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By Will iam J. CromieGazette Staff

For about $20 you can determine your risk of a future heart attack,according to a new study from Harvard Medical School.

The test measures levels of a protein that increase with the amountof inflammation in coronary arteries. The study showed that healthywomen with the highest levels of this substance, known as high-sensitivity C-reactive protein, have more than four times the risk ofsuffering a heart or blood-vessel problem than women with lowerlevels of the marker. Previous research revealed that men_with thehighest levels of this protein in their blood haye tlrpp tinles the riskof heart attack and two times the. risk of stroke compared to menwith the lowest levels.

Better Way To Predict Heart Attacks Is Discovered

Paul Ridker uses a heartmodel to expla in why h ighlevels of a protein l inked toinf lammat ion candramat ica l ly ra ise the r isk ofa heart attack.

"Cholesterol screening is currently the gold standard for predictingheart-attack risk, but nearly half of all heart attacks occur among men and women with norrnalcholesterol levelso" notes Paul Ridker, a cardiologist at Harvard-affiliated Brigham andWomen's Hospital in Boston.

"In fact, the amount of risk associated with hieh-sensitivity C-reactive protein is aknost twicethat associated with high levels of low density cholesterol."

The Food and Drug Administration approved the first test for this protein last November."It's now available to all doctors and costs about $15-$20," says Ridker, who is also anassociate professor of medicine at Harvard Medical School.

An improved ability to predict risk of heart attack can reveal who will benefit most frompreventive strategies, such as increased exercise, a healthier diet, and quitting smoking.Also, it pinpoints the best candidates for so-called statin drugs, such as pravastatin, which lowerlevels of both high-sensitivity C-reactive protein and low-density, or harmful, cholesterol.

"These drugs can prevent first heart attacks," Ridker points out, "but they axe too expensive toprescribe for everyone. The new test, along with cholesterol screening, should enable doctorsto better determine who is most likelv to benefit from their use."

Not all tests for the orotein are equal, however. o'Doctors who use this new approach must usean accurate high-sensitivitv test for C-reactive protein. not one ofthe older tests. which are farless reliable," cautions Nader Rifai, a Harvard associate professor of pathology, whoparticipated in this research.

Healing Begets HarmExactly how the protein is linked to heart disease and sffoke remains unclear. It's known tohelp white blood cells destroy invading bacteria and viruseso a process accompanied byinflammation. But there's a harmful side to such healing. Inflammation sometimes leads tovulnerable plaques, or raised clumps of cholesterol in the lining of blood vessels. The plaquesare vulnerable because they are likely to rupture, and the fragments can block narrower arteriesdownstream, leading to a heart attack or stroke.

"lnflarnmation is now understood to play a critical role in the conversion ofa stable cholesterolplaque into a worrisome, unstable lesion (injury)," Ridker points out.To clarifu the relationship between various markers involved in this process, includingC-reactive protein, total cholesterol, low-density cholesterol, and other compounds, Ridker andhis colleagues checked blood samples from 28,263 healthy, middle-aged women. The womenwere followed for three years, and levels of 12 different markers were compared withincidences ofdeath from heart disease, heart attacks, stroke, and need for procedures to unblocktheir coronary arteries.High-sensitivity C-reactive protein levels turned out to be the strongest and most significantpredictor of who would suffer these cardiovascular problems. The relationship held true evenamong people with cholesterol levels considered safe by national guidelines.

"Heart disease is the number one killer of men and women in the United Stateso" Ridker says."Any improvement we can make in a doctor's ability to predict heart attacks will increase thenumber of lives we can save through targeted use of drugs like the statins and more aggressivechanges in lifestyles."

A report on this research was published today in the March 23 issue of the Nelt EnglandJournal of Medicine.

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The Fires Within

Inflammation is the body's first defense against infection, but when it goes awry, it can lead to heart attacks,

colon cancer, Alzheimer's and a host of other diseases

By CHRISTINE GORMAN; ALICE PARK; KRISTINA DELL

Feb. 23, 2004

What does a stubbed toe or a splinter in a finger have to do with your risk of developing Alzheimer's disease,

suffering a heart attack or succumbing to colon cancer? More than you might think. As scientists delve

deeper into the fundamental causes of those and other illnesses, they are starting to see links to an age-old

immunological defense mechanism called inflammation--the same biological process that turns the tissue

around a splinter red and causes swelling in an injured toe. If they are right--and the evidence is starting to

look pretty good--it could radically change doctors' concept of what makes us sick. It could also prove a

bonanza to pharmaceutical companies looking for new ways to keep us well.

Most of the time, inflammation is a lifesaver that enables our bodies to fend off various disease-causing

bacteria, viruses and parasites. (Yes, even in the industrialized world, we are constantly bombarded by

pathogens.) The instant any of these potentially deadly microbes slips into the body, inflammation marshals a

defensive attack that lays waste to both invader and any tissue it may have infected. Then just as quickly, the

process subsides and healing begins.

Every once in a while, however, the whole feverish production doesn't shut

down on cue. Sometimes the problem is a genetic predisposition; other times

something like smoking or high blood pressure keeps the process going. In any

event, inflammation becomes chronic rather than transitory. When that occurs,

the body turns on itself--like an ornery child who can't resist picking a scab--

with aftereffects that seem to underlie a wide variety of diseases.

Suddenly, inflammation has become one of the hottest areas of medical

research. Hardly a week goes by without the publication of yet another study

uncovering a new way that chronic inflammation does harm to the body. It

destabilizes cholesterol deposits in the coronary arteries, leading to heart attacks

and potentially even strokes. It chews up nerve cells in the brains of Alzheimer's

victims. It may even foster the proliferation of abnormal cells and facilitate their

transformation into cancer. In other words, chronic inflammation may be the

engine that drives many of the most feared illnesses of middle and old age.

This concept is so intriguing because it suggests a new and possibly much simpler way of warding off

disease. Instead of different treatments for, say, heart disease, Alzheimer's and colon cancer, there might be a

single, inflammation-reducing remedy that would prevent all three.

Chronic inflammation also fascinates scientists because it indicates that our bodies may have, from an

evolutionary perspective, become victims of their own success. "We evolved as a species because of our

ability to fight off microbial invaders," says Dr. Peter Libby, chief of cardiovascular medicine at Brigham

and Women's Hospital in Boston. "The strategies our bodies used for survival were important in a time when

we didn't have processing plants to purify our water, when we didn't have sewers to protect us."

