Aor Vol 4 1 Inflammation1

8/13/2019 Aor Vol 4 1 Inflammation1

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VOLUME 4 ISSUE 1

InflammationQuenching the Fire Within

vances

I N O R T H O M O L E C U L A R R E S E A R C H

RESEARCH-DRIVEN BOTANICAL INTEGRATIVE ORTHOMOLECULAR INNOVATIVE

InflammationA Double-Edged Sword

Inflammation and Diseasechronic inflammation as a factor inthe progression of cancer, diabetes,cardiovascular disease

Natural Solutions for InflammationTargets of InflammationNatural Anti-inflammatory AgentsA Note on Bioavailability


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Advances 3

Advances in Orthomolecular Research

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Volume 4 Issue 1

Inflammation:A Double edged sword

Inflammation and Disease

Natural Solutions or Inflammation

Digital version o this magazine and back issues are

available online at www.AOR.ca

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4

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ADVANCEDORTHOMOLECULAR RESEARCH

4


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4 Advances

INFLAMMATION

A Double edged sword


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Advances 5

Epidermis (skin)

Mast Cell

Blood Vessel

Macrophage

Plasma

Injury

Bacteria

Mast cells produce histamine and

other chemicals in response to

trauma. This initiates the

inflammatory response

Plasma leaks from the bloodvessels into the affected area,

causing swelling and delivering

clotting proteins and other

healing factors

White blood cells called

Macrophages move out of the

blood vessels and consume

bacteria and other cellular debris

Blood vessels dilate, bringing

more blood to the damaged or

infected site. This causes redness

and heat

Understanding InflammationInflammation is a double-edged sword; it plays animportant and beneficial role in the body, but it can also be

very dangerous, causing damage to the body and ultimatelyleading to disease and even death! Whether inflammation

will be beneficial or harmul depends on its type andduration. In general, there are two distinct categories oinflammation: acute or short term inflammation and chronicor long term inflammation. While short term inflammationplays a beneficial role in the body, long term or chronicinflammation can be very harmul. Tese harmul effectswill be examined in more detail in a subsequent section.First, it is important to discuss the role o inflammation inthe body. I inflammation can be so dangerous, why does itoccur in the first place?

Inflammation plays a vital role in the repair processollowing injury or inection. Without inflammation,

disease and damage would quickly progress beyond thebodys ability to recover, and death would result quickly.Te body initiates the repair process almost instantaneouslyupon injury. It is a highly intricate process that involves acomplex cascade o processes, many o which proceedconcurrently, and many different players including cells andsoluble actors (chemicals called chemokines and cytokines)that work synergistically with each other in a very specificmanner (see Note: What are Cytokines?).

Tere are five key characteristics o inflammation, whichwe have all experienced when we get a cut or a sprained

ankle: swelling, pain, redness, heat and loss o unction.Each o these characteristics is the result o the bodysefforts to protect the damaged area and to speed up healingand repair. More details about these five characteristics areincluded in able 1.

The Inflammatory Response:An Overview

In a nut shell, inflammation is a system o inormationwith multiple check points where a decision making process

Inflammation is a double-edged sword. While it plays an important role in healing and

repair, chronic inflammation can be deadly!

Figure 1.The Inflammatory response


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6 Advances

must occur. Te body reacts to challengeslike oreign invaders or trauma muchin much the same way that a computermakes decisions based on a yes orno ormat. Te bodys inflammatoryresponse is controlled by the immunesystem, and is part o what is called theinnate or non-specific deense system.It is reerred to as non-specific, becauseunlike the bodys specific immune

deenses, it does not target specificviruses or pathogens; instead, it acts ina non-specific manner to deal with awide variety o threats or injuries. Teinflammatory response is initiated asa response to trauma, chemical agentsor microbial pathogens, and is a highlyprogrammed cascade o actions thatoccurs immediately in order to preventthe spread o pathogens, minimizeurther damage to cells and tissues andto promote repair and healing. When

damage, trauma or inection occurs, cellsin the tissue called mast cells will producecertain chemicals, including histamine.Histamine is a key chemical trigger othe bodys inflammatory response. Tepresence o histamine and other chemicalactors causes the initiation o three keyinflammatory processes: vasodilatation(widening o the blood vessels) in theaffected area, increased permeabilityo the blood vessel, and a movement o

Cytokines are small protein moleculesthat play a key role in cell signaling,that is, they act as cellular messengers,with different cytokines providingdifferent messages to cells about howthey should act or react in varioussituations. Cytokines are produced by

cells o the nervous system and also bycells o the immune system, especially

macrophages. Cytokines act bybinding to surace receptors on othercells, where they initiate a specificresponse. For example, a cytokinemay cause a cell to start producingcertain proteins or molecules, or evento produce more cytokines. Cytokinesmay also be inhibitory and reducethe production o proteins or othercytokines. In this way, the interplay

o different cytokines is involved inthe regulation and progression o

various cellular responses in the body,including the inflammatory response.

Cytokines that play key rolesin the inflammatory process areofen reerred to as inflammatory

cytokines. Cytokines can be urtherbroken down into three generalcategories: chemokines, interleukinsand lymphokines. Chemokines arechemicals that attract cells to othercells or a certain area. For example,chemokines are responsible orattracting phagocytes rom the bloodstream to damaged areas as part o theinflammatory response. Interleukins(abbreviated as IL) were initiallydescribed as cytokines produced by

leukocytes, but now this categoryincludes a broad range o differentsignaling molecules involved in theimmune response. Many interleukinsplay a very important role in themediation o inflammation in thebody. Finally, lymphokines areproduced by cells called lymphocytes,and are generally involved in thebodys immune response.

Many pharmaceutical drugs for inflammation target

only one mechanism of action. In contrast, natural

anti-inflammatory agents like curcumin have multiple

mechanisms and a more balanced effect

What are Cytokines?


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Advances 7

white blood cells rom the blood to thedamaged area (Figure 1).

Vasodilation o the blood vesselsin the affected or damaged area bringsmore blood to the affected area. Tiscauses redness and heat, but the main

purpose o this is to supply moreimmune system cells and other actorsto aid in healing and repair. Next, thewalls o the blood vessels become morepermeable, causing plasma to leak outo the blood vessels and into the affectedarea. Tis causes swelling or edema, canlead to pain due to increased pressure,and can impede the unction o jointsor muscles. Te reason or this leakageis that the plasma contains proteins andother actors that are critical or the

initiation o healing. For example, theplasma contains clotting proteins andother proteins that stimulate the bodysimmune system to destroy bacteria.Finally, white blood cells calledphagocytes will move out o the blood

vessels and migrate to the affected site.Tese important immune system cellswill consume and destroy bacteriaand pathogens in the inected area,as well as cleaning up dead cells andother cellular debris during the healingprocess (Figure 1).

Te above description outlines howinflammation is initiated and progresses,leading to eventual healing. In mostcases, the inflammatory response isthen complete, and things go back totheir normal state. However, althoughthis short-term inflammatory process isessential or healing and repair, in somecases the inflammation process doesnot stop, and it continues on in a longterm cycle o chronic inflammation.Tis chronic inflammation is not

beneficial; it can actually cause evenmore damage and can eventuallycontribute to the development o

various diseases. Te same process thatthe body uses to deend itsel duringshort-term inflammation backfireswhen it becomes chronic and ends upharming the body. It is much like anarmy that turns on the citizens and thecountry it was meant to deend! In act,many diseases have now been linked

to inflammation, or example, heartdisease, stroke, diabetes, liver disease,and even obesity, among others!Although acute inflammation is a vitalprocess, scientists and physicians arebeginning to understand that there isa very real need to bring a stop to thislong- term inflammation

Te inflammation process ishighly complex, however, in general,we can think o inflammation as being

divided into short-term and long-termtypes. I short-term inflammation isbeneficial and long term inflammationis unhealthy, the key question is: atwhat stage does the balance tip?When does inflammation turn rombeing beneficial to harmul? Andmost importantly, when should weintervene? For example, i one wereto intervene immediately upon theonset o inflammation, theoretically

Table 2. Comparison between Acute and Chronic Inflammation

Acute Inflammation Chronic Inflammation

Cause Pathogens, injured tissues Persistent acute inflammation,

persistent foreign bodies, or

autoimmune reactions

Onset Immediate Delayed

Duration A few days Up to many months or years

Cells Involved neutrophils (primarily), eosinophils,basophils , monocytes, macrophages monocytes, macrophages,lymphocytes, plasma cells, fibroblasts

Outcome Healing, abscess formation or chronic

inflammation

Tissue destruction, disease

Table 1. The Five Key Characteristics of Inflammation

1. Swelling Caused by an accumulation of fluid and pus called edema.

2. Pain Ser ves as a warning signal to help prevent further injury.

3. Redness Caused by increased blood flow to the area. This occurs as the body tries

to improve its defenses at the site of injury by delivering the key cellular

players and soluble fa ctors to initiate repair.

