming to light.

Antioxidants Antioxidants are known to reduce inflammation and cancer risk.

The identification of NFkB as the common link to both processes may serve to

explain how these substances operate. Vitamins E and C have been shown to reduce

inflammatory cytokine production that is a consequence of NFkB activation.20

N-acetylcysteine inhibits NFkB, which is likely the mechanism by which it

confers its health-promoting effects.21 S-adenosyl-methionine (SAMe) exerts some

of its powerful anti-inflammatory effects by reducing NFkB activation.22 The

potent antioxidant lipoic acid binds to and inhibits NFkB in the cell’s

nucleus.23 Zinc may also exert its antioxidant effect by reducing NFkB

activation.24

Essential Fatty Acids and Other Lipids The omega-3 fatty acids are also

known to reduce inflammation and decrease the production of inflammatory

cytokines. Evidence is emerging that these effects occur due to inhibition of

NFkB activity by eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and

other essential fatty acids in this class.25-27

EPA and DHA protect the eye’s retinal cells from oxidative damage. Moreover,

these fatty acids may impair the overgrowth of blood vessel cells that occurs in

several retinal diseases, by reducing the production of inflammatory cytokines,

vascular growth factors, and adhesion molecules, all via the common pathway of

NFkB inhibition.28

Isoflavones and Phytoestrogens Soy isoflavones and other plant flavonoids are

well-established modulators of the immune system’s inflammatory responses. These

phytoestrogens (plant-derived, estrogen-like molecules) are known to help reduce

the risk of certain hormone-dependent cancers, as well as the risk and severity

of osteoporosis.29 Researchers have shown that the isoflavone-induced inhibition

of NFkB is the mechanism by which isoflavones reduce the invasiveness of breast

cancer and increase programmed cell death in various human cancer cell

lines.30-32 Evidence also indicates that isoflavones may act by the same

mechanism to inhibit bone loss in osteoporosis.33

Some researchers have speculated that one of the reasons women live longer

than men is related to the favorable effects of estrogen on up-regulating

antioxidant genes often suppressed by NFkB, suggesting that the phytoestrogens

might have similar effects in promoting longevity.34

From Garden to Medicine Chest Herbs and spices from around the world have

long been sought for their pleasing flavors and healing qualities. Even today,

these plant extracts are valued worldwide for promoting health and fighting

disease. Scientists are discovering that many of these natural agents act

through the universal mechanism of inhibiting the over-expression of NFkB.

Turmeric (Curcuma longa)

Curcumin is a compound found in a number of South Asian spices, most

prominently in turmeric, a component of curry seasoning.

Curcumin has well-established antioxidant and anti-inflammatory effects.35,36

The extent to which curcumin exerts these effects by inhibiting NFkB is becoming

increasingly clear.37 Curcumin acts directly within the cell’s nucleus and also

acts on substances that activate NFkB. For example, it binds iron and copper in

brain tissue, reducing the activation of NFkB that is associated with the

production of amyloid beta proteins in Alzheimer’s disease.35

Strong evidence suggests that curcumin may fight the following inflammatory

diseases:

Colitis. Dietary curcumin supplements strongly suppressed NFkB activation in

a rat model of colitis,38 resulting in both decreased tissue wasting and colonic

inflammation. When curcumin was given to experimental animals before the

induction of colitis, there was reduced NFkB activation and less visible damage

to the colon.39 This effect was accompanied by reduced activity of several

enzymes involved in inflammation in the gut.

Liver disease. The development of alcoholic liver disease, resulting in

chemical hepatitis and eventually cirrhosis, has recently been associated with

NFkB-mediated gene expression. When laboratory rats were fed sufficient alcohol

to produce alcoholic fatty liver with liver cell inflammation and necrosis,

dietary curcumin inhibited NFkB activation, preventing both the microscopic and

biochemical changes associated with alcoholic liver disease.40 In an

experimental model of non-alcoholic fatty liver degeneration (which induces

substantial oxidative stress), investigators found that dietary curcumin

significantly reduced inflammation and the release of inflammatory modulators

through NFkB inhibition.41

Chronic neurodegenerative diseases. NFkB-induced inflammation involving brain

glial cells is thought to be one mechanism contributing to the formation of

amyloid beta proteins, which are characteristic of Alzheimer’s and other

degenerative brain diseases.42 In several recent studies, curcumin has been

shown to reduce the glial cell expression of inflammatory mediators.43,44

Curcumin likewise has been shown to reduce amyloid beta formation in animal

models by inhibiting NFkB.45,46

Arthritis. Curcumin’s inhibition of NFkB reduces the degenerative changes to

arthritic joints.47,48 Just this year, curcumin was shown to enhance the

anti-inflammatory effects of the COX-2 inhibitor drug celecoxib.49 This is an

important finding, since COX-2 inhibitors have adverse effects on the

cardiovascular system. This caused scientists to propose that co-treatment with

curcumin could reduce the dose of selective COX-2 inhibitors required to achieve

significant relief from inflammation.