ALSO IN THIS

ISSUE

Feb. 23, 2004

Table of Contents »

But now that we are living longer, those same inflammatory strategies are more likely to slip beyond our

control. Making matters worse, it appears that many of the attributes of a Western lifestyle--such as a diet

high in sugars and saturated fats, accompanied by little or no exercise--also make it easier for the body to

become inflamed.

At least that's the theory. For now, most of the evidence is circumstantial. (A few researchers think chronic

inflammation can in some cases be good for you.) But that hasn't stopped doctors from testing the anti-

inflammatory drugs that are already on pharmacy shelves to see if they have any broader benefits. What

they've found is encouraging:

--In 2000 researchers concluded that patients who take Celebrex, a prescription drug from Pfizer that was

originally designed to treat inflammation in arthritis, are less likely to develop intestinal polyps--abnormal

growths that can become cancerous. Now there are dozens of clinical trials of Celebrex, testing, among other

things, whether the medication can also prevent breast cancer, delay memory loss or slow the progression of

the devastating neurodegenerative disorder known as Lou Gehrig's disease.

--As cardiologists gain more experience prescribing cholesterol-lowering statins, they are discovering that

the drugs are more effective at preventing heart attacks than anyone expected. It turns out that statins don't

just lower cholesterol levels; they also reduce inflammation. Now statins are being tested for their anti-

inflammatory effects on Alzheimer's disease and sickle-cell anemia.

--DeCode Genetics, an Icelandic biotech firm, announced last week that it is launching a pilot study to test

whether an anti-inflammatory drug that was under development for use in treating asthma might work to

prevent heart attacks.

--Of course the granddaddy of all anti-inflammatories is aspirin, and millions of Americans already take it to

prevent heart attacks. But evidence is growing that it may also fight colon cancer and even Alzheimer's by

reducing inflammation in the digestive tract and the brain.

This new view of inflammation is changing the way some scientists do medical research. "Virtually our

entire R.-and-D. effort is [now] focused on inflammation and cancer," says Dr. Robert Tepper, president of

research and development at Millennium Pharmaceuticals in Cambridge, Mass. In medical schools across the

U.S., cardiologists, rheumatologists, oncologists, allergists and neurologists are all suddenly talking to one

another--and they're discovering that they're looking at the same thing. The speed with which researchers are

jumping on the inflammation bandwagon is breathtaking. Just a few years ago, "nobody was interested in

this stuff," says Dr. Paul Ridker, a cardiologist at Brigham and Women's Hospital who has done some of the

groundbreaking work in the area. "Now the whole field of inflammation research is about to explode."

To understand better what all the excitement is about, it helps to know a little about the basic immunological

response, a cascade of events triggered whenever the body is subjected to trauma or injury. As soon as that

splinter slices into your finger, for example, specialized sentinel cells prestationed throughout the body alert

the immune system to the presence of any bacteria that might have come along for the ride. Some of those

cells, called mast cells, release a chemical called histamine that makes nearby capillaries leaky. This allows

small amounts of plasma to pour out, slowing down invading bacteria, and prepares the way for other

faraway immune defenders to easily enter the fray. Meanwhile, another group of sentinels, called

macrophages, begin an immediate counterattack and release more chemicals, called cytokines, which signal

for reinforcements. Soon, wave after wave of immune cells flood the site, destroying pathogens and damaged

tissue alike--there's no carrying the wounded off the battlefield in this war. (No wonder the ancient Romans

likened inflammation to being on fire.)

Doctors call this generalized response to practically any kind of attack innate immunity. Even the bodies of

animals as primitive as starfish defend themselves this way. But higher organisms have also developed a

more precision-guided defense system that helps direct and intensify the innate response and creates

specialized antibodies, custom-made to target specific kinds of bacteria or viruses. This so-called learned

immunity is what enables drug companies to develop vaccines against diseases like smallpox and the flu.

Working in tandem, the innate and learned immunological defenses fight pitched battles until all the

invading germs are annihilated. In a final flurry of activity, a last wave of cytokines is released, the

inflammatory process recedes, and healing begins.

Problems begin when, for one reason or another, the inflammatory process persists and becomes chronic; the

final effects are varied and depend a lot on where in the body the runaway reaction takes hold. Among the

first to recognize the broader implications were heart doctors who noticed that inflammation seems to play a

key role in cardiovascular disease.

IS YOUR HEART ON FIRE?

Not long ago, most doctors thought of heart attacks as primarily a plumbing problem. Over the years, fatty

deposits would slowly build up on the insides of major coronary arteries until they grew so big that they cut

off the supply of blood to a vital part of the heart. A complex molecule called LDL, the so-called bad

cholesterol, provided the raw material for these deposits. Clearly anyone with high LDL levels was at greater

risk of developing heart disease.

There's just one problem with that explanation: sometimes it's dead wrong. Indeed, half of all heart attacks

occur in people with normal cholesterol levels. Not only that, as imaging techniques improved, doctors

found, much to their surprise, that the most dangerous plaques weren't necessarily all that large. Something

that hadn't yet been identified was causing those deposits to burst, triggering massive clots that cut off the

coronary blood supply. In the 1990s, Ridker became convinced that some sort of inflammatory reaction was

responsible for the bursting plaques, and he set about trying to prove it.

To test his hunch, Ridker needed a simple blood test that could serve as a marker for chronic inflammation.

He settled on Creactive protein (CRP), a molecule produced by the liver in response to an inflammatory

signal. During an acute illness, like a severe bacterial infection, levels of CRP quickly shoot from less than

10 mg/L to 1,000 mg/L or more. But Ridker was more interested in the low levels of CRP--less than 10

mg/L--that he found in otherwise healthy people and that indicated only a slightly elevated inflammation

level. Indeed, the difference between normal and elevated is so small that it must be measured by a specially

designed assay called a high-sensitivity CRP test.

By 1997, Ridker and his colleagues at Brigham and Women's had shown that healthy middle-aged men with

the highest CRP levels were three times as likely to suffer a heart attack in the next six years as were those

with the lowest CRP levels. Eventually, inflammation experts determined that having a CRP reading of 3.0

mg/L or higher can triple your risk of heart disease. The danger seems even greater in women than in men.