4. Heat The injured area is warm to the touch since more blood is being

delivered. Also raising the temperature acts as a defensive measure by

eliminating and/or preventing infection.

5. Loss of Function This is generally temporary and is a precautionary measure to allow the

damaged part to heal quickly. For example, the inability to move a body

part like a sprained ankle.

The same process that the body uses to defend itself duringshort-term inflammation backfires when it becomes chronic and

ends up harming the body


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8 Advances

one would be preventing the bodyrom doing its job o protection! Tisis where the checkpoints come in.Tese checkpoints involve eedbackand actions rom the bodys immunesystem, which is the great orchestratoro the inflammatory process. At somestage in the inflammatory process, thebodys immune system will decide,based on the evidence available and

eedback rom key cells, that a certaincheckpoint has been reached and willproceed with a specific course o actionbased on this inormation. It is thesecheck points that ultimately determinethe ate o the inflammatory process.

Unortunately, as o now, nodefinite signs or symptoms havebeen identified that could be used toindicate that a critical checkpoint hasbeen reached and that the balance isabout to tip rom beneficial to harmul

inflammation. Tis knowledge wouldcertainly make the lives o physiciansmuch easier as they would be betterable to identiy at what precise pointto intervene. Fortunately, biologicalchemistry comes to the rescue as

various biomarkers or markers oinflammation have been identifiedthat can be used to help us make thisdecision. Whilst these markers do notprovide a perect solution, they are a

very useul aid in making the decisiono how and when to intervene withtreatment or an inflammatorycondition. Measurement o variousbiomarkers like NF-KB, CRP, COX,LOX, IL-6 and others (which will be

discussed in greater detail in a latersection) as well as the presence o

various cells and inflammatory geneproducts are useul markers that areused in the decision o when to act inthe treatment o inflammation.

Treating InflammationIn the pharmaceutical world wehave a class o drugs called nonsteroidal anti-inflammatory drugs(NSAIDs) that are ofen used to

treat inflammation. Tese includedrugs like the commonly used over-the-counter ibuproen or the morepowerul COX-2 inhibitors likeCelebrex. Unortunately, these drugsare associated with many unpleasantside-effects, including gastrointestinalproblems or bleeding, heartburnand even kidney or cardiovascularcomplications. In act some o thesedrugs, like Vioxx or example, have

been withdrawn rom the market.Fortunately, the natural world offerspowerul and effective yet saealternatives which can meet thechallenges o inflammation.

Unlike the pharmaceutical

drugs that act solely on a silverbullet model, meaning that theyusually have only one mechanism oaction, natural products ofen havemultiple mechanisms o action. Tisis important because inflammation isa process that acts through numerouspathways. Tereore, dealing withonly one pathway will never addressthe situation effectively; it is not goingto put out all o the fires. Generally, themore pathways that are blocked, the

more effective the treatment is likelyto be. Moreover, natural products tendto be less potent but more balancedin their action because they ofencontain additional molecules thatsupport the major compounds inperorming their actions. Severalnatural solutions or inflammationand their mechanisms o action arediscussed in detail in a later section othis magazine.

Fortunately, the natural world offers powerful and effective yetsafe alternatives which can meet the challenges of inflammation


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10 Advances10 Advances

More and more studies are showingthe potentially damaging effects ochronic inflammation and its link to thedevelopment o various serious chronicdiseases. Research has now identifiedchronic inflammation as a actor inthe progression o cancer, diabetes,cardiovascular disease and Alzheimersdisease, along with many others! Telink between inflammation and these

diseases is discussed in the ollowingsections.

Inflammation and CancerIn his 1971 State o the Union addressPresident Richard Nixon pledged I willask or an appropriation o an extra $100million to launch an extensive campaignto find a cure to cancer. Let us make atotal national commitment to conquerthis dread disease. America has longbeen the wealthiest nation in the world.

Now it is time we become the healthiestnation in the world. Tis appropriationled to the creation o the NationalCancer Institute (NCI). Since then over200 billion dollars have been spent, 1.56million papers published, and 150,855studies in mice reported. In spite o this,the US cancer death rate was the same in2002 as it was in 1950 (193.9 per 100,000

versus 193.4 per 100,000)! Hopeully,however, research will continue, and we

will move closer to finding the key to thisdeadly disease. Tere is evidence thatchronic inflammation is an importantcontributing actor.

In general, cancers are a chronicdisease caused by the prolonged exposureto a long list o damaging stimuli. Tesestimuli can include: inections or toxinslike aflatoxin, hormonal insult like excessestrogen exposure post menopause,

chronic irritation rom tobacco smoke,carcinogens or asbestos exposure, a diethigh in ats or sugar, alcohol, radiationand many more. In the early 1860s therenowned German pathologist RudolVirchow mentioned that certain cancersseemed to occur at sites o chronicinflammation. He based his hypothesison the act that certain irritants, togetherwith long standing tissue injury invokedinflammation that ultimately led tocancer. In act, all o the damaging stimuli

listed above could contribute to chronicinflammation. Tere is a significantbody o evidence demonstrating thatchronic inflammation over a longperiod o time (20-30 years) can leadto cancer. For example, inflammationo the bronchus (bronchitis) due to theconstant irritation rom tobacco smokecan lead to cancer o the lung. Similarly,inflammation o the bladder (cystitis),colon (colitis), esophagus (esophagitis)

and liver (hepatitis) leads to cancerso these tissues. Unortunately, in the1860s this link between inflammationand cancer was considered too bold andlargely went ignored.

Recently, however, studiesconducted in large groups o people

have reinorced Virchows originalobservation suggesting a strongrelationship between stimulatorso inflammation and cancer. Teseepidemiological studies have identifiedstimulators o inflammation in theorm o chronic irritants like tobaccosmoke, alcohol, ried oods, UV light,inections, stress, red meat, grilledood, various heavy metals, solventsand trauma as major risk actors in

various types o cancer. For example,

the human papilloma virus has beenlinked to cervical cancer and chronicviral hepatitis B and C (HBV andHBC) inections have been identifiedas major risk actors or a specific livercancer called hepatocellular carcinoma.Similarly, the bacteria Helicobacterpylori which is widely present in thestomach o most people world-wideand has a propensity to burrow its wayinto the lining o the stomach wall, isnot only a primary contributor to thedevelopment o ulcers, but has also been

strongly linked to the developmento stomach cancer. Other chronicinections and/or inflammation likeinflammatory bowel disease (IBD) alsoincrease the risk o cancer o the colon.In act it is estimated that approximately15-20% o all human cancers are linkedto inection and/or inflammation!

Perhaps the best evidence or thesignificance o inflammation duringcancerous growth comes rom longterm users o aspirin and non-steroidal

anti-inflammatory drugs. Recent dataindicates that these drug users reducecolon cancer risk by 40-50% and theyalso may be preventive or other cancersincluding lung, esophagus and stomachcancers. Additionally, other strongerNSAIDs have been shown to prevent themetastases or spread o certain orms ocancer. A summary o the cancers linkedto chronic inflammation is listed inable 3.

Inflammation and Disease


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Advances 11

Inflammation is rightly regardedas a secret killer in diseases such ascancer. It is clear that there is a linkbetween the two. However, this begs thequestion, how is inflammation linkedto cancer? What is the mechanism oaction? Which cellular processes are

involved? I we can understand thesethings then perhaps we can use specificnutrients to target the key moleculesor mechanisms that are involved in thedevelopment o cancer.

Cancer is a multistage processdefined by at least three main stages:initiation, promotion, and progression(Figure 2). Tese stages can then beurther subdivided into various steps,including cellular transormation (wherecells change their look and behaviour),

promotion, survival, prolieration(multiplication o cells), invasion,angiogenesis (ormation o blood vesselsso that the tumour can be continually edand grow), and metastasis (spreading ocancer to distant sites). Tese stages, whiledistinct, overlap considerably and involve

various players like initiating compounds,signaling molecules, growth actors andnumerous other mediators in a complexrole play that links chronic inflammationto all o these stages. A list o these varioussignaling molecules, growth actors and

other key players linking inflammationand cancer are described in able 4,and their actions in the body and theircontribution to inflammation and cancerinitiation are shown in Figure 3.

Tese molecular players arelegitimate targets or the anti-cancereffects o various nutrients. For example,it has been shown that certain anti-inflammatory agents like the non-steroidal anti-inflammatory drugs(NSAIDs) reduce chronic inflammation

and thus reduce the incidence o variouscancers. Unortunately, some o theseNSAIDs are themselves harmul, andcause side-effects like gastric irritationand liver and kidney toxicity. However,it is possible that certain naturalcompounds could target such pathwayswithout having the associated side-effects and thus could be used to helpprevent or reduce the incidence ocancer.