Cancer. Curcumin has been found to suppress, retard, and even reverse cancer

development at each stage of the disease.50 By inhibiting NFkB, curcumin reduced

expression of proteins needed by cancer cells for proliferation (the promotion

stage) and for invasion and metastasis (the progression stage).51 Curcumin also

reduces cancer progression by increasing cell death in cancer cells, thereby

depriving them of the “immortality” they need to survive and invade other

tissues.52,53 This has allowed curcumin to be effective in highly

chemotherapy-resistant cancers;54 it has also been shown to increase the effect

of chemotherapy in animal models of advanced human cancer.51

By Julius G. Goepp, MD

CURCUMIN: POTENT CANCER FIGHTER

Curcumin has been specifically evaluated against the following human cancer

types: Skin cancer. Curcumin has been hailed as one of the most promising

agents in preventing “photocarcinogenesis,” or cancer caused by ultraviolet

light.55 Researchers have found that by inhibiting NFkB, curcumin dramatically

increases the rate of cell death in human melanoma cells in culture.56 The

effect was both dose- and time-dependent, meaning that more curcumin exposure

over a longer time increased the rate of cancer cell destruction. Virtually

identical effects have been demonstrated in malignant squamous cell carcinoma of

the head and neck.57

Prostate cancer. Curcumin inhibits NFkB and sensitizes human prostate cancer

cells to the lethal effects of tumor necrosis factor, which speeds up cell

death58 and reduces the ability of cancer cells to proliferate.59 In a 2006

study, curcumin was also shown to decrease the invasiveness of prostate cancer

cells, by reducing their production of certain protein-digesting enzymes that

help the cancerous cells force their way between healthy cells in order to

spread. This resulted in significantly fewer metastatic nodules in the

experimental animals fed curcumin than in the controls.60

Breast cancer. Primary breast cancers are treated using surgery, radiation,

estrogen modulators, and chemotherapy. Curcumin functions via additional

anti-cancer mechanisms. Through its effects on NFkB, curcumin enhances the

programmed death of cells from human breast cancers61 and their lung

metastases.51 In a 2005 study, curcumin also reduced cancer cells’ production of

vascular growth factors, adhesion molecules, and other proteins required for

sustaining the cells.51 This study also demonstrated that dietary administration

of curcumin to laboratory animals decreased the incidence of cancer metastasis

to the lung. These results have staggering implications for human use of

curcumin as an adjunctive breast cancer treatment.

Cervical cancer. One of the best-known examples of virally induced human

cancer is cervical cancer, which is often caused by infection with human

papillomavirus. In 2006, curcumin was shown to inhibit the expression of viral

cancer genes (initiation), while also down-regulating inflammatory mediators

that cervical cells produce under the influence of NFkB during cancer

promotion.62

Colon cancer. Although colon cancer is a major cause of death in Western

countries, many scientists believe that dietary modification could reduce its

impact by as much as 90%.63 Animals with colorectal cancer showed a reduction in

their tumor burden when fed curcumin.64 Human colon cancer cells in culture are

inhibited by curcumin,65 and their death is markedly enhanced by curcumin.66

Both effects appear to be mediated by NFkB inhibition and related effects on

tumor survival genes. Curcumin was also recently found to markedly enhance the

anti-tumor effectiveness of the COX-2 inhibitor drug celecoxib.67

Lung cancer. Curcumin down-regulates NFkB activation caused by cigarette smoke

in human lung cells68 and reduces the expression of genes required for tumor

promotion and progression of human non-small cell lung cancers.69 Curcumin also

induces cell death in multiple human lung cancer cell lines.70

Blood malignancies. Leukemia and multiple myeloma, two cancers of the immune

system cells in the blood, are known to be highly dependent on NFkB activity,71

which makes them natural targets for curcumin treatment. Multiple myeloma cells

treated with curcumin showed down-regulation of several gene products required

for proliferation, and demonstrated arrested growth and increased cell death.71

In one type of human leukemia cell, curcumin inhibited expression of a variety

of NFkB-dependent genes needed for both tumor initiation and progression.72 In

adult T-cell leukemia, curcumin prevented the growth of virus-infected cells,

but not of normal blood immune system cells.73 Curcumin also stopped cell

replication and induced cell death by inhibiting NFkB. These results are

promising as a means of suppressing this currently incurable form of leukemia.

Human studies are rapidly catching up with these exciting laboratory findings

about curcumin. Phase I (safety and tolerability) trials among patients with

high-risk cancers or pre-cancerous conditions have demonstrated that curcumin is

absorbed after oral dosing and that humans can tolerate up to 8000 mg per day

for up to four months without toxicity.74,75 The scientists who authored these

studies have recommended further phase II studies of curcumin for the prevention

or treatment of various cancers.