By contrast, folks with extremely low levels of CRP, less than 0.5 mg/L, rarely have heart attacks.

Physicians still don't know for sure how inflammation might cause a plaque to burst. But they have a theory.

As the level of LDL cholesterol increases in the blood, they speculate, some of it seeps into the lining of the

coronary arteries and gets stuck there. Macrophages, alerted to the presence of something that doesn't belong,

come in and try to clean out the cholesterol. If, for whatever reason, the cytokine signals begin ramping up

the inflammatory process instead of notching it down, the plaque becomes unstable. "This is not about

replacing cholesterol as a risk factor," Ridker says. "Cholesterol deposits, high blood pressure, smoking--all

contribute to the development of underlying plaques. What inflammation seems to contribute is the

propensity of those plaques to rupture and cause a heart attack. If there is only inflammation but no

underlying heart disease, then there is no problem."

At this point, cardiologists are still not ready to recommend that the general population be screened for

inflammation levels. But there's a growing consensus that CRP should be measured in those with a

moderately elevated risk of developing cardiovascular disease. At the very least, a high CRP level might tip

the balance in favor of more aggressive therapy with treatments--such as aspirin and statins--that are already

known to work.

A NEW VIEW OF DIABETES

Before Dr. Frederick Banting and his colleagues at the University of Toronto isolated insulin in the 1920s,

doctors tried to treat diabetes with high doses of salicylates, a group of aspirin-like compounds. (They were

desperate and also tried morphine and heroin.) Sure enough, the salicylate approach reduced sugar levels, but

at a high price: side effects included a constant ringing in the ears, headaches and dizziness. Today's

treatments for diabetes are much safer and generally work by replacing insulin, boosting its production or

helping the body make more efficient use of the hormone. But researchers over the past few years have been

re-examining the salicylate approach for new clues about how diabetes develops.

What they have discovered is a complex interplay between inflammation, insulin and fat--either in the diet or

in large folds under the skin. (Indeed, fat cells behave a lot like immune cells, spewing out inflammatory

cytokines, particularly as you gain weight.) Where inflammation fits into this scenario--as either a cause or

an effect--remains unclear. But the case for a central role is getting stronger. Dr. Steve Shoelson, a senior

investigator at the Joslin Diabetes Center in Boston, has bred a strain of mice whose fat cells are

supercharged inflammation factories. The mice become less efficient at using insulin and go on to develop

diabetes. "We can reproduce the whole syndrome just by inciting inflammation," Shoelson says.

That suggests that a well-timed intervention in the inflammatory process might reverse some of the effects of

diabetes. Some of the drugs that are already used to treat the disorder, like metformin, may work because

they also dampen the inflammation response. In addition, preliminary research suggests that high CRP levels

may indicate a greater risk of diabetes. But it's too early to say whether reducing CRP levels will actually

keep diabetes at bay.

CANCER: THE WOUND THAT NEVER HEALS

Back in the 1860s, renowned pathologist Rudolf Virchow speculated that cancerous tumors arise at the site

of chronic inflammation. A century later, oncologists paid more attention to the role that various genetic

mutations play in promoting abnormal growths that eventually become malignant. Now researchers are

exploring the possibility that mutation and inflammation are mutually reinforcing processes that, left

unchecked, can transform normal cells into potentially deadly tumors.

How might that happen? One of the most potent weapons produced by macrophages and other inflammatory

cells are the so-called oxygen free radicals. These highly reactive molecules destroy just about anything that

crosses their path--particularly DNA. A glancing blow that damages but doesn't destroy a cell could lead to a

genetic mutation that allows it to keep on growing and dividing. The abnormal growth is still not a tumor,

says Lisa Coussens, a cancer biologist at the Comprehensive Cancer Center at the University of California,

San Francisco. But to the immune system, it looks very much like a wound that needs to be fixed. "When

immune cells get called in, they bring growth factors and a whole slew of proteins that call other

inflammatory cells," Coussens explains. "Those things come in and go 'heal, heal, heal.' But instead of

healing, you're 'feeding, feeding, feeding.'"

Sometimes the reason for the initial inflammatory cycle is obvious--as with chronic heartburn, which

continually bathes the lining of the esophagus with stomach acid, predisposing a person to esophageal

cancer. Other times, it's less clear. Scientists are exploring the role of an enzyme called cyclo-oxygenase 2

(COX-2) in the development of colon cancer. COX-2 is yet another protein produced by the body during

inflammation.

Over the past few years, researchers have shown that folks who take daily doses of aspirin--which is known

to block COX2--are less likely to develop precancerous growths called polyps. The problem with aspirin,

however, is that it can also cause internal bleeding. Then in 2000, researchers showed that Celebrex, another

COX-2 inhibitor that is less likely than aspirin to cause bleeding, also reduces the number of polyps in the

large intestine.

So, should you be taking Celebrex to prevent colon cancer? It's still too early to say. Clearly COX-2 is one of

the factors in colon cancer. "But I don't think it's the exclusive answer," says Ray DuBois, director of cancer

prevention at the Vanderbilt-Ingram Cancer Center in Nashville, Tenn. "There are a lot of other components

that need to be explored."

ASPIRIN FOR ALZHEIMER'S DISEASE?

When doctors treating Alzheimer's patients took a closer look at who seemed to be succumbing to the

disease, they uncovered a tantalizing clue: those who were already taking anti-inflammatory drugs for

arthritis or heart disease tended to develop the disorder later than those who weren't. Perhaps the immune

system mistakenly saw the characteristic plaques and tangles that build up in the brains of Alzheimer's

patients as damaged tissue that needed to be cleared out. If so, the ensuing inflammatory reaction was doing

more harm than good. Blocking it with anti-inflammatories might limit, or at least delay, any damage to

cognitive functions.

The most likely culprits this time around are the glial cells, whose job is to nourish and communicate with

the neurons. Researchers have discovered that glial cells can also act a lot like the mast cells of the skin,

producing inflammatory cytokines that call additional immune cells into action. "The glial cells are trying to

return the brain to a normal state," explains Linda Van Eldik, a neurobiologist at Northwestern University

Feinberg School of Medicine in Chicago. "But for some reason, in neurodegenerative diseases like

Alzheimer's, the process seems to be out of control. You get chronic glial activation, which results in an

inflammatory state."