Inflammation can work both wayswith short term inflammation beingprotective and having anti-cancereffects, while long term inflammationcan cause cancer. Te intent o manynatural products is to reduce chronicinflammation by targeting one or moreo the above pathways that involve

numerous inflammatory playersincluding NF-B, which plays anenormous role in inflammation and isdiscussed in greater detail in the nextarticle, as well as various cytokines,chemokines, growth actors andhormones. For example, it has beennoted that NF-B is raised in every

NORMAL CELL

INITIATION PROMOTION PROGRESSION

MUTATED CELL

MALIGNANT

TUMOR

The mutated cell is

stimulated to proliferate

rapidly , producing more

mutated cells

Mutation and rapid division

continue. A malignant tumor

forms. Eventually can spread to

other parts of the body by

metastasis

A Carcinogenic Agent

(chemicals, radiation,

viruses) causes DNA

damage and mutation

Table 3. Cancers Linked to Chronic Inflammation(Adapted from Maeda and Omata, 2008)

Infection Related Conditions Tumour Type Causative Agent

Tuberculosis Lung Cancer Mycobacterium tuberculosis

Chronic Gastritis Gastric Cancer Helicobacter pylori

Chronic Hepatitis Hepatocellular Carcinoma Hepatitis B or C virus

Mononucleosis Lymphoma Epstein-Barr virus

Chronic Cervitis Cervical Cancer Papilloma virus

Non-Infection Related Conditions Tumour Type Causative Agent

Asbestosis Lung Cancer,

Mesothelioma

Asbestos

Reflux Esophagitis Esophageal Cancer Gastric Acid

Chronic Pancreatitis Pancreatic Cancer Alcohol

Inflammatory Bowel Disease Colon Cancer Ulcerative Colitis

Crohns Disease

Skin Inflammation Melanoma UV light

Figure 2.The Stages of Tumour Development


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inflammatory condition, with especiallystrong links to cancer. Bharat Aggarwalo Te University o exas M.D.Anderson Cancer Center in Houston,exas is one o the oremost researchers

on NF-B and its association withcancer. Afer thirty years o research,Aggarwal is convinced that NF-B isthe key culprit in cancer. According toAggarwal all roads to cancer go throughthis single molecule!

Several lines o evidence pointsto the key role NF-B plays ininflammation and cancer. NF-B hasbeen associated with every knowncarcinogen and has also been linked

with other inflammatory mediatorslike COX-2 and 5-LOX enzymes,tumour necrosis actor (NF) andothers. Furthermore, NF-B levelsare dramatically reduced by anti-

cancer agents like natural polyphenols,flavonoids, vitamin E, lycopene, vitaminC and many others. All these findingsprovide compelling evidence that NF-B is likely a major mediator o cancer.

Inflammation and DiabetesTe association between a

reduced production o insulin andtype-2 diabetes has been consideredthe hallmark o this condition. Tis

reduction in insulin production causesan inability o insulin to transportsufficient quantities o glucose romthe blood and into the tissues. Te netresult o this is that glucose is excretedinto the urine. In act, early physiciansremarked that the high sugar content

o the urine produced by diabeticpatients could be used as a diagnosticmarker o the disease.

Te insulin producing cells arecalled Beta cells and they are locatedin the islets o Langerhans in thepancreas. In diabetic patients, theseBeta cells are either destroyed duringthe course o the disease and/or areunable to be regenerated quickly toproduce sufficient quantities o insulinto handle the bodys requirements.

However, type-2 diabetes is not onlyassociated with a decreased productiono insulin but also with a more recentlydiscovered phenomenon called insulinresistance. Insulin resistance is acondition in which insulin becomesless effective at lowering glucose levelsin the body even when it is present atnormal levels.

ype-2 diabetes is associated witha number o long term consequencesincluding atherosclerosis or hardeningo the blood vessels which leads to poor

circulation and a loss o vessel elasticityas well as eventual heart disease andhigh blood pressure. Furthermore,diabetes can also affect smaller vessels,like those in the eyes, kidneys andthe central nervous system, causingretinopathy, nephropathy andneuropathy which results in damage tothe nerves, kidneys and blindness.

Several theories have beenproposed to help explain why someindividuals develop inadequate insulin

production and insulin resistance. Oneo the most credible o these theoriesis inflammation. Te link betweeninflammation and type-2 diabetes hasbecome increasingly strengthened bythe results o numerous scientific studiesin both animals and humans. Tere areseveral actors that may induce chronicinflammation in the body. Tose mostcritical to the development o type-2diabetes are shown in able 5.

Table 4. Key Molecular Players Linking Inflammation to Cancer(Adapted from Lu et al., 2006)

Molecule Function linking Inflammation to Cancer

IL-6 (cytokine) Promote tumour growth

TNF- (cytokine) Induce DNA damage and inhibit DNA repair, Promote

tumour growth, Induce angiogenic factors

Chemokines Promote tumour cell growth, Facilitate invasion and

metastasis by directing tumour cell migration and

promoting basement membrane degradation

NF-B Mediate inflammation, promote chronic inflammation,

promote production of mutagenic reactive oxygen species,

protect transformed cells from apoptosis, promote tumour

invasion and metastasis, feedback loop between pro-

inflammatory cytokines

iNOS Downstream of NF-B and pro-inflammatory cytokines,

induce DNA damage, regulate angiogenesis and metastasis

COX-2 Produce inflammation mediators, promote cell

proliferation, anti-apoptotic activity, angiogenesis, and

metastasis

HIF-1 Promote chronic inflammation, induced by pro-

inflammatory cytokines, contribute to angiogenesis,

tumour invasion, and metastasis

STAT3 Activated by pro-inflammatory cytokines, promote

proliferation, apoptosis resistance, and immune tolerance

Nrf2 Anti-inflammatory activity, protect against DNA damage

NFAT Regulate pro-inflammatory cytokine expression, required

in cell transformation


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Advances 13

Microbial Infection, Chemical Irritation, Injury

Acute Inflammation

Chronic Inflammation

Inflammatory CellsReactive Oxygen Species

iNOS and COX-2

Inflammatory Environment in the Body

HIF-1

Chemokines

Resolution of Inflammation

DNA Damage & Mutation

Other Inflammatory Mediators (e.g. NF-kB, NFAT, STAT3)

Pro-Inflammatory Cytokine (e.g. TNF-a, IL-1,IL-6)

Hypoxia (Low Oxygen)

Tumour Initiation Tumour Promotion Tumour ProgressionTumour Invasion &

Metastasis

Helicobacterpylori

Papillomavirus

Infectious Agents

Inflammatory Agents

Carcinogens that Activate NF-B

NF-B

Hepatitis B or Cvirus

Epstein-BarrVirus

UV Obesity

Stress

Drug Use

Cigarette Smoke

Alcohol

Poor Diet

Diesel

Ozone

Heavy Metals

DBMA

Radiation

TNF IL-1 IL-17 IL-18 H2O2 PMA

Figure 3.Summary of mechanisms for the involvement of inflammation in cancer development. For more information see Table

4. (Adapted from Lu et al., 2006)

Figure 4. NF-B, a key inflammation inducing molecule is activated by a large number of carcinogens, and is thought to play a

major role in the development of cancer. (Adapted from Ralhan et al., 2009)


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14 Advances

Tere are several lines o evidencethat implicate inflammation in thedevelopment o diabetes. Te strongestis data rom both animal and human

studies that shows raised levels o keyinflammatory markers like C-reactiveprotein (CRP) or certain interleukinslike IL-1B or IL-6 in patients or animalswith ype-2 diabetes. Moreover, thesestudies have shown that the higherthe levels o these inflammatorymarkers, the greater the chance theindividual has diabetes. In act, it hasbeen argued that raised levels o theseinflammatory biomarkers indicated

that inflammation also results in theactivation o the immune system,which may then actually attack varioustissues o the body. Diabetes specialists

call this auto-inflammatory diseasewhich is similar to an auto-immunedisease in that it results in the bodyattacking its own tissues; the differenceis that the primary cause o an auto-inflammatory disease is inflammation.Te second strong evidence o a linkbetween inflammation and type-2 diabetes comes rom biopsies o

various tissues that show clear evidenceo inflammatory cell involvement.

Despite the overwhelmingevidence o the involvement oinflammation in diabetes, it remainsuncertain whether inflammation is acause o the disease or whether it is aresulting symptom. It is a classic caseo a chicken or the egg scenario, which

are so common in biological science.I inflammation is in act a cause odiabetes, then we must examine themechanisms by which this occurs. Tatis, how can inflammation cause type-2 diabetes? Research in this area hassuggested that inflammation may leadto diabetes by causing cell death andby creating hypoxic conditions; thismeans that inflammation causes anenvironment in which the tissues areliterally starved or oxygen, leading to

cellular death.Multiple mechanisms maycontribute to increased inflammationin type-2 diabetes, some o which arequite general and others that are highlyspecific. In the pancreas, inflammationmay be initiated by excessive nutrientslike glucose or ree atty acids thatcan activate the immune system (seeable 5). Tere are a large number obiochemical pathways and moleculesthat are implicated in the inflammatoryprocess; however, as with cancer, the

most extensively studied o these indiabetes is the NF-B pathway.