Licorice root extracts are among the oldest remedies in Chinese medicine, and

have long been used for their anti-inflammatory, anti-viral, anti-ulcer, and

cancer-preventive properties.76,77 More recently, scientists discovered that a

major component of licorice inhibited NFkB and protected rat liver cells from

alcohol toxicity.78 Another licorice extract inhibited NFkB activation and

decreased production of a pro-inflammatory cytokine in human colon cells that

had been exposed to an inflammatory challenge.79 These results elegantly

demonstrate how NFkB inhibition can interrupt the inflammatory cycle by which

cytokines stimulate the production of still more cytokines. Glabridin, another

licorice root extract, produces similar anti-inflammatory effects by inhibiting

NFkB.80

Capsaicin, the main ingredient in red pepper, has both anti-inflammatory and

anti-cancer effects.81-83 Red pepper compounds have long been used to manage

inflammatory joint conditions.37 Capsaicin inhibits the induction of two

inflammation-provoking enzymes in stimulated macrophage immune cells.82 This

effect is attributable to its inhibition of NFkB activation.83 Capsaicin also

induces cell death in many cancers by modulating NFkB.81 Like curcumin,

capsaicin inhibits the growth of adult T-cell leukemia cells by impairing NFkB

activation.84 Capsaicin further impairs cancer progression by reducing levels of

vascular endothelial growth factor, thus depriving growing cancers of

nutrients.85

Clove extract (eugenol) inhibits NFkB-mediated expression of inflammatory

cytokines.86,87 Like capsaicin, eugenol inhibits NFkB activation in stimulated

macro-phage immune cells,87 reducing their synthesis of COX-2 and inflammatory

cytokines.86 Oil of cloves has been used in dental care for centuries, and

eugenol is now widely used to promote healing and prevent excessive inflammation

after root canal surgery.88,89

Ginger extracts exert anti-inflammatory activity and stimulate cancer cell

death by inhibiting NFkB.90-92 Ginger reduces expression of the key inflammatory

enzymes COX-1 and COX-2.93 Topical application of ginger extract inhibits skin

inflammation in a mouse model92 by inhibiting NFkB.91 A ginger extract was shown

to enhance tumor cell death and down-regulate production of tumor invasion

factors by preventing activation of NFkB.90

Basil and rosemary extracts, which contain ursolic acid, reduce cancer cell

proliferation and tumor progression through NFkB inhibition.94-96 By

inactivating NFkB, ursolic acid prevents initiated cells from reproducing and

also triggers tumor cell death.95 This compound further down-regulates molecules

that are required for tumor invasion and metastasis.96 Ursolic acid works

through its effects on NFkB to induce resting macrophage immune cells, and thus

to participate in tumor cell destruction in the early stages of cancer.97

Ursolic acid derivatives that inhibit NFkB have been shown to suppress

pro-inflammatory enzyme expression in mouse models of inflammation.98 This

effect has been associated with reduced cardiac fibrosis (scar tissue) in the

heart tissue of diabetic mice.94

Garlic has now been shown to exert its anti-inflammatory and immunomodulatory

effects by inhibiting NFkB.37,99 Garlic extracts lowered NFkB activity by up to

41% in human blood and kidney cells that had been exposed to an

inflammation-provoking challenge, thus reducing the expression of certain

cytokines.100 These effects may be linked to the observation that a garlic

compound inhibits damage to endothelial cells lining blood vessels and reduces

atherosclerotic changes.101 Garlic’s inhibition of NFkB leads to reduced

production of chemicals that cause lipid peroxidation, and this could provide

further protection from atherosclerosis.102 NFkB inhibition is credited for

garlic’s ability to protect liver cells from auto-immune damage in an animal

model,103 as well as induce cell death in leukemia.104

Pomegranate fruit extract protects cells against the effects of ultraviolet B

radiation by inhibiting ultraviolet light-stimulated NFkB activation.105

Pomegranate fruit extract also prevented chemically induced skin cancers in mice

through NFkB-mediated effects on both cancer initiation and promotion.106

Blockade of NFkB by pomegranate fruit extract has shown promise in

osteoarthritis by inhibiting the production of protein-digesting enzymes and

inflammatory cytokines.107 Pomegranate wine reduced the activation of NFkB in

vascular endothelial cells by inflammatory mediators or biomechanical

stresses,108 thus protecting against atherosclerosis.109

Summary Scientists have discovered that by controlling our DNA, nuclear

factor-kappa beta (NFkB) plays a central role in determining our health and

longevity. By integrating signals of inflammation, NFkB appears to be the common

link between such diverse conditions as heart disease, cancer, and arthritis.

Agents that control NFkB’s influence within the human body—such as omega-3

fatty acids, phytoestrogens, curcumin, garlic, licorice, ginger, rosemary, and

pomegranate—hold great promise in fighting many diverse diseases and in

promoting long and healthy lives.

Julius G. Goepp, MD, is a pediatrician with additional certification in

pediatric emergency medicine. He received his MD from the University of land

and is currently Senior Consultant at Lupine Creative Consulting, Inc., in

Rochester, NY.

NFkB-Mediated Diseases: The activation of NFkB has been linked

with a wide variety of diseases in humans. Below is a partial list of disorders

that scientists have linked with NFkB:

Aging

Headaches

Pain

Cardiac hypertrophy

Type I diabetes

Type II diabetes

Elevated cholesterol

Atherosclerosis

Heart disease

Chronic heart failure

Angina pectoris

Cancer

Alzheimer’s disease

Pulmonary disease

Kidney disease

Gut diseases

Skin diseases

Sleep apnea

Asthma

Arthritis

Crohn’s disease

Ocular allergy

Appendicitis

Pancreatitis

Periodontitis

Sepsis.

Source: Ahn KS, Aggarwal BB. Transcription Factor NF-{kappa}B: A Sensor for

Smoke and Stress Signals. Ann N Y Acad Sci. 2005 Nov;1056:218-33.

References

1. Ahn KS, Aggarwal BB. Transcription Factor NF-{kappa}B: A Sensor for

Smoke and Stress Signals. Ann N Y Acad Sci. 2005 Nov;1056:218-33.