It appears that some people are more sensitive to plaques and tangles than others. Perhaps they have a

genetic predisposition. Or perhaps a long-running bacterial infection, like gum disease, keeps the internal

fires burning and tips the balance toward chronic inflammation.

Preliminary research suggests that low-dose aspirin and fish-oil capsules--both of which are known to reduce

inflammatory cytokines--seem to reduce a person's risk of Alzheimer's disease. Unfortunately, most of these

preventive measures need to be started well before any neurological problems develop. "What we've learned

with dementia is that it's very hard to improve people who already have it," says Dr. Ernst Schaefer, a

professor of medicine and nutrition at Tuft's Friedman School of Nutrition in Boston. "But it may be possible

to stabilize people and to prevent disease."

WHEN THE BODY ATTACKS ITSELF

No doctors have more experience treating chronic inflammation than the physicians who specialize in

rheumatoid arthritis, multiple sclerosis, lupus and other autoimmune disorders. For decades these diseases

have provided the clearest example of a body at war with itself. But the spark that fuels their internal

destruction doesn't come from excess cholesterol deposits or a stubborn bacterial infection. Instead, in a

bizarre twist of fate, the body's supersophisticated, learned immunological defenses mistakenly direct an

inflammatory attack against healthy cells in such places as the joints, nerves and connective tissue.

Over the past few years, powerful drugs like Remicade and Enbrel, which target specific inflammatory

cytokines, have worked wonders against rheumatoid arthritis and other autoimmune disorders. But as often

happens in medicine, the drugs have also created some problems. Patients who take Remicade, for example,

are slightly more likely to develop tuberculosis; the same inflammatory cytokines that attacked their joints, it

seems, also protected them against TB.

Inflammation may be more of a problem in the earlier stages of autoimmune diseases like multiple sclerosis.

So much tissue is eventually destroyed that nerve damage becomes permanent. "Your initial goal is to keep

the immune response in check, but then you have to ask how you encourage regrowth of damaged tissue,"

says Dr. Stephen Reingold, vice president for research programs at the National Multiple Sclerosis Society.

It could take decades to figure that one out.

ASTHMA WITHOUT ALLERGIES?

One of the most intriguing questions in immunology today is why everyone doesn't suffer from asthma.

After all, the air we breathe is full of germs, viruses and other irritants. Since half of the 17 million

Americans with asthma are hypersensitive to common substances like cat dander or pollen, it stands to

reason that their allergic reactions trigger the chronic inflammation in their bodies. Yet the people who

develop asthma as adults--one of the most rapidly growing segments of the population--often don't have

allergies. Doctors still don't know what's driving their disease, but the signs of inflammation are every bit as

present in their lungs.

Many treatments for asthma are designed to control inflammation, although they still don't cure the disease.

"It may mean that the inflammatory hypothesis is not entirely correct or the drugs that we use to treat

inflammation aren't fully potent," says Dr. Stephen Wasserman, an allergist at the University of California at

San Diego. "There are a lot of gaps to fill in."

Everywhere they turn, doctors are finding evidence that inflammation plays a larger role in chronic diseases

than they thought. But that doesn't necessarily mean they know what to do about it. "We're in a quandary

right now," says Dr. Gailen Marshall, an immunologist at the University of Texas Medical School at

Houston. "We're advancing the idea to heighten awareness. But we really can't recommend specific

treatments yet."

That may soon change. Researchers are looking beyond aspirin and other multipurpose medications to

experimental drugs that block inflammation more precisely. Any day now, Genentech is expecting a decision

from the FDA on its colon-cancer drug, Avastin, which targets one of the growth factors released by the

body as inflammation gives way to healing. Millennium Pharmaceuticals is testing a different kind of drug,

called Velcade, which has already been approved for treating multiple myeloma, against lung cancer and

other malignancies. But there is a sense that much more basic research into the nature of inflammation needs

to be done before scientists understand how best to limit the damage in chronic diseases.

In the meantime, there are things we all can do to dampen our inflammatory fires. Some of the advice may

sound terribly familiar, but we have fresh reasons to follow through. Losing weight induces those fat cells--

remember them?--to produce fewer cytokines. So does regular exercise, 30 minutes a day most days of the

week. Flossing your teeth combats gum disease, another source of chronic inflammation. Fruits, vegetables

and fish are full of substances that disable free radicals.

So if you want to stop inflammation, get off that couch, head to the green market and try not to stub your toe

on the way.

--With reporting by Dan Cray/Los Angeles

New heart villain seenInflammation as potent as bad cholesterolBy Steve Sternberg, USA TODAYThursday, January 06, 2005

Two leading research groups independently reported today that lowerhg blood levels of a protein thatpromotes artery inflammation is just as important as reducing bad cholesterol for preventing heartattacks and strokes.

Their conclusions reflect a major shift away from the notion that bad cholesterol, or LDL, is theprimary villain in heart disease. Levels of C-reactive protein (CRP) also must be reduced to halt thedisease's progression, researchers said.

In that simple assertion lies the seed of a major debate among heart specialists. Revised just last year,current treatnent guidelines reflect what studies then showed: the importance of lowering LDL tobelow 70 milligrams per deciliter of blood in high-risk patients.

But most doctors don't track CRP as they do cholesterol or prescribe drugs to reduce i! such as Lipitorand other potent statins. If doctors are to provide quality care, the researchers said, that will have tochange. The inexpensive CFP test ($10 to $15) is widely available and can be done as part ofotherblood tests. "If we think only about cholesterol, we now have hard evidence that we're not doing thebest we can for our patients," said the lead author ofone ofthe papers, Paul Ridker ofBrighanr andWomen's Hospital in Boston.

Steven Nissen of the Cleveland Clinic, and lead author of the second study, agrees: "Our studiessuggest that the higher your level ofCRP, the more your coronary artery disease progresses."

But Scott Grundy of the University of Texas Southwestern Medical Center in Dallas, and author of thecurrent guidelines, challoged the findings. "I agree loweriug LDL only reduces heart attack risk byone-third. You've got two-thirds of the risk remaining. CRP is responsible for some of that risk, butthere are other factors involved, too."