Treatments to Reduce Inflammation

in Type-2 Diabetes

Evidence or the role o inflammationin type-2 diabetes is quite strongand new treatments that block theactivation o various inflammatorymarkers like NF-B or interleukin areactively being developed. Researchis beginning to show that an anti-

inflammatory approach to treatmento the disease seems to lower bloodglucose levels and improve insulinrelease as well as helping to limitthe damaging effects that ensue.In particular, anti-inflammatorytreatments appear to be very helpul orreducing the glycation o hemoglobin(also reerred to as HbAC1) which is acommonly used marker or diagnosingdiabetes. Glycation is a major actor

Table 5. Causes of Inflammation Linked to Diabetes

1. Oxidative Stress Oxidative stress in the pancreas and/or cellular organelles

like the endoplasmic reticulum (ER) results in highly reactive

oxygen and nitrogen free radicals which damage the tissue in

a chain reaction or domino effect process.

2. Plaque Plaque -like deposits can form in the pancreas, much like

the plaque that get deposited in the arteries. These deposits

cause both destruction of the insulin producing Beta cells and

also prevent regeneration of the pancreatic tissue.

3. Glucotoxicity Toxic effects of excess glucose in the body. Can cause tissue

damage and disrupt the uptake of glucose by the cells.

4. Lipotoxicity Toxic effects of excess fats and increased concentrations of

free fatty acids that may cause cell death.


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Advances 15

in the development o diabeticcomplications. Glycation is a chroniccondition brought upon by consistentlyhigh levels o glucose in the blood.Te resulting effect is that glucosemolecules bind to various proteinsin the body like hemoglobin or otherproteins in the plasma, tissues or blood

vessels. When a protein is glycated itbecomes warped, which changes thestructure and thereore the unction o

the protein. In the case o blood vessels,or example, glycation may result in aweakening o the blood vessel walls ora reduction in elasticity. Tese effectscan lead to increased blood pressureand an increased incidence o vesselrupturing. Te glycation o hemoglobincan be a major problem in diabetes.

Te use o anti-inflammatorycompounds in the treatment o diabeteshas also been shown to improve the

release o insulin by the Beta cells.Many o these studies validate thepotential o targeting inflammationas a therapeutic approach to treatingtype-2 diabetes and support a causativerole o inflammation in this disease.Obviously more work is needed totest the effects o either single anti-inflammatory compounds or cocktailsthat will target the various pathways oinflammation involved in diabetes to

achieve improved results. Nevertheless,there is ample evidence o a significantrole o inflammation in type-2 diabetesas either the underlying cause or aresulting symptom that needs to beaddressed.

Inflammation andCardiovascular DiseaseCardiovascular disease includes aspectrum o closely related conditions

associated with the heart andcirculation and is the leading cause odeath in the western world. Conditionsincluded under the umbrella oCardiovascular Disease include: heartailure, angina, heart attacks, highblood pressure and the ormationthrombi, or large blood clots, whichare the primary cause o stroke.

Peter Libby o Harvard MedicalSchool was among the first researchers

to uncover a connection betweeninflammation and cardiovasculardisease (CVD). Libby was studyingatherosclerosis, a condition thatresults in hardening o the arteriesdue to the accumulation o plaque inthe blood vessels. Tis plaque can thenlead to urther damage to the vessels,and a large number o cardiovascularcomplications including high bloodpressure and heart attacks. In the

Normal Artery

Blood vessel

lining

(endothelium)

Smooth muscle cells

Healed Ruptured Plaque

Reduced blood flowFibrous vessel wall

Early Plaque

Formation

Fibrous Cap

Plaque Ruptures

Blood clot (thrombus) forms

Heart Attack occursVulnerable Plaque

Thin fibrous cap

Large lipid core

Many inflammatory cells

Stabilized Plaque

Thick fibrous cap

Small lipid core

Blood flow normal

Figure 5. In early plaque formation the recruitment of inflammatory cells and the accumulation of fat leads to formation of a lipid

core in the artery. Initially the artery enlarges in an outward direction to accommodate the increasing fat build-up. At this point,

blood flow is largely maintained (stabilized plaque). This may be maintained if diet and lifestyle factors are improved. However, if

inflammatory conditions persist, the lipid core can grow, resulting in a thinning of the fibrous cap, which can eventually rupture.

When the plaque ruptures, blood that contact it will start to clot, resulting in the formation of large blood clot or thrombus. If

the thrombus blocks the flow of blood through the vessel a heart attack can occur. The thrombus may also be resorbed into the

blood vessel wall, resulting in a thickened, fibrous wall and a narrowed blood vessel. This narrowing can greatly restrict blood flow,

resulting in conditions like angina (Adapted from Libby, 2002).


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Cholesterol is oxidized and

activates the immune

system, attracting

monocytes, which enter the

vessel wall and become

macrophages

Blood Vessel

Interior of the Blood Vessel

Monocyte

Fibrous CapEndothelium

(blood vessel lining)

OxidizedCholesterol

INFLAMMATION

Cytokines

Muscle Cells

Lipid core

of plaque

Foam

Cell

Macrophage

Macrophages induce

inflammation. They Produce

inflammatory cytokines and

attract more immune cells.

They consume cholesterol,

becoming foam cells, a key

component of

atherosclerotic plaque

Cytokines stimulate

proliferation of blood vessel

muscle cells, expanding the

artery around the growing

plaque

A fibrous cap forms.

Inflammation continues.

Eventually, the plaque may

rupture, leading to clot

formation and heart attack

Figure 6.The cellular basis of inflammation in the development of atherosclerosis

1970s, most researchers had acceptedthat there is a connection betweenhigh at intake and atherosclerosis.Later, it was ound that the type o atintake is also important. For example,the consumption o saturated atsand especially trans ats, is largelyresponsible or the development oatherosclerosis. However, researchersstill lacked a clear understanding o

the sequence o events involved in theinitiation o atherosclerosis.

In piecing together thissequence o events, Libby noted thatimmune system cells associated withinflammation, like macrophages, werethe first cells to arrive at the scene oblood vessel damage. Based on thisinitial observation, Libby then piecedtogether the events o atherosclerosis,

much like a orensic scientist solving acrime. Te first step o atherosclerosisinvolves cholesterol, which is a largemolecule that in and o itsel is notharmul, and has an important rolein the healthy unctioning o thebody. For example, cholesterol playsan important role in the synthesiso various hormones (like estrogen,testosterone and stress hormones)


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and is an important component themembranes lining the cells o the body.

Unortunately, the cholesterolmolecule has a number o protrudingarms called hydroxyl groups that areespecially susceptible to damage byhighly reactive molecules called ree

radicals. Tese ree radicals includereactive oxygen and nitrogen speciesthat commonly lurk in areas o thebody that experience high levels ostress, like the blood vessels. When itis attacked by ree radicals cholesterolbecomes oxidized or nitrated,meaning that an oxygen or nitrogenatom is added to the molecule. It isthis damaged cholesterol that is thebad cholesterol that gets depositedon the walls o the blood vessels as

a atty build-up. When the immunesystem detects this aberrant and non-sel orm o cholesterol building upin the blood vessels it acts quickly tosend the various immune cells intoaction. Te damaged or oxidizedcholesterol causes immune systemcells, called monocytes to latch ontothe walls o the blood vessels. Tesecells then migrate into the wallso the vessel, and transorm intomacrophages which initiate the bodysinflammatory response and begin to

devour cholesterol molecules. Tesecholesterol filled macrophages arecalled oam cells and orm the attylipid core o the plaque. Immunecells also act to cordon off the oreigncholesterol molecules by orming afibrous capsule around the lipid coreto help prevent it rom spreading toother areas. Unortunately, there areusually many affected areas, whichresults in these capsules being ormedin many areas along the walls o the

blood vessels.At this point, the cholesterol filledoam cells begin to burrow deeper intothe vessel wall and into the muscle layeraround the blood vessel. Te muscle cellsin this layer respond to the aggressiveexpansionist behaviour by multiplyingurther. In the midst o this battle, otherimmune players send out signals torecruit more cells and immune systemactors to the site o damage, and also

release various inflammatory cytokines,resulting in a continuing loop o

increasing inflammation. Eventually,the plaque can rupture, leading to theormation o a blood clot, which in turncan cause a heart attack and possibledeath. Te details o plaque ormationin the arteries are shown in Figure 5.