2. Orozco G, E, Collado MD, et al. Analysis of the functional NFKB1

promoter polymorphism in rheumatoid arthritis and systemic lupus erythematosus.

Tissue Antigens. 2005 Feb;65(2):183-6.

3. Sato Y, Kato J, Takimoto R, et al. Hepatitis C virus core protein promotes

proliferation of human hepatoma cells through enhancement of transforming growth

factor-{alpha} expression via activation of NF-{kappa}B. Gut. 2006 Mar 31;[Epub

ahead of print].

4. Di Sabatino A, Morera R, Ciccocioppo R, et al. Oral butyrate for mildly to

moderately active Crohn’s disease. Alimen Pharmacol Ther. 2005 Nov

1;22(9):789-94.

5. Kawano S, Kubota T, Monden Y, et al. Blockade of NF-{kappa}B improves

cardiac function and survival after myocardial infarction. Am J Physiol Heart

Circ Physiol. 2006 Apr 21;[Epub ahead of print].

6. Uzzo RG, Crispen PL, Golovine K, Makhov P, Horwitz EM, Kolenko VM. Diverse

effects of zinc on NF-{kappa}B and AP-1 transcription factors: implications for

prostate cancer progression. Carcinogenesis. 2006 Apr 10;[Epub ahead of print].

7. Sriwijitikamol A, Christ- C, Berria R, et al. Reduced skeletal

muscle inhibitor of kappaB content is associated with insulin resistance in

subjects with type 2 diabetes: reversal by exercise training. Diabetes. 2006

Mar;55(3):760-7.

8. Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer

development and progression. Nat Rev Immunol. 2005 Oct;5(10):749-59.

9. Steinbach G, Lynch PM, RK, et al. The effect of celecoxib, a

cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med.

2000 Jun 29;342(26):1946-52.

10. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated

with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005

Mar 17;352(11):1092-102.

11. SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated

with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J

Med. 2005 Mar 17;352(11):1071-80.

12. Karin M, Yamamoto Y, Wang QM. The IKK NF-kappa B system: a treasure trove

for drug development. Nat Rev Drug Discov. 2004 Jan;3(1):17-26.

13. Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev

Immunol. 2002 Oct;2(10):725-34.

14. Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent

bystander to major culprit. Nat Rev Cancer. 2002 Apr;2(4):301-10.

15. Maeda S, Kamata H, Luo JL, Leffert H, Karin M. IKKbeta couples hepatocyte

death to cytokine-driven compensatory proliferation that promotes chemical

hepatocarcinogenesis. Cell. 2005 Jul 1;121(7):977-90.

16. Kamata H, Honda S, Maeda S, et al. Reactive oxygen species promote

TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase

phosphatases. Cell. 2005 Mar 11;120(5):649-61.

17. Vakkila J, Lotze MT. Inflammation and necrosis promote tumour growth. Nat

Rev Immunol. 2004 Aug;4(8):641-8.

18. Becker C, Fantini MC, Schramm C, et al. TGF-beta suppresses tumor

progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity.

2004 Oct;21(4):491-501.

19. Greten FR, Eckmann L, Greten TF, et al. IKKbeta links inflammation and

tumorigenesis in a mouse model of colitis-associated cancer. Cell. 2004 Aug

6;118(3):285-96.

20. Grimble RF. Effect of antioxidative vitamins on immune function with

clinical applications. Int J Vitam Nutr Res. 1997;67(5):312-20.

21. Lee JY, Je JH, Jung KJ, Yu BP, Chung HY. Induction of endothelial iNOS by

4-hydroxyhexenal through NF-kappaB activation. Free Radic Biol Med. 2004 Aug

15;37(4):539-48.

22. Majano PL, -Monzon C, -Trevijano ER, et al.

S-Adenosylmethionine modulates inducible nitric oxide synthase gene expression

in rat liver and isolated hepatocytes. J Hepatol. 2001 Dec;35(6):692-9.

23. Lee HA, DA. Alpha-lipoic acid modulates NF-kappaB activity in human

monocytic cells by direct interaction with DNA. Exp Gerontol. 2002

Jan;37(2-3):401-10.

24. Prasad AS, Bao B, Beck FW, Kucuk O, Sarkar FH. Antioxidant effect of zinc

in humans. Free Radic Biol Med. 2004 Oct 15;37(8):1182-90.

25. Zhao G, Etherton TD, KR, et al. Anti-inflammatory effects of

polyunsaturated fatty acids in THP-1 cells. Biochem Biophys Res Commun. 2005 Oct

28;336(3):909-17.

26. Jia Y, Turek JJ. Altered NF-kappaB gene expression and collagen formation

induced by polyunsaturated fatty acids. J Nutr Biochem. 2005 Aug;16(8):500-6.

27. Li H, Ruan XZ, Powis SH, et al. EPA and DHA reduce LPS-induced

inflammation responses in HK-2 cells: evidence for a PPAR-gamma-dependent

mechanism. Kidney Int. 2005 Mar;67(3):867-74.

28. SanGiovanni JP, Chew EY. The role of omega-3 long-chain polyunsaturated

fatty acids in health and disease of the retina. Prog Retin Eye Res. 2005

Jan;24(1):87-138.