Still, Nissen predicted that the study will generate interest in other drugs that reduce CRP, includingthe experimental anti-smoking, anti-obesity drug rimonabant and some diabetes drugs.

Ridker's team analyzed the cases of 3,745 patients in a comparison of cholesterol-lowering drugsLipitor and Pravachol. Ridker said the drug used is not as important as reducing LDL to below 70 forhigh-risk patients, and reducing CRP to below 2 milligrams per liter of blood. Even when you hit theLDL targeL you reduce the risk ofrecurrent heart attacks or of dying from a heart attack or strokeanother 50%by lowering the CRP to 2.

In a sfudy of the same drugs sponsored by Lipitor maker Pfizer, Nissen's team examined arteries to seewhat role inflammation plays in the progression of coronary artery disease. People with better-than-average reductions ofLDL and CRP cut the progression rate to zero.

Both studies appear in today's New England Joumal of Medicine.

Body heat

Inflammation has been linked to diseases from Alzheimer's to cancer, and the list just keeps swelling

By Scott LaFee STAFF WRITER

March 30, 2005

Inflammation isn't pretty. And it often hurts.

But the tell-tale swelling and ache, the redness and heat are signs that our bodies are fighting back against microbial invaders that might otherwise harm or kill us. Inflammation is our first line of defense and sometimes, it now seems, our worst enemy.

In multiple sclerosis, lupus and rheumatoid arthritis, the body turns upon itself with often catastrophic results. But the danger is not limited to these classic inflammatory diseases. Increasingly, scientists are linking inflammation to an expanding list of disparate and sometimes surprising diseases, from Alzheimer's, autism and asthma to cirrhosis, cardiovascular disease and cancer.

"We're converging toward what I believe may eventually be a unifying hypothesis of human disease," said Michael Karin, a professor of pharmacology and molecular biologist at UCSD. "I think we will find that inflammation and infection will account for 90 percent of human misery."

The evidence is compelling. For example, the Women's Health Study, a landmark research program involving almost 28,000 women, has found that women with the highest measures of inflammation in their blood face a seven-fold increased risk of heart attack or stroke. Sufferers of inflammatory bowel disease have a five-to seven-fold higher incidence of developing colon cancer. And studies have shown that people who take anti-inflammatory drugs seem to get Alzheimer's disease later in life than those who do not.

"Inflammation may be driving a lot of what we're seeing, in a lot of different diseases. It may be that the things that cause these diseases are related to inflammation," said Dr. Barrett Rollins, chief science officer at the Dana-Farber Cancer Institute in Boston.

"But that being said, there are still a lot of things we need to learn."

Basic biology

The basics, though, are pretty well-known. Inflammation is the body's biggest weapon, the biological equivalent of shock and awe. It is meant to overwhelm and destroy an enemy – regardless of collateral damage – in an effort to secure quick and total victory. The fundamental process is the same whether you're sneezed upon by someone with a cold, inhale a snoutful of allergenic pollen or cut your finger.

For illustration purposes, let's say the last happens, triggering a cascade of events known collectively as innate immunity.

Sentries called mast cells in the injured finger (they're stationed everywhere) detect the presence of pathogens and sound the alarm, secreting proteins called cytokines to summon help and histamines to make nearby capillaries suddenly porous. The leaky blood vessels flood the wounded area with plasma, producing swelling and discomfort, but also isolating pathogens from the rest of the body and slowing their spread.

CRISTINA MARTINEZ / Union-Tribune

Soon, the body's immunological warriors, a class of white blood cells called phagocytes, arrive. They are meat-eaters. Their job is to engulf and digest foreign material, including dead and dying cells.

As the phagocytes work, they secrete more cytokines, summoning more reinforcements and provoking greater and sharper symptoms of inflammation. Their fight will rage on until there is nothing left to kill or eat.

Under normal circumstances, said Geert Schmid-Schoenbein, a UCSD professor of bioengineering, "once the infection is cleared up, inflammation goes away." The phagocytes die. The wound heals. Tissues return to normal.

Only sometimes the process doesn't stop. Sometimes inflammation smolders like a fire within. It becomes chronic, though its consequences might not be immediately noticed or felt. Why this happens is not fully understood, but the tally of known or suspected causes of chronic inflammation is long and growing.

Some people appear to be genetically predisposed to chronic inflammation. Obesity is a huge factor. Fat cells, researchers have discovered, produce and spew their own pro-inflammatory cytokines. The fatter you are, say scientists, the bigger the threat of chronic inflammation.

Bacteria and viruses provoke an inflammatory response, and when they linger in conditions like gum disease and stomach ulcers, they foster a chronic inflamed state, even though the sufferer may initially feel no ill effect.

Numerous environmental and external stimuli have been linked to chronic inflammation. Among them: asbestos, smoking, coffee, alcohol, birth control pills, some medical treatments such as hormone replacement therapy, even prolonged or recurrent bouts of anger, hostility and depression.

"Every time we look for signs of inflammation, we find them," said Schmid-Schoenbein. "Even in apparently young, healthy, asymptomatic college students who consume tobacco products."

It has only been in the last decade – and most keenly in just the last few years – that researchers have begun to identify chemical biomarkers that signal inflammation even when symptoms are not present or obvious.

These biomarkers tend to be the working elements and products of inflammation: the various proteins, chemicals and cells that, in a normal, healthy state, are present only in modest amounts, if at all.

The current poster child of inflammatory biomarkers is C-reactive protein, a tool of the inflammatory process thought to help white blood cells bind to foreign and damaged cells. Higher-than-normal levels of CRP, however, have been connected to a number of diverse diseases and conditions.

For example, men with the highest levels of CRP have a three-fold increased risk of heart attack and a two-fold increased risk of stroke compared to men with the lowest levels. Obese people have elevated levels of CRP, as do people suffering from macular degeneration, an age-related condition in which central vision gradually declines, often leading to blindness.

"CRP levels always go up with inflammation," said Ken Buechler, president of Biosite, a San Diego-based company that creates diagnostic tools to quickly measure biomarkers like CRP. "It's non-specific to a disease. CRP rises whether it's a stroke or sepsis (the presence of pathogens in the blood)."

The question is whether elevated CRP causes disease or simply reflects a diseased condition. Researchers don't yet know. It may be a combination of both, depending upon the disease.