Tis series o events suggests aconnection between a chronic state oinflammation and the progression oatherosclerosis. Inflammation plays arole at every stage in the progressiono atherosclerosis. In act, very early

atherosclerotic lesions are almost purelyinflammatory in nature, consisting o acollection o at laden inflammatoryimmune cells like macrophages. Asatherosclerosis progresses, even moreimmune cells infiltrate the region oplaque ormation, where they are acomponent o the cap covering the lipidcore o the plaque. Tese immune cellsexhibit signs o activation and release

various inflammatory cytokines. When

plaque rupture occurs, this happens atareas where the cap is thinnest. Tese

areas tend to be highly abundant inactivated immune cells which producehigh levels o inflammatory moleculesand various enzymes that can weakenthe cap and activate cells in the core.Tis process transorms the stableplaque into a vulnerable, unstablestructure that can rupture, leading tothrombosis or clot ormation.

Overall, Libbys major contributionwas to link high levels o variousinflammatory markers like C-reactive

protein (CRP) with the extent oinflammation and the extent ovascular damage. Tis connectionbetween inflammatory markers andcardiovascular disease progressionprovides a series o predictivemarkers that may be able to be usedto help identiy patients with plaquebuild-up and the beginning stageso atherosclerosis earlier, allowingtreatment to give at a an earlier stage


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o the disease. Te value o thesepredictive, inflammatory markers hasbeen shown in a variety o studies.Research has clearly shown that elevatedinflammatory markers are associatedwith increased cardiovascular riskamong healthy individuals as wellas those at higher risk. For example,Lindahl and colleagues ound that inpatients with unstable coronary arterydisease, levels o the inflammatory

marker CRP was directly and stronglyrelated to the long-term risk o deathrom cardiac causes (see Figure 7).Furthermore, various prescription drugsthat are used to treat various aspectso cardiovascular disease, like statins,aspirin, fibrates and ACE inhibitorshave also been shown to have the effecto reducing levels o various markerso inflammation, especially in patientswith very high levels to start with.

Inflammation and AlzheimersDiseaseAlzheimers Disease (AD) is adevastating and a progressivedegenerative disease o the centralnervous system that dramaticallyaffects both the patient and their care-givers. Over two thirds o all cases odementia (memory decay, diminishedreasoning and personality changesaffecting all areas o daily living) are

associated with AD. It is estimated thatby the age o 85, between a quarter andone third o all individuals will developAD.

How does Alzheimers disease

Develop?

Amyloid-beta precursor protein (APP)is a protein molecule composed oaround 700 amino acids and is locatedin within the membrane o nerve cells.

An enzyme called BACE1 breaks downAPP into smaller subunits, one owhich is called amyloid beta peptide(A). Tis small, 42 amino acid subunitis thought to be one o the majorcontributors o to the developmentand progression o Alzheimers disease.Once ormed, multiple A join togetherto orm large aggregates that are evenmore aggressive and damaging. TeseA aggregates produce a plaque-like

deposit around the nerve cells in thebrain; much like a cholesterol ladenplaque in the blood vessels orms andcauses atherosclerosis or damage oblood vessels.

Te other possible contributingcause o AD are specific tau proteinscalled neurofibrillary tangles (NF)which also orm around nerve cells.Proponents o the A theory are

jokingly reerred to as Baptists while

Figure 7. Probability of death from cardiac causes in relation to the level of C-reactive protein (CRP), a marker of inflammation, in

the blood (Adapted from Lindahl et al., 2000)


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Advances 19

those in the NF camp are reerred toas aoists. Whether the main causeis A or NF, the net result is thedestruction o the nerve cells. Both Aplaque ormation and the ormation oNF are thought to stimulate localizedand chronic inflammation around

the affected nerve cells. Over manyyears, this chronic inflammation islikely to significantly exacerbate thepathogenesis o the disease. In theend, chronic inflammation combinedwith the generation o damaging reeradical species and the destruction osynapses or connections betweenthe nerve cells ultimately leads to thedegeneration o the neural circuitry.Te progression o Alzheimers diseaseis also accompanied by the eventual

loss o brain volume or atrophy, and aloss o neurons and unctional neuralsynapses. A theoretical progressiono events involved in this process isshown in Figure 8.

Te role on inflammation inAlzheimers may be even morenearious than initially thought.New research shows that not only isinflammation a contributor to theprogression o the disease, it mayactually be one o the main causes!wo studies conducted at the Saint

Louis University School o Medicinehave suggested that AD occurs due toa malunction in a transporter proteinthat is supposed to clear A across theblood brain barrier and out o the brain.When this transporter malunctions,the result is that A accumulates in thebrain, leading to AD. However, whenthe researchers looked urther intowhat actually caused the transporter tomalunction, they ound that the keywas inflammation! When they induced

inflammation in healthy mice theyound that it turned off the transporterthat lets A exit the brain into thebloodstream. Tey also ound that itrevved up an entrance transporter thatactually transported more A into thebrain! When the mice were given theNSAID indomethacin, the transporterswent back to their normal unctioning.Tis provides an explanation or a

variety o epidemiological studies

in humans that have shown thatindividuals using NSAIDs over a longperiod o time have a reduced risko developing Alzheimers disease.However, as previously discussed, the

chronic use o NSAIDs comes with itsown risks and side-effects. Te goodnews is that some natural products arealso beginning to show considerablepromise or reducing inflammationand other symptoms associated withAD.

For example, one significantproblem encountered in AD is thatthe A is not cleared rapidly enoughby the bodys phagocytes. Tese

specialized white blood cells have theability o engul and eliminate oreignmolecules, cells or other debris. Arecent study in humans has shownthat the combination o curcumin

and vitamin D was able to enhancethe clearance o the A by phagocytes.An interesting aspect o the study isthat the two nutrients were synergetic,meaning that the effect t together wasgreater than the sum o their individualeffects on A clearance (Masoumi et al.2009). Te role and actions o curcuminand other natural anti-inflammatoryagents are discussed in detail in thenext article in this magazine.

Amyloid Accumulation and Plaque Formation

Oxidative

Damage

Dysfunctional signal

transduction

Failure of Phagocytic

clearance

NFT Accumulation

Glutamate

AccumulationSynapse LossNeuron Loss

Inflammation

Cognitive Decline(memory loss, cognitive deficits, agitation, depression)

Figure 8. A hypothesized sequence of events in the development of Alzheimers

disease (Adapted from Frautschy and Cole, 2010)


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As a primary deense system o thebody, inflammation is critical in bothhealing and repair ollowing exposure

to a wide array o diverse stimuli. Tesestimuli can include UV radiation romexcessive sun exposure, dietary actorslike oods with a high glycemic indexoods or high in saturated ats, variousallergens like pollen, animal dander,certain oods or cosmetics, harmulchemicals, tobacco, alcohol, stress,microbial inections, cuts, burns andmany more (See Figure 9).

Short term inflammation is sel-limiting and stops as quickly as it starts

once healing and repair is under control.However, serious problems arise wheninflammation continues and becomes along-term condition. Tis can occur dueto continuous provocation or exposureto inflammation-inducing stimuli (likethose shown in Figure 9), the ailureo this usually careully controlledprocess to stop when it should, or acombination o these two actors. Tisresults in chronic inflammation, which

is associated with a whole range odiseases rom Alzheimers disease toSystemic Lupus Erythematosus and

even obesity (see Figure 10).It is unclear at this stage whether

inflammation is the cause or theconsequence. Much debate rages,nevertheless, the association is verystrong, leading some researchers tostate that All roads to chronic diseaseslead through inflammation.

Te inflammatory process is highlycomplex and proceeds in a mannerthat can be described as a domino-like process. Te inflammatory

response consists o a series o eventsthat involve many players includingvarious cells (mainly white bloodcells), and chemicals called cytokines,chemokines, adhesion molecules,growth actors, hormones and thenervous system. Te interplay betweenthese players is not completelyunderstood, but the end result is theclassical signs o inflammation, namelyheat, redness, swelling and pain,

plus the (usually temporary) loss ounction o the tissue in question.

Molecular Targets forAnti-inflammatory ActionCurrently the intricate and complexprocess o inflammation is ar rom

being completely understood, whichmeans that the control o inflammationpresents a huge challenge to scientistsand physicians. Nevertheless, researchhas revealed that there are a numbero cracks in the inflammatoryarmour that can be targeted ortherapeutic purposes. Generallythese include certain molecules thatplay key roles in the progression oinflammation. For example, somewell-known inflammatory targets

include: protein kinases (PK), NF-B, tumour necrosis actor (NF),ree radicals or radical oxygen species(ROS), and cyclooxygenase (COXenzymes). Te way in which eacho these can be targeted to controlinflammation is discussed below. Itmust be remembered, however, thatthese represent only a ew players inthe inflammatory cycle; there are manymore possible targets and the wholeprocess is a biochemists nightmarewith intricate and ofen seemingly

conflicting interactions and rolesbetween a huge number o molecularactors and chemical signals.