29. Dijsselbloem N, Vanden BW, De NA, Haegeman G. Soy isoflavone

phyto-pharmaceuticals in interleukin-6 affections. Multi-purpose nutraceuticals

at the crossroad of hormone replacement, anti-cancer and anti-inflammatory

therapy. Biochem Pharmacol. 2004 Sep 15;68(6):1171-85.

30. Kang JS, Yoon YD, Han MH, et al. Estrogen receptor-independent inhibition

of tumor necrosis factor-alpha gene expression by phytoestrogen equol is

mediated by blocking nuclear factor-kappaB activation in mouse macrophages.

Biochem Pharmacol. 2005 Dec 19;71(1-2):136-43.

31. Li Y, Ahmed F, Ali S, et al. Inactivation of nuclear factor kappaB by soy

isoflavone genistein contributes to increased apoptosis induced by

chemotherapeutic agents in human cancer cells. Cancer Res. 2005 Aug

1;65(15):6934-42.

32. Valachovicova T, Slivova V, Bergman H, Shuherk J, Sliva D. Soy isoflavones

suppress invasiveness of breast cancer cells by the inhibition of

NF-kappaB/AP-1-dependent and -independent pathways. Int J Oncol. 2004

Nov;25(5):1389-95.

33. Jimi E, Ghosh S. Role of nuclear factor-kappaB in the immune system and

bone. Immunol Rev. 2005 Dec;208:80-7.

34. Vina J, Borras C, Gambini J, Sastre J, Pallardo FV. Why females live

longer than males? Importance of the upregulation of longevity-associated genes

by oestrogenic compounds. FEBS Lett. 2005 May 9;579(12):2541-5.

35. Baum L, Ng A. Curcumin interaction with copper and iron suggests one

possible mechanism of action in Alzheimer’s disease animal models. J Alzheimers

Dis. 2004 Aug;6(4):367-77.

36. Holt PR, Katz S, Kirshoff R. Curcumin therapy in inflammatory bowel

disease: a pilot study. Dig Dis Sci. 2005 Nov;50(11):2191-3.

37. Aggarwal BB, Shishodia S. Suppression of the nuclear factor-kappaB

activation pathway by spice-derived phytochemicals: reasoning for seasoning. Ann

NY Acad Sci. 2004 Dec;1030:434-41.

38. Jian YT, Mai GF, Wang JD, et al. Preventive and therapeutic effects of

NF-kappaB inhibitor curcumin in rats colitis induced by trinitrobenzene sulfonic

acid. World J Gastroenterol. 2005 Mar 28;11(12):1747-52.

39. Salh B, Assi K, Templeman V, et al. Curcumin attenuates DNB-induced murine

colitis. Am J Physiol Gastrointest Liver Physiol. 2003 Jul;285(1):G235-43.

40. Nanji AA, Jokelainen K, Tipoe GL, et al. Curcumin prevents alcohol-induced

liver disease in rats by inhibiting the expression of NF-kappa B-dependent

genes. Am J Physiol Gastrointest Liver Physiol. 2003 Feb;284(2):G321-7.

41. Leclercq IA, Farrell GC, Sempoux C, dela PA, Horsmans Y. Curcumin inhibits

NF-kappaB activation and reduces the severity of experimental steatohepatitis in

mice. J Hepatol. 2004 Dec;41(6):926-34.

42. Cole GM, Morihara T, Lim GP, et al. NSAID and Antioxidant Prevention of

Alzheimer’s Disease: Lessons from In Vitro and Animal Models. Ann NY Acad Sci.

2004 Dec;1035:68-84.

43. Kang G, Kong PJ, Yuh YJ, et al. Curcumin suppresses

lipopolysaccharide-induced cyclooxygenase-2 expression by inhibiting activator

protein 1 and nuclear factor kappab bindings in BV2 microglial cells. J

Pharmacol Sci. 2004 Mar;94(3):325-8.

44. Witek-Zawada B, Koj A. Regulation of expression of stromyelysin-1 by

proinflammatory cytokines in mouse brain astrocytes. J Physiol Pharmacol. 2003

Dec;54(4):489-96.

45. Yang F, Lim GP, Begum AN, et al. Curcumin inhibits formation of amyloid

beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol

Chem. 2005 Feb 18;280(7):5892-901.

46. Giri RK, Rajagopal V, Kalra VK. Curcumin, the active constituent of

turmeric, inhibits amyloid peptide-induced cytochemokine gene expression and

CCR5-mediated chemotaxis of THP-1 monocytes by modulating early growth

response-1 transcription factor. J Neurochem. 2004 Dec;91(5):1199-210.

47. Shakibaei M, Schulze-Tanzil G, T, Mobasheri A. Curcumin protects

human chondrocytes from IL-l1beta-induced inhibition of collagen type II and

beta1-integrin expression and activation of caspase-3: an immunomorphological

study. Ann Anat. 2005 Nov;187(5-6):487-97.

48. Banerjee M, Tripathi LM, Srivastava VM, Puri A, Shukla R. Modulation of

inflammatory mediators by ibuprofen and curcumin treatment during chronic

inflammation in rat. Immunopharmacol Immunotoxicol. 2003 May;25(2):213-24.

49. Lev-Ari S, Strier L, Kazanov D, et al. Curcumin synergistically

potentiates the growth-inhibitory and pro-apoptotic effects of celecoxib in

osteoarthritis synovial adherent cells. Rheumatology (Oxford). 2006

Feb;45(2):171-7.