A hand in many things

More and more, researchers suspect inflammation is at work in heart attacks. In one widely held scenario, white blood cells attempting to clear away arterial plaques of cholesterol inadvertently damage healthy tissues as well. This escalates the inflammatory process until one or more plaques burst, blocking an artery and causing either a heart attack or stroke.

"It's a host of factors," said Rollins. "High cholesterol predisposes people to hardening of the arteries, but inflammation plays a role and seems to make things worse."

Likewise with Type 2 diabetes, which afflicts almost 16 million Americans. The disease is characterized by the inability to produce, use or regulate insulin, a hormone that transports sugars from the blood into cells for energy. Obesity is the biggest risk factor for developing diabetes, and here, too, inflammation plays a villainous role.

Dr. Steve Shoelson, of the Joslin Diabetes Center in Boston, has found that obese people accumulate fat in their livers. Excessive levels of fat cause a protein in the liver called NF-kB to be activated. NF-kB turns out to be a kind of master switch for starting the inflammatory response.

Shoelson thinks the resulting chronic inflammation disrupts the body's ability to process insulin, leading to diabetes. In experiments, Shoelson has activated the gene that produces NF-kB in mice, triggering inflammation. Though the mice are lean and apparently healthy, they display symptoms of diabetes.

Some forms of cancer are clearly exacerbated, if not caused outright, by inflammation. For example, in gastroesophageal reflux disease, the lining of the esophagus is routinely doused with stomach acid, causing inflammation and heightening the risk of esophageal cancer.

One of the products of inflammation is oxygen-free radicals – unstable and highly reactive molecules that damage or destroy anything they touch, friend or foe.

Some researchers have speculated that free-radical damage to healthy cells and their DNA sometimes results in cancerous mutations. The resulting tumors are then fed and nurtured by inflammatory growth factors intended to spur wound repair.

Similar explanations are proposed for neurological disorders such as Alzheimer's and autism. Biochemist Jeffrey W. Kelly and colleagues at the Scripps Research Institute in La Jolla, for example, have hypothesized that inflammation could disrupt normal neuron activity, causing amyloid beta proteins in the brain to misfold. Such plaques have been strongly linked to the development of Alzheimer's.

A study published last year by researchers at the Johns Hopkins University School of Medicine reported the first direct evidence linking brain inflammation to autism. They examined brain tissue from 11 people with autism who had died of accidents or injuries. They found that, compared to normal brains, the autistic brains contained abnormal patterns of cytokines and chemokines – indicators of inflammation. Samples of cerebrospinal fluid taken from six living children with autism showed elevated levels of cytokines.

Whether the inflammation causes or contributes to autism or is the result of the brain attempting to fend off some other damaging process remains to be determined.

Promise in the problem

Revelations of inflammation's links to many diseases have opened up new possibilities for drug therapies and treatments. New drugs are in development, and approved drugs are being given new jobs.

Statins, for example, are used to lower cholesterol and reduce inflammation. They are being tested for their efficacy in treating Alzheimer's disease and sickle-cell anemia, in which red blood cells become misshapen and cause painful clots.

And then there's aspirin, which is now widely prescribed in small, daily doses for people at risk of cardiovascular disease.

But aspirin has its drawbacks, including side effects such as internal bleeding when used in large doses over extended periods.

Shoelson will soon launch long-term clinical trials on an alternative that avoids aspirin's shortcomings. Salsalate is an aspirin-like drug already approved for treating arthritis and related inflammatory conditions. Preliminary studies have shown that it improves insulin sensitivity and lowers blood glucose and lipids after just two weeks of use. Shoelson and colleagues think it may help prevent diabetes.

"We are trying to determine if the drug may help in people who do not yet have diabetes, but are overweight and at risk to develop disease," said Dr. Allison Goldfine, of the Joslin Clinical Research section and, like Shoelson, a Harvard

© Copyright 2007 Union-Tribune Publishing Co. ? A Copley Newspaper Site

professor.

Other researchers are investigating the use of COX-2 inhibitors, anti-inflammatory drugs like Vioxx, Celebrex and Bextra. The problem with these pharmaceuticals, of course, is that they may create other problems. Merck withdrew Vioxx from the market last year after it was linked to increased risk of heart attack and stroke. An FDA panel has since ruled that Vioxx can be sold with a stronger warning label.

"Everything is a balancing act of risks and benefits," said Rollins. "COX-2 inhibitors may be beneficial for preventing colon cancer, but at the increased risk of cardiovascular disease."

At UCSD, Schmid-Schoenbein has focused on shock with Tony Hugli, of Torrey Pines Institute for Molecular Studies, and David Hoyt, of UCSD. A major cause of death in hospital emergency rooms, shock can cause massive, rapid organ failure when the body suffers inadequate blood flow, often due to severe trauma. In shock, when blood flow drops dangerously low, digestive enzymes escape into the wall of the intestine, peritoneal cavity, lymphatic system and bloodstream, where they break down tissues, causing organs to fail.

Understanding this sequence of events, said Schmid-Schoenbein, means doctors can now search for ways to preserve the intestinal barrier, perhaps by introducing drugs to inhibit or block digestive enzymes.

Better remedies, though, will take time, researchers caution. Inflammation is a tricky business.

"When you block some of the inflammatory reactions, you're also blocking part of the repair process," said Schmid-Schoenbein.

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Quieting a Body's DefensesResearchers are linking inflammation to an ever-wider array of chronic illnesses. Buttreatments that block the inflammatory response can backfire.By Anne UnderwoodNewsweek

Summer 2005 - A decade ago, the cause of meta Kiss's heart attack might havebeen written off as a medical mystery. The S9-year-old homemaker had neversmoked, weighed in at a slender 119 pounds and had fabulous cholesterol readirgs,with her good cholesterol actually surpassing the bad. And there was no history ofheart disease in her family. So what put her at risk for the heart attack she sufferedin 2000? To Eric Matteson, one of her doctors at the Mayo Clinic, the answer leaptright out. "She had rheumatoid arthrit is," he says.