Protein Kinases (PK)

Protein Kinases are a very largeamily o enzymes including severalhundred different but related enzymes.Enzymes in general act to speed up ormodiy the unction o their target, andPK enzymes are no different. ypicallyPKs achieve their action through a

process called phosphorylation, whichmeans that they add a molecule calleda phosphate group to their target. Teprocess o phosphorylation changes thestructure and thus the unction o theenzymes target. For example, it is PKsthat are responsible or de-activating aparticular subunit o a key mediator oinflammation called NF-B. With thissubunit (called IKK) disabled, NF-B isree to initiate inflammation by reading

20 Advances

Natural Solutions forInflammation


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Advances 21

and activating key inflammatory genes.Tis process is discussed in more detailbelow.

PKs are airly high up in theinflammatory cascade and as one o theearly players in the process their job isto fine tune the careully controlledinflammatory process. Unortunately,despite the potential or fine controlover inflammation, PKs are a hugeamily o enzymes, responsible or

hundreds o different activities inthe body. It is incredibly difficult tomodulate the unction o one specificPK, which means that they are not theideal target or intervention to treat andcontrol inflammation. Additionally,because there are so many differentPKs, and at the moment researchershavent figured out which PK actswhere. Nevertheless, many naturalproducts do have some influence on

various PKs, which does contribute totheir anti-inflammatory actions.

NF-B

NF-B is complex our proteinmolecule that acts as a nucleartranscription actor, meaning that itplays a role in controlling whethercertain genes are activated or inhibited.Te major role o NF-B is to read (ortranscribe) the DNA code and turn

on or regulate over 400 genes (out othe 30,000 that we humans have) thatwill produce specific protein productsthat play a major role in inflammationand cancer-associated pathologies likeinvasion, angiogenesis, prolierationand others.

NF-B was discovered in 1986 andis one o the most researched proteinso the inflammation process. Present inevery cell rom the ruit fly to man, NF-

B consists o three subunits, two owhich activate genes and a third, calledIKK, which is an inhibitor that keepsthe other two in check. Essentially,once stimulated by any o a multitudeo provocative stimuli (see Figure 9)enzymes called protein kinases (PKs)inactivate the inhibitor protein IKK,which rees the two active subunits.Te active subunits then move romthe cell towards the nucleus where

they act to read hundreds o differentgenes associated with inflammation.Once read, the genes become active,producing a series o downstreamproducts including proteins, receptors,enzymes and other actors like NF,COX, LOX, IL-2 and others. Teseproducts then instigate and sustain theinflammatory process.

NF-B levels are raised in everyinflammatory condition including

Inflammation

Harmful Solevents

Solvents

Gasoline

Pesticides, etc.

Allergens

Pollen, Foods

Pet DanderCosmetics etc.

Tobacco Smoke

&

Alcohol

Stress

Injury

Cuts

Burns

Sprains

Infections

Fungi

Bacteria

Viral

Unhealthy Diet

High Sugar

High Saturated

or Trans Fats

UV Radiation

Figure 9. Stimuli for Inflammation


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heart disease, diabetes, allergies,asthma, various orms o arthritis(osteo and rheumatoid), Crohnsdisease, multiple sclerosis, Alzheimersdisease, osteoporosis and many more

(See Figure 10). Unlike PKs, NF-Bis arther down in the process and isthus closer to the scene o action.Te advantage o targeting NF-B isthree-old: first, it is a key moleculethat can read the inflammatoryscript allowing expression o variousinflammatory genes, second, NF-Bis very well researched and has showna strong correlation with virtually allinflammatory diseases and third, NF-

B, unlike PKs, is a single molecule,which allows it to be manipulatedwithout significantly affecting otherpathways.

TNF-alphaNF-, or umour NecrosisFactor alpha, is a molecule that ispositioned on the outside o cellularmembranes. Once activated by the

various provocative stimuli, NF-leaves the membrane and docks onreceptors at distant sites to promote aninflammatory reaction.

Regulation o NF- is complex and,like many o the inflammatory players,

it is a double-agent. At times it can bea beneficial anti-inflammatory agentthat helps to destroy tumours andimproves healing o damaged tissues,however, at other times acts as an agent

provocateur causing damage itsel!In many cases NF-B will activateNF-, however, at other times thereverse can happen, and through apositive eedback loop NF- canurther activate NF-B! NF- alsoacts to activate specific downstreaminflammatory products like adhesionmolecules. Tese adhesion moleculesare akin to the cholesterol plaque thatbuilds up in blood vessels, and they

Neurodegenerative

Diseases

Parkinsons, Alzheimers,

Multiple Sclerosis,

Epilepsy

Heart Disease

Atherosclerosis, High

Cholesterol, Heart Attack

Lung Diseases

Bronchitis, Cystic Fibrosis

Infectious Diseases

Malaria, Measles, Small

Pox, Fevers

Bone or Muscle

Disorders

Osteoporosis, muscle

sprains or dysfunction

Skin Diseases

Psoriasis, Eczema,

Wounds, Scleroderma

Liver Diseases

Alcohol induced,

Cirrhosis, Fibrosis

Endocrine Disorders

Hypothyroidism, Diabetes

Other Diseases

Ulcers, Allergy,

Gall Stones,

Asthma, IBD,

Arthr itis, Fatigue,Depression

Diseases

Linked to

Inflammation

Cancer

Breast, Colorectal,

Prostate, Stomach,

Lung, Skin, Myeloma

Kidney etc

Figure 10.Diseases Associated with Inflammation (adapted from Aggarwal and Harikumar, 2009)


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cause damage to the delicate endothelialcells that line the blood vessels andwhich are vital or the health o the

vessels. Te ensuing dysunction o theendothelial cells is one o the majorcauses o cardiovascular problems.

In other cases NF- activates

proteolytic enzymes like matrixmetalloproteins (MMPs), which is oneo the main mechanisms that tumoursuse to spread to distant sites. umourscan use enzymes like MMPs to eataway the surrounding tissue, allowingthem to spread into these areas.

Free Radicals ROS and RNS

Tere is a constant battle between theorces o good and evil within the bodyand in every cell. Biochemists reer to

these competing orces as antioxidantsand oxidants or pro-oxidants (SeeFigure 11).

Oxidants are a motley groupo reactive oxygen species (ROS)including superoxide anion O2-,hydrogen peroxide H2O2, hydroxylradical OH- as well as nitrogenspecies collectively termed reactivenitrogen species (RNS) including4-hydroxynonenal and various otherreactive aldehydes. Tese moleculesor ree radicals cause much damage

to proteins, membranes, DNA andother targets. Certain chemicals ormolecules (like cytokines) promotethe production o ree radicals, andthereore they can be reerred to aspro-oxidants.

Antioxidants are a collection oprotective agents that can be producedby the body or derived rom the diet.Tese include glutathione, catalase,superoxide dismutase as well as

vitamins C, D and E to name a ew. Te

net effect o all o these antioxidantsis to act as scavengers o oxygen andnitrogen ree radicals.

When oxidative stress occurs as aresult o exposure to allergens, radiationor toxic chemicals or example, certaindeensive cells like mast cells and whiteblood cells (leukocytes) are quicklyrecruited to the site o damage whichleads to a respiratory burst releasingboth ROS and RNS into the area. In the

short term ROS and RNS are beneficialand have the effect o neutralizingthe offending stimuli and causingacute inflammation. I however,the stressors persist, the continuedproduction o these ree radicals

begins to cause damage to the healthytissue. A therapeutic strategy involvesneutralizing both ROS and RNS aferthe initial acute inflammatory process.

COX Enzymes

Cyclooxygenase is a amily o enzymesthat work on arachidonic acid, whichis a component o the cell membrane.Tere are two major types o COXenzymes, reerred to as COX-1 and

COX-2. Te ormer is a housekeepingenzyme that works on maintaininghomeostasis or status-quo o the cells.It is an essential enzyme without whichcells would be unable to maintain ahealthy state. COX-2, on the other

hand, is an enzyme that is inducedby many o the actors responsibleor inflammation: stress, UV light,toxins etc. COX-2 generates a serieso products called prostaglandins(specifically PGE2) that are highlyinflammatory.

Several pharmaceutical drugs targetCOX-2 without affecting COX-1; theseare called COX-2 selective drugs.Celebrex and Vioxx are examples

Cytokines

Growth Factors

Chemotherapy

Radiation

Pro - oxidants Anti - oxidants

SOD

Catalase

Glutathione

Heme Oxygenase

Peroxidase

Figure 11. Under normal conditions, antioxidants outbalance pro-oxidants, but

under oxidative conditions, pro-oxidants prevail over antioxidants, which can lead

to many inflammatory diseases, including cancer (from Reuter et al., 2010)


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o this type o anti-inflammatorypharmaceutical. Unortunately, someo these drugs can cause harmulside-effects like kidney, liver andgastrointestinal damage, and as resultthey have had to be withdrawn romthe market.