50. Duvoix A, Blasius R, Delhalle S, et al. Chemopreventive and therapeutic

effects of curcumin. Cancer Lett. 2005 Jun 8;223(2):181-90.

51. Aggarwal BB, Shishodia S, Takada Y, et al. Curcumin suppresses the

paclitaxel-induced nuclear factor-kappaB pathway in breast cancer cells and

inhibits lung metastasis of human breast cancer in nude mice. Clin Cancer Res.

2005 Oct 15;11(20):7490-8.

52. RK, Sos ML, Zander T, et al. Inhibition of nuclear translocation of

nuclear factor-kappaB despite lack of functional IkappaBalpha protein overcomes

multiple defects in apoptosis signaling in human B-cell malignancies. Clin

Cancer Res. 2005 Nov 15;11(22):8186-94.

53. Aggarwal S, Ichikawa H, Takada Y, et al. Curcumin (diferuloylmethane)

down-regulates expression of cell proliferation and antiapoptotic and metastatic

gene products through suppression of IkappaBalpha kinase and Akt activation. Mol

Pharmacol. 2006 Jan;69(1):195-206.

54. Kim K, Ryu K, Ko Y, Park C. Effects of nuclear factor-kappaB inhibitors

and its implication on natural killer T-cell lymphoma cells. Br J Haematol. 2005

Oct;131(1):59-66.

55. Baliga MS, Katiyar SK. Chemoprevention of photocarcinogenesis by selected

dietary botanicals. Photochem Photobiol Sci. 2006 Feb;5(2):243-53.

56. Bush JA, Cheung KJ, Jr., Li G. Curcumin induces apoptosis in human

melanoma cells through a Fas receptor/caspase-8 pathway independent of p53. Exp

Cell Res. 2001 Dec 10;271(2):305-14.

57. LoTempio MM, Veena MS, Steele HL, et al. Curcumin suppresses growth of

head and neck squamous cell carcinoma. Clin Cancer Res. 2005 Oct 1;11(19 Pt

1):6994-7002.

58. Deeb D, Jiang H, Gao X, et al. Curcumin sensitizes prostate cancer cells

to tumor necrosis factor-related apoptosis-inducing ligand/Apo2L by inhibiting

nuclear factor-kappaB through suppression of IkappaBalpha phosphorylation. Mol

Cancer Ther. 2004 Jul;3(7):803-12.

59. Kumar AP, GE, Ghosh R, et al. 4-Hydroxy-3-methoxybenzoic acid

methyl ester: a curcumin derivative targets Akt/NF kappa B cell survival

signaling pathway: potential for prostate cancer management. Neoplasia. 2003

May;5(3):255-66.

60. Hong JH, Ahn KS, Bae E, Jeon SS, Choi HY. The effects of curcumin on the

invasiveness of prostate cancer in vitro and in vivo. Prostate Cancer Prostatic

Dis. 2006 Jan 3.

61. Ramachandran C, S, Ramachandran R, et al. Expression profiles of

apoptotic genes induced by curcumin in human breast cancer and mammary

epithelial cell lines. Anticancer Res. 2005 Sep;25(5):3293-302.

62. Divya CS, Pillai MR. Antitumor action of curcumin in human papillomavirus

associated cells involves downregulation of viral oncogenes, prevention of NFkB

and AP-1 translocation, and modulation of apoptosis. Mol Carcinog. 2006

May;45(5):320-32.

63. Plummer SM, Holloway KA, Manson MM, et al. Inhibition of cyclo-oxygenase 2

expression in colon cells by the chemopreventive agent curcumin involves

inhibition of NF-kappaB activation via the NIK/IKK signalling complex. Oncogene.

1999 Oct 28;18(44):6013-20.

64. Garcea G, Berry DP, DJ, et al. Consumption of the putative

chemopreventive agent curcumin by cancer patients: assessment of curcumin levels

in the colorectum and their pharmacodynamic consequences. Cancer Epidemiol

Biomarkers Prev. 2005 Jan;14(1):120-5.

65. Chen A, Xu J, AC. Curcumin inhibits human colon cancer cell growth

by suppressing gene expression of epidermal growth factor receptor through

reducing the activity of the transcription factor Egr-1. Oncogene. 2006 Jan

12;25(2):278-87.

66. Jung EM, Lim JH, Lee TJ, et al. Curcumin sensitizes tumor necrosis

factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through

reactive oxygen species-mediated upregulation of death receptor 5 (DR5).

Carcinogenesis. 2005 Nov;26(11):1905-13.

67. Lev-Ari S, Strier L, Kazanov D, et al. Celecoxib and curcumin

synergistically inhibit the growth of colorectal cancer cells. Clin Cancer Res.

2005 Sep 15;11(18):6738-44.

68. Shishodia S, Potdar P, Gairola CG, Aggarwal BB. Curcumin

(diferuloylmethane) down-regulates cigarette smoke-induced NF-kappaB activation

through inhibition of IkappaBalpha kinase in human lung epithelial cells:

correlation with suppression of COX-2, MMP-9 and cyclin D1. Carcinogenesis. 2003

Jul;24(7):1269-79.