If the two conditions sound unrelated, that's because most of us are just nowawakening to the risks of chronic inflammation. A decade ago, researchers wereblaming oxidative damage for everything from cancer to heart disease. Now chronic,low-grade inflammation is seizing the spotl ight. "Inflammation is the evil twin ofoxidation," says neuroscientist James Joseph of Tufts University. "Where you findone, you find the other." That would include not only such obvious inflammatoryconditions as asthma and rheumatoid arthritis, but also ailments never previouslyassociated with inflammation*such as atherosclerosis, Alzheimer's disease, coloncancer and diabetes. Suddenly medical puzzles seem to be fitting together, such aswhy hypertension puts patients at increased risk of Alzheimer's, or why rheumatoid-arthritis sufferers have higher rates of sudden cardiac death. They're all connectedon some fundarnental level*which raises a tantalizing question. If there are commonthreads in the development of all these diseases, are there common treatments?Drug companies are eager to find out. But it's not as simple as it seems.

If you can't live with inflammation, you can't live without it, either. Inflammation is akey component of the immune system's defenses. If you cut yourself, the bodysends in a barrage of microbe-fighting molecules (including oxidants), and the woundbecomes red, hot and swollen. When the threat of infection recedes, so does theinflammation. But persistent insults like cigarette smoke, excess cholesterol andlingering infections can produce a low*grade, chronic inflammation that simmers on,like the low flame on the back burner that we're unaware of until the pot burns.

Diabetes has emerged as a recent example. The correlation between type 2 diabetesand obesity is so well established that some researchers refer to the two collectivelyas "diabesity." Now we're starting to understand why they're linked. When you gainweight, fat cells g!"ow more biochemically active, churning out inflammatorycompounds, As obesity ratchets up inflammation, inflammation in turn promotesinsulin resistance, a central feature of diabetes and the so-called metabolic syndromethat precedes it. Just why inflammation leads to insulin resistance is unclear. But Dr.Steven Shoelson, associate director of research at loslin Diabetes Center, has bred astrain of mice whose fat cells produce exceptional levels of inflammatory compoundslike TNF-alpha, IL-1 and resistin (as in insulin resistancc). "We reproduced the wholeconstellation of metabolic syndrome in these mice," he says, 'Just by incitinginflammation."

In addition to diabetes, heart disease is a risk for people who are overweight.Inflammation may be the common denominator. "Inflammation is the alpha andomega of atherosclerosisr" says Dr. Peter Libby, chief of cardiovascular medicine atBrigham and Women's Hospital in Boston. "It's there at every step of the process."Plaque formation begins when cholesterol gets stuck in arterial walls and oxidizes,prompting the immune system to attempt a cleanup. Although inflammation is thebody's attempt to heal, it only encourages the formation of bigger, more complicatedplaques. With luck, plaques will remain stable for decades and cause no trouble. Butinflammatory chemicals can weaken the fibrous cap that holds a plaque in place. If itruptures, fat spills into the blood, where it collides with clotting factors, producing aclot that can block an artery and cause a heart attack or stroke.

Even certain cancers are being linked to inflammation. "People with chronicinflammatory bowel diseases have tremendously enhanced risk of colon cancer,"says Lisa Coussens, a cancer biologist at the University of California, San Francisco.Other triggers of tumor-inducing inflammation include cigarette smoke in the lungs,persistent infections like hepatitis C in the liver and chronic heartburn, whichrepeatedly irritates the lining of the esophagus with gastric acid. Whatever thecause, says Coussens, the result is a series of changes that can set a cell on the roadto malignancy. These include oxidative damage to DNA, the disabting of suicidernechanisms that should cause an abnormal cell to self-destruct, and the release ofgrowth factors that can make the abnormal cell grow and divide.

This knowledge is beginning to change clinical approaches to treatment. Forexample, doctors used to use bare wire-mesh frames called stents to hold openclogged arteries, but the blood vessels routinely formed scar tissue over the stentsand often narrowed again. Now doctors are achieving much better success rates withstents that are coated with anti-inflammatory drugs. And they're starting to lookbeyond cholesterol alone for the keys to reducing heart attacks. Several large trialssuggest that those patients who do best reduce both cholesterol and inflammation.Statin drugs help rnany patients reduce both, but future treatments may targetinflammation more directly. Millennium Pharmaceuticals in Cambridge, Mass., isworking with an experimental drug that blocks macrophages, a type of inflammatoryimmune cell, from moving out of the bloodstream and into vessel walls and othertissues.

But taming the immune system isn't as simple as it sounds. As Libby explains, thereare three ways to go about it. You can reduce the triggers that cause inflammation.You can hamper the cellular "master switches" that orchestrate the body'sinflammatory response. Or you can knock out the inflammatory chemicals-the "footsoldiers," as Libby dubs them-that actually produce the inflammation. Here's thecatch. If you turn down the central switches too much, "you run the untoward risk ofsecondary infections," says Dr. Mark Fishman, president of the Novartis Institutes forBioMedical Research. Tysabri, an immune-modulating drug for multiple sclerosis, wasvoluntarily withdrawn from the market earlier this year after two patients taking itwith another medication called Avonex developed an additional neurodegenerativedisease, this one caused by a latent virus most of us harbor. Scientists need a muchmore detailed knowledge of how the various parts of the immune system interactand overlap, so they can develop key blood tests to tell them just how much they'returning down the system.

As for the foot soldiers, it turns out that many of the body's inflammatory chemicalsalso have beneficial functions, like protecting the stomach or guarding the lining ofblood vessels against clots. If you knock out something that causes harm in one partof the body, you may eliminate positive effects elsewhere. Drugs like Vioxx andtsextra are a case in point. By inhibiting inflammatory Cox-2 enzymes, they relievedpain, but also hampered a compound that helps prevent dangerous blood clots fromforming in arteries. A second problem with the foot soldiers is that there are so manywith overlapping functions that eliminating a single one doesn't necessarily help you.The drugs Enbrel and Remicade fight rheumatoid arthritis by targeting theinflammatory cornpound TNF-alpha, but they do nothing for congestive heart failure,which many cardiologists believe is also an inflammatory condition.