Natural Anti-inflammatory AgentsWith so many actors at work,

how does one put out all othese inflammatory fires within?Although this is a huge challenge,the numerous pathways allow anopportunity to tackle a multitude omechanisms simultaneously. Unlikepharmaceuticals that only address onespecific pathway, like the classic silverbullet mechanism o action o COX-inhibitors, natural products tend tohave much more widespread activity.

Nature is ull o anti-inflammatoryagents that target many o the pathwaysassociated with inflammation. In act,unlike pharmaceuticals that have asingle target, natural products ofenhave multiple mechanisms. Becausewe do not yet know which pathwaysare most critical, this multi-targetedapproach to inflammation makes moresense, at least or now since single-

targeted therapy has shown littlepromise. Moreover, an added advantageis that multi-targeted natural productsare generally saer since a lower dose isrequired than or pharmaceuticals.

Boswellia serrata

Te herb Boswellia serrata or Indianrankincense has been used in Ayurvedaor thousands o years or a multitudeo diseases. Te empirical evidence

or its anti-inflammatory benefits isstrong. More recently, researchers haveconducted animal and human studiesto veriy these anti-inflammatoryeffects, with several human studiesshowing very positive results orBoswellias anti-inflammatory benefits.An incredibly important aspect oBoswellia is that it does not havea significant immediate effect on

inflammation. One study ound thatwhile Boswellia showed no significanteffect on inflammation in the firstmonth o use, rom the second monthonward, symptoms were reduced to thesame degree as with powerul COX-2inhibitor pharmaceuticals. All o thiswas without the side effects associatedwith COX-2 inhibitors, and, amazingly,the reduction o inflammation in thosetaking Boswellia was maintained even

Boswellia serrata


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Advances 25

Poor bioavailability is a problem that has plaguedmany natural supplements over the years. Simply put,bioavailability is the percentage o an ingested ingredientthat makes it into your bloodstream, where it can exert

a physiological effect. For example, something likecurcumin, the active medicinal antioxidant ound inturmeric root, has incredibly poor bioavailability; up to 8grams o pure curcumin can be consumed without gainingANY detectable levels in the blood.

Because o these bioavailability issues, many ingredientsthat have shown incredibly promising results in early in

vitro studies end up having their benefits significantlyreduced or even completely eliminated when the ingredientis taken by humans! Tis has led scientists to look into thecauses o poor bioavailability and also to develop a varietyo technologies and strategies that can be used to help

enhance the bioavailability o molecules, allowing theirbenefits to be better harnessed in medications and naturalsupplements.Tere are several actors that can cause a substance to bepoorly bioavailable:

1. Poor solubility Many medicinal herb extracts, vitaminsand coactors are what scientists call hydrophobic,meaning they do not dissolve in water. Much o digestionis based on solubility in water, so many o these end uppassing straight through the GI system with little medicinaleffect.2. Low stability Many molecules have low stability in

the digestive system. Te process o digestion, combiningthe low pH o the stomach and the higher pH o theintestines, both ull o powerul enzymes, break downmany molecules that could be beneficial.3. Absorption I a molecule survives the harsh conditionso the digestive tract and is successully solubilized by thebody, it still needs to be absorbed. Tis is more difficultthan one might think, because the body is very selective,especially when it is something outside o the normalregime o carbohydrates, proteins and ats that the GIsystem is designed to absorb.4. Metabolism Poorly bioavailable molecules and extracts

are also ofen degraded by the body, because they arerecognized as oreign, even i they have helpul medicinalproperties. Tis system is highly important, because,while it may rustrate us by causing low bioavailability osupplements that we want to absorb, it also results in thedetoxification o molecules that are dangerous.

How can Bioavailability be increased?

Tere are many ways to get around the bioavailabilityproblem, by improving each o the above limiting actors.

Many approaches aim to increase all o these actors, butthe real question is, is this wise? ests on the ingredientsin supplements have shown that most can be saely

taken at higher doses, which indicates that increasingbioavailability is sae, but is that the only concern? One

very common method to increase bioavailability isthe inclusion o piperine, a component o black pepperextract. Tis molecule inhibits the degradation o alloreign molecules. Tis works very well to increasebioavailability, but has the unintended effect o increasingthe amounts o toxins, carcinogens and chemicals retainedby the body.

I altering the metabolism o a compound can havenegative effects, are there ways to saely increasebioavailability? Definitely. Tree o the best ways to

increase bioavailability are by improving the solubility,stability and absorption o compounds. Unlike theoverly complicated nano-technology used by thepharmaceutical and biotechnology industries, like nano-tubes or other structures, the nano-technology used bythe ood industry makes use o particle size reductionand various methods to prevent particle clumping. Telatter technology is sae and uses ingredients that are saeor use in oods, and it is a strategy that can also be saelyand effectively applied to natural health supplements.

Whats the Deal with Bioavailability?


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afer patients stopped taking it or amonth! A large amily o compoundscalled saponins, and in particularthe boswellic acids (BA), have beenconfirmed as the principal activecompounds in this plant. Boswellic

acids likely have the most powerulanti-inflammatory effect o all naturalproducts!

It is a common theme that virtually allnatural anti-inflammatory ingredientsalso have an anti-cancer effect. Recallearlier in this issue o Advances wediscussed that the German pathologistVirchow made a unique observationthat the site o inflammation was ofenaccompanied by cancers at the same

site. Boswellia has been shown toexert anti-cancer effects in-vitro andin animal studies, where it has beenshown to reduce both tumour burdenand requency.

In terms o its effects on

inflammation in humans, a recentGerman clinical study showed thatinflammation o the brain could besignificantly reduced by bioavailableBoswellia extracts which preventededema, one o the hallmark signs oinflammation. Furthermore, Boswelliahas been shown in clinical trials tobe more effective than conventionalNSAIDs, like ibuproen, or thetreatment o symptoms associated with

osteoarthritis. Moreover, Boswelliaextract showed ewer gastrointestinaland kidney side effects than ibuproen.

Boswellias anti-inflammatory actionhas also resulted in several humantrials looking at its potential use in thetreatment o inflammatory conditionso the bowel including ulcerative colitisand Crohns disease. So ar, the results ohave been mixed, with some reporting

good results and others reporting noeffect. One possible reason or thisdiscrepancy is that Boswellia, likemany natural products, has a hugebioavailability issue (see Note: Whatsthe Deal with Bioavailability?). It isconceivable that studies that did notreport any effect could have usedproducts that were poorly bioavailable.Food science nano-technology is a saeand effective way o improving the

It is a common theme that virtually all natural anti-inflammatoryingredients also have an anti-cancer effect


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bioavailability o many products likeBoswellia.

Finally, Boswellia has been shownto exert a powerul protective effecton the stomach. Boswellia extractshave been shown to prevent or reducegastric ulcers, yet another action that

can be linked to its anti-inflammatoryeffects.

Curcumin

Curcumin is one o the three activecomponents called curcuminoidsthat are present in turmeric root, aspice widely used by many culturesor culinary, colouring and healingpurposes. Curcumin accounts orapproximately two thirds o allcurcuminoids in the root, with the

other two (demethoxycurcumin andbisdemethoxycurcumin) making upthe remaining third. In Ayurvedaand the traditional Chinese system omedicine, curcumin has been used ora wide range o conditions including,ever, liver and gall bladder ailments,diabetes, heart conditions, gastricproblems, skin conditions, inections,diarrhea, memory, cancers and manymore.

Curcumin is possibly the most widelyresearched natural product available,

with thousands o in vitro mechanisticand animal studies to back up its effects.More recently, urther support or the

benefits o this spice has come roma large number o studies in humans,

with several dozen human studiesbeing conducted using curcuminevery year! Te results o this immense

body o research have repeatedlyconfirmed that curcumin possesses

not only powerul anti- inflammatoryproperties, but also antioxidant,anticancer and neuroprotective effects.

Potently reduces NF-B by both preventing theactivation o PKs so the inhibitor IKK remains activeand keeps NF-B in check and by directly breakingdown excess NF-B.

Inhibits other inflammatory mediators like NF-, thevarious interleukins and others.

Benefits Alzheimers disease by reducing the ormationand aggregation o amyloid beta peptide (A) andpreventing ormation o neurofibrillary tangles (NF).

In the central nervous system, curcumin stimulatesphagocytes so that A is rapidly cleared. Tis effect isenhanced in the presence o vitamin D.

Stimulates the prolieration o nerve cells.

Reduces the COX-2 enzyme selectively withoutsignificantly affecting the housekeeping enzyme COX-

1, all without the gastric, kidney and cardiovascularside effects o pharmaceutical NSAIDs and COX-2inhibitors.

Chelates heavy metals like copper and iron which areknown to cause inflammation via enzymatic reactionsthat produce ree radicals.

Stimulates the bodys own deensive enzymes likeglutathione, catalase, superoxide dismutase and others.

Directly quenches both oxygen and nitrogen reeradicals, which are primary sources o inflammation.