69. Lee J, Im YH, Jung HH, et al. Curcumin inhibits interferon-alpha induced

NF-kappaB and COX-2 in human A549 non-small cell lung cancer cells. Biochem

Biophys Res Commun. 2005 Aug 26;334(2):313-8.

70. Radhakrishna PG, Srivastava AS, Hassanein TI, Chauhan DP, r E.

Induction of apoptosis in human lung cancer cells by curcumin. Cancer Lett. 2004

May 28;208(2):163-70.

71. Bharti AC, Donato N, Singh S, Aggarwal BB. Curcumin (diferuloylmethane)

down-regulates the constitutive activation of nuclear factor-kappa B and

IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of

proliferation and induction of apoptosis. Blood. 2003 Feb 1;101(3):1053-62.

72. Han SS, Keum YS, Seo HJ, Surh YJ. Curcumin suppresses activation of

NF-kappaB and AP-1 induced by phorbol ester in cultured human promyelocytic

leukemia cells. J Biochem Mol Biol. 2002 May 31;35(3):337-42.

73. Tomita M, Kawakami H, Uchihara JN, et al. Curcumin (diferuloylmethane)

inhibits constitutive active NF-kappaB, leading to suppression of cell growth of

human T-cell leukemia virus type I-infected T-cell lines and primary adult

T-cell leukemia cells. Int J Cancer. 2006 Feb 1;118(3):765-72.

74. Cheng AL, Hsu CH, Lin JK, et al. Phase I clinical trial of curcumin, a

chemopreventive agent, in patients with high-risk or pre-malignant lesions.

Anticancer Res. 2001 Jul;21(4B):2895-900.

75. Sharma RA, Euden SA, Platton SL, et al. Phase I clinical trial of oral

curcumin: biomarkers of systemic activity and compliance. Clin Cancer Res. 2004

Oct 15;10(20):6847-54.

76. Wang ZY, Nixon DW. Licorice and cancer. Nutr Cancer. 2001;39(1):1-11.

77. Shibata S. A drug over the millennia: pharmacognosy, chemistry, and

pharmacology of licorice. Yakugaku Zasshi. 2000 Oct;120(10):849-62.

78. Wang JY, Guo JS, Li H, Liu SL, Zern MA. Inhibitory effect of glycyrrhizin

on NF-kappaB binding activity in CCl4- plus ethanol-induced liver cirrhosis in

rats. Liver. 1998 Jun;18(3):180-5.

79. Kang OH, Kim JA, Choi YA, et al. Inhibition of interleukin-8 production in

the human colonic epithelial cell line HT-29 by 18 beta-glycyrrhetinic acid. Int

J Mol Med. 2005 Jun;15(6):981-5.

80. Kang JS, Yoon YD, Cho IJ, et al. Glabridin, an isoflavan from licorice

root, inhibits inducible nitric-oxide synthase expression and improves survival

of mice in experimental model of septic shock. J Pharmacol Exp Ther. 2005

Mar;312(3):1187-94.

81. Lee YS, Kang YS, Lee JS, Nicolova S, Kim JA. Involvement of NADPH

oxidase-mediated generation of reactive oxygen species in the apototic cell

death by capsaicin in HepG2 human hepatoma cells. Free Radic Res. 2004

Apr;38(4):405-12.

82. Chen CW, Lee ST, Wu WT, et al. Signal transduction for inhibition of

inducible nitric oxide synthase and cyclooxygenase-2 induction by capsaicin and

related analogs in macrophages. Br J Pharmacol. 2003 Nov;140(6):1077-87.

83. Kim CS, Kawada T, Kim BS, et al. Capsaicin exhibits anti-inflammatory

property by inhibiting IkB-a degradation in LPS-stimulated peritoneal

macrophages. Cell Signal. 2003 Mar;15(3):299-306.

84. Zhang J, Nagasaki M, Tanaka Y, Morikawa S. Capsaicin inhibits growth of

adult T-cell leukemia cells. Leuk Res. 2003 Mar;27(3):275-83.

85. Patel PS, Yang S, Li A, Varney ML, Singh RK. Capsaicin regulates vascular

endothelial cell growth factor expression by modulation of hypoxia inducing

factor-1alpha in human malignant melanoma cells. J Cancer Res Clin Oncol. 2002

Sep;128(9):461-8.

86. Murakami Y, Shoji M, Hirata A, et al. Dehydrodiisoeugenol, an isoeugenol

dimer, inhibits lipopolysaccharide-stimulated nuclear factor kappa B activation

and cyclooxygenase-2 expression in macrophages. Arch Biochem Biophys. 2005 Feb

15;434(2):326-32.

87. Murakami Y, Shoji M, Hanazawa S, Tanaka S, Fujisawa S. Preventive effect

of bis-eugenol, a eugenol ortho dimer, on lipopolysaccharide-stimulated nuclear

factor kappa B activation and inflammatory cytokine expression in macrophages.

Biochem Pharmacol. 2003 Sep 15;66(6):1061-6.

88. Ozalp N, Saroglu I, Sonmez H. Evaluation of various root canal filling

materials in primary molar pulpectomies: an in vivo study. Am J Dent. 2005

Dec;18(6):347-50.

89. Damle SG, Nadkarni UM. Calcium hydroxide and zinc oxide eugenol as root

canal filling materials in primary molars: a comparative study. Aust Endod J.