Instead of aiming at narrower and narrower targets, some scientists are doing theopposite and striving for broader "immune modulation." One such treatment, calledCelecade, is now in advanced testing for congestive heaft failure. Doctors withdraw atest tube of the patient's blood and place it in a machine that delivers bursts of UVradiation for 10 to 15 minutes. The radiation kills immune-system white cells bytriggering mechanisms of self-destruction. The blood is then reinjected into thepatient's hip. As the procedure is repeated during the following weeks and months,the immune system interprets the self- destruction of white cells as a signal that thedanger is reduced and responds by turning down systemic inflammation across theboard. "When I first saw this data, I was intrigued but highly skeptical," sayscardiologist lames Young of the Cleveland Clinic Foundation. Now that he has takenpart in trials, he's cautiously optimistic that it will become a useful treatment. W. R.Woofter, 59, of Berea, Ohio, is one patient who's tried it. He's had five heart attackssince 1968 and severe congestive heart failure since 2002. Since last August, he'sbeen going for monthly treatments. "I haven't deteriorated any morer" h€ says. "I'vebeen able to cut back on diuretic drugs by a third and cut another medicine forcardiac dysrhythmia by half." And he's back to golfing. "I'm still taking people'smoneyr" he says.

Medicine doesn't provide the only way to beat inflammation. Exercise and weight losswork to reduce inflammation in the fat cells and liver. And a diet rich in fruits,vegetables, whole grains and omega-3 fatty acids tones down inflammation overall.

The omega-3s are particularly important. Found in coldwater fish like salmon,sordines and mackerel, as well as walnuts, flaxseed and dark leafy greens, they formthe building blocks of a number of anti-inflammatory compounds in the body. Dozensof studies have shown that the omega-3s can help prevent heart attacks and suddencardiac death by preventing arrhythmias, making blood less likely to clot in arteries,improving the balance of good and bad cholesterol and limiting inflammation. But themodern diet is generally deficient in them. That's why a growing number of doctorsare recommending fish-oil capsules.

A diet rich in fruits and vegetables also helps. One anti-inflammatory compound infood that has been studied extensively is curcumin, the yellow pigment in the curryspice turmeric. Greg Cole, professor of medicine and neurology at UCl3, has foundthat small doses reduce TNF-alpha and IL-1. Larger doses lead to a decrease in Cox-2 enzymes. But Cole considers curcumin a far safer Cox-Z inhibitor than, soy, Vioxx.While drugs usually block a single target molecule and reduce its activitydramatically, he says, natural anti-inflammatories gently tweak a broader range of

inflammatory compounds. "You'll get greater safety and efficacy reducing fiveinflammatory mediators by 30 percent than reducing one by 100 percent," he notes.

The beauty of these lifestyle changes is that they're so low tech, affordable andeffective. When patients with a sedentary lifestyle and miserable diets come into theoffice of cardiologist Herbert Insel at New York University, they invariably ask if hecan help them. "Sure," he replies. "But you can help yourself better." We may allhave it within our grasp to reduce inflammation-if we can just muster the willpower.

@ 2006 Newsweek, Inc.

@ 2006 MSNBC.com

URL: h t tp : l /www. msnbc . msn .com/ id /827 J -053

Inflammation: A unifying theory of disease? Research is showing that chronic inflammation may be the common factor in many diseases.

hen it comes to risk reduc-tion, it often seems as though we need to keep a running tab of things to avoid or embrace.

Lay off saturated fats to keep our arteries clean. Steer clear of carbs to stave off diabetes. Stay away from smoking to prevent lung cancer. Solve the sudoku puzzle to outwit dementia. And exercise, exercise, exercise! Wouldn't it be nice if there were a one-stop approach to health just as there is to shopping?

Although there may never be such a single path, mounting evidence suggests a common underlying cause of major degenerative diseases. The four horsemen of the medical apocalypse— coronary artery disease, diabetes, cancer, and Alzheimer's—may be riding the same steed: inflammation.

New research on inflammation has created a shift in medical thinking. For two millennia it has been viewed mainly as a necessary, even beneficial, response to illness or injury. But now both obser-vational studies and laboratory research are indicating that inflammation can be more of a bane than boon, the common, causative factor in many diseases.

What is inflammation? Inflammation is part of the immune response. It's a process that depends both on the physical actions of white blood cells and the chemicals that they produce: antibodies, cytokines, and the like. Over the last several decades, scientists have identified dozens of new immunological and inflammatory molecules and the pathways through which they interact. The loops and feedbacks of those pathways mean inflammation can be turned on and off in any number of ways. The problem comes when it is left on, for no apparent reason.

For simplicity's sake, immunologists still describe inflammation as dependent on two basic processes. The first, innate immunity, relies on granule-

cytes and complement. Granulocytes are short-lived white blood cells containing enzyme-filled granules that dissolve foreign substances. Complement is an array of circulating proteins produced in a cascade of enzymatic activity in the presence of microbes.

The second process, adaptive immu-nity, is directed specifically at microbes that have invaded the body previously. Its largely the responsibility of white blood cells called lymphocytes. T lymphocytes, or T cells, are the master strategists of the process, directing cells and chemicals to eradicate the invader. B lymphocytes, or B cells, produce antibodies, which attach to specific pathogens and call in the complement to help dispatch the invader. Macrophages (literally "big eaters") are the scavengers, swooping in to eliminate the remains of microbes, dead granulocytes, and cellular debris created in the skirmish. While they clean up, macrophages also process information about individual pathogens and transmit it to the lymphocytes, which store the information for future reference.

As pathogens are eliminated, sup-pressor T cells turn down the inflamma-tory response, so the regeneration of tissue injured either by the invader or by "friendly fire" from the immune system can begin. Fibroblasts, cells that produce collagen and fibrin, arrive to create a scaffold for new tissue cells. If the damage is extensive, fibrin and collagen may become thick enough to replace the original tissue and form a scar.

Chronic inflammation The first-century Roman physician Aurelius Cornelius Celsus described the four cardinal signs of inflammation— color (heat), dolor (pain), rubor (red-ness), and tumor (swelling)—a Latin litany still learned by medical students today. But these symptoms are mainly tip-offs for acute inflammation. Chronic inflammation often stays

under the patient's—and doctor's— radar. It occurs when the triggering agent isn't entirely eliminated or the suppressor T cells don't call off the immune system after the body has repulsed the invasion.

All of us adults have some level of chronic inflammation slowly waging a war of attrition on tissues and organs, its activity often evidenced only in blood tests. But if it's turned up a notch or two, chronic inflammation can wear away at the body so that the damage is devastating.

We've some evidence of inflamma-tions sweeping, "cross-platform" effects