Limits arachidonic acid release rom cellular membranesby inhibiting an enzyme called phospholipase A2. As aresult, there is less substrate or COX and LOX enzymesto work on, reducing the production o inflammatorymolecules.

Curcumin

The key anti-inflammatory actions of curcumin


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As an anti-inflammatory molecule,curcumin significantly reduces a hugenumber o inflammatory biomarkers,especially the very important NF-B.

Bharat Aggarwal at exas A&MUniversity is a world leader incurcumin and inflammation research.Aggarwal has published hundreds oreviews and original research on thisascinating molecule. Aggarwal is astrong proponent o reduction o NF-B as a means o reducing the effectso chronic inflammation. Overall, hisresearch has concluded that curcuminsanti-inflammatory properties are

wide ranging, and include a variety odifferent mechanisms and targets.

It must be pointed out thatcurcumin has a huge bioavailability

issue. Bioavailability reers to theamount o the active compound thatreaches the target site. In the case ocurcumin, or example, this wouldbe the amount that reaches the nervecells in the brain or the joints, liver,kidneys or other target tissues. Tereare many possible reasons or thepoor bioavailability o curcumin. Forexample, the curcumin molecule isnt

very soluble in the digestive tract,

it is unstable due to pH conditions,it is too big to be easily absorbed bythe gastrointestinal tract and finally,it is rapidly broken down by thedetoxification enzymes that protect thebody. Numerous approaches have beenutilized to improve the bioavailability

o curcumin, or example, usingsmaller particles o curcumin canhave a significant effect on improvingthe bioavailability o this beneficialmolecule. For more inormation aboutimproving bioavailability, see the Notein this article: Whats the Deal withBioavailability?

Green Tea Polyphenols

Green tea is another widelystudied natural product. Te active

components in green tea are a groupo polyphenols called catechins,including epigallocatechin gallate(EGCG). Tese catechins are typicallyound in unermented green tea leaves.Fermented black tea leaves generallyhave little or no catechin content, butinstead are high in theaflavins, whichhave different physiological actions.

Catechins and other polyphenolshave been shown to act at multiplesites in the inflammatory cascade. Forexample, they act to quench oxygen and

nitrogen ree radicals, inhibit COX-2enzymes, and prevent the IKK rombeing inactivated, thus preventing NF-B rom becoming activated. Green teaalso prevents NF and other signalingmolecules rom being activated. Morerecent research suggests that greentea polyphenols act through over twodozen different mechanisms, muchlike the curcumin molecule. Clinicalresearch also suggests that EGCG hasa powerul anti-cancer effect, especially

or breast, prostate, skin and coloncancers. Tese anti-cancer effects couldbe closely linked to EGCGs role ininhibiting inflammation.

Omega 3 fatty acids rich in EPA and

DHA

Eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA) aretwo o the many omega-3 atty acidsound in nature, and especially in

Camellia sinensis

Recent research suggests that green tea polyphenols act through

over two dozen different mechanisms


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Advances 29

atty fish like salmon and anchovies.Plant sources o omega-3 atty acidsare also becoming more common.For example, algae are an excellentsource o DHA, and nowadays algaecan be commercially harvested undercontrolled conditions. Most other

plant sources contain predominatelyother omega-3 atty acids, like alphalinolenic acid, which are not converted

very efficiently into EPA/DHA. Newresearch is starting to look at thepotential to extract EPA rom algaesources as well.

Many o us have heard that omega-3atty acids are important or goodhealth, and part o this health benefitcomes rom the role they play inreducing inflammation. Arachidonic

acid (AA) is abundantly present inthe membranes o cells. When a cell isexposed to an inflammatory stimulus,an enzyme called phospholipaseis released that causes AA to leavethe membrane and move into theinterior o the cell. Inside the cell,two sets o enzymes called COX andLOX utilize AA breaking it down totwo highly inflammatory moleculescalled prostaglandin E2 (PGE2) andleukotriene B4 (LB4).

EPA and DHA are important because

they can actually take the place o AAin cell membranes. In individuals witha high intake o EPA/DHA the cellmembranes contain more EPA andDHA and less AA. As a result, whenprovoked by inflammatory signals,EPA or DHA leaves the cell membraneinstead o AA. COX and LOX enzymesthen act on these atty acids, but insteado orming the highly inflammatoryPGE2 or LB4 that come rom AA,they orm airly innocuous and non-

inflammatory molecules.Additionally, both EPA and DHAhave been shown to possess potentanti-inflammatory properties in theirown right. For example, in animalsed DHA and then provoked with aninflammatory stimulus, the amount oresulting inflammation is considerablyreduced. Similarly, in humans ahigh intake o EPA and/or DHAsignificantly reduces key inflammatory

markers like NF and NF-B.Furthermore, omega-3 atty acidintake has been shown to reduce theintake o NSAIDs by arthritis patients.DHA intake is also associated with areduced risk o Alzheimers disease.For example, research has shown thatrestricting DHA in laboratory animals

increases their risk o Alzheimersdisease while the addition o DHA tothe diet reduces the pathology o thedisease. Similarly, EPA has been shownto powerully reduce inflammation othe blood vessels.

Not only do omega-3 atty acidsact as anti-inflammatory molecules,they also act directly as antioxidantsby quenching ree radicals o oxygenand nitrogen species and indirectly by

boosting the bodys own antioxidantdeense system through the stimulationo antioxidant enzymes like catalase,superoxide dismutase and glutathioneperoxidase.

Ashwagandha

Ashwagandha is another Ayurvedic

herb that has been used or centuries.Ofen but erroneously called theIndian ginseng, ashwagandha is apowerul anti-inflammatory agentwith a strong action against NF-B.Ashwagandha has been shown toaccelerate the breakdown o NF-B,which is different than other naturalagents that act to prevent its activationin the first place. As such, ashwagandhaprovides a unique alternative pathway


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or reducing NF-B levels, and thusinflammation.

Unortunately, while ashwagandhahas excellent supporting empiricaldata, there are ew well controlledhuman studies that have examinedits anti-inflammatory action.

Nevertheless, animal studies confirmthat ashwagandha, and its activecomponents the sitoindosides, arepowerul anti-inflammatory agents.

In addition to this, ashwagandha hasbeen shown to have other physiologicaleffects, including anti-cancer actions,anxiety reducing properties and apowerul immune system stimulatingeffect. It can thereore be speculated thatsince ashwagandha acts to stimulatethe immune system (particularly the

action o macrophages), its use inconjunction with more traditionaland well known anti-inflammatoryherbs like curcumin and Boswelliacould result in the exertion o a morepowerul anti-inflammatory effect.

Putting it all TogetherIn the end, there are a wide varietyo powerul natural herbs andmolecules that have shown verypromising results or the reductionand prevention o inflammation.

Te advantage o these natural anti-inflammatory agents is that they actthrough a variety o mechanisms

and influence a wide range o targetsand molecules involved in the bodysinflammatory response. Tese naturalagents are sae and effective, and canbe used in combination to help control

and prevent chronic inflammationthroughout the body. By preventingand treating chronic inflammation, it

may be possible to reduce the risk andprogression o many serious diseasesthat have been linked to inflammation.Finally, through the use o various noveltechniques to improve bioavailability,

the ull extent o the benefits o thesenatural anti-inflammatory agents canbe realized.

Ashwagandha

Key References

Aggarwal B et al. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. 2004. Anticancer Res. 24:2783-840.

Aggarwal B et al. From traditional Ayurvedic medicine to modern medicine: identification of therapeutic targets for suppression ofinflammation and cancer. Expert Opin Ter argets. 2006. 10: 87-118.

Aggarwal B et al. Inflammation and Cancer: How hot is the link? Biochem Pharmacol. 2006. 72: 1605-1621.

Aggarwal B and Harikumar K. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative,cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biology. 2009. 41: 4059

Fox JG and Wang C. Inflammation, atrophy, and gastric cancer. J Clin Invest. 2007. 117:60-69Frautschy S and Cole B. Why pleiotropic interventions are needed for Alzheimer s disease. Mol Neurobiol. 2010. 41: 392-409

Karin M and Lin A. NF-kappa B at the crossroads of life and death. Nat Immunol. 2002. 3: 221-227

Libby P. Atherosclerosis and Inflammation. Nature. 2002; 420: 19/26.

Liu H et al. Inflammation: A key event in Cancer development. Mol Cancer Res. 2006: 4(4)

Madea S and Omata M. Inflammation: A key role in Cancer. Cancer Sci 2008; 99: 836842

Nathan C. Points of Control in Inflammation. Nature. 2002. 420: 846-852

Ralhan R et al. Nuclear Factor-Kappa B links carcinogenesis and chemopreventive agents. Front Biosciences. 2009. S1: 45-60.

Rodger K and Crabtree JF. Helicobacter pylori and gastric inflammation. Br Med Bull. 1998. 54: 139-150


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Advances 31

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