2005 Dec;31(3):114-9.

90. Takada Y, Murakami A, Aggarwal BB. Zerumbone abolishes NF-kappaB and

IkappaBalpha kinase activation leading to suppression of antiapoptotic and

metastatic gene expression, upregulation of apoptosis, and downregulation of

invasion. Oncogene. 2005 Oct 20;24(46):6957-69.

91. Kim SO, Kundu JK, Shin YK, et al. [6]-Gingerol inhibits COX-2 expression

by blocking the activation of p38 MAP kinase and NF-kappaB in phorbol

ester-stimulated mouse skin. Oncogene. 2005 Apr 7;24(15):2558-67.

92. Kim SO, Chun KS, Kundu JK, Surh YJ. Inhibitory effects of [6]-gingerol on

PMA-induced COX-2 expression and activation of NF-kappaB and p38 MAPK in mouse

skin. Biofactors. 2004;21(1-4):27-31.

93. Grzanna R, Lindmark L, Frondoza CG. Ginger—an herbal medicinal product

with broad anti-inflammatory actions. J Med Food. 2005;8(2):125-32.

94. Huang TH, Yang Q, Harada M, et al. Pomegranate flower extract diminishes

cardiac fibrosis in Zucker diabetic fatty rats: modulation of cardiac

endothelin-1 and nuclear factor-kappaB pathways. J Cardiovasc Pharmacol. 2005

Dec;46(6):856-62.

95. Hsu YL, Kuo PL, Lin CC. Proliferative inhibition, cell-cycle

dysregulation, and induction of apoptosis by ursolic acid in human non-small

cell lung cancer A549 cells. Life Sci. 2004 Sep 24;75(19):2303-16.

96. Shishodia S, Majumdar S, Banerjee S, Aggarwal BB. Ursolic acid inhibits

nuclear factor-kappaB activation induced by carcinogenic agents through

suppression of IkappaBalpha kinase and p65 phosphorylation: correlation with

down-regulation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin D1.

Cancer Res. 2003 Aug 1;63(15):4375-83.

97. You HJ, Choi CY, Kim JY, et al. Ursolic acid enhances nitric oxide and

tumor necrosis factor-alpha production via nuclear factor-kappaB activation in

the resting macrophages. FEBS Lett. 2001 Dec 7;509(2):156-60.

98. Suh N, Honda T, Finlay HJ, et al. Novel triterpenoids suppress inducible

nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) in mouse

macrophages. Cancer Res. 1998 Feb 15;58(4):717-23.

99. Geng Z, Rong Y, Lau BH. S-allyl cysteine inhibits activation of nuclear

factor kappa B in human T cells. Free Radic Biol Med. 1997;23(2):345-50.

100. Keiss HP, Dirsch VM, Hartung T, et al. Garlic (Allium sativum L.)

modulates cytokine expression in lipopolysaccharide-activated human blood

thereby inhibiting NF-kappaB activity. J Nutr. 2003 Jul;133(7):2171-5.

101. Ho SE, Ide N, Lau BH. S-allyl cysteine reduces oxidant load in cells

involved in the atherogenic process. Phytomedicine. 2001 Jan;8(1):39-46.

102. Ide N, Lau BH. Garlic compounds minimize intracellular oxidative stress

and inhibit nuclear factor-kappa b activation. J Nutr. 2001

Mar;131(3s):1020S-6S.

103. Bruck R, Aeed H, Brazovsky E, Noor T, Hershkoviz R. Allicin, the active

component of garlic, prevents immune-mediated, concanavalin A-induced hepatic

injury in mice. Liver Int. 2005 Jun;25(3):613-21.

104. Dirsch VM, Antlsperger DS, Hentze H, Vollmar AM. Ajoene, an experimental

anti-leukemic drug: mechanism of cell death. Leukemia. 2002 Jan;16(1):74-83.

105. Afaq F, Malik A, Syed D, et al. Pomegranate fruit extract modulates

UV-B-mediated phosphorylation of mitogen-activated protein kinases and

activation of nuclear factor kappa B in normal human epidermal keratinocytes

paragraph sign. Photochem Photobiol. 2005 Jan;81(1):38-45.

106. Afaq F, Saleem M, Krueger CG, JD, Mukhtar H. Anthocyanin- and

hydrolyzable tannin-rich pomegranate fruit extract modulates MAPK and NF-kappaB

pathways and inhibits skin tumorigenesis in CD-1 mice. Int J Cancer. 2005 Jan

20;113(3):423-33.

107. Ahmed S, Wang N, Hafeez BB, Cheruvu VK, Haqqi TM. Punica granatum L.

extract inhibits IL-1beta-induced expression of matrix metalloproteinases by

inhibiting the activation of MAP kinases and NF-kappaB in human chondrocytes in

vitro. J Nutr. 2005 Sep;135(9):2096-102.

108. Schubert SY, Neeman I, Resnick N. A novel mechanism for the inhibition of

NF-kappaB activation in vascular endothelial cells by natural antioxidants.

FASEB J. 2002 Dec;16(14):1931-3.

109. Tzima E, Irani-Tehrani M, Kiosses WB, et al. A mechanosensory complex

that mediates the endothelial cell response to fluid shear stress. Nature. 2005

Sep 15;437(7057):426-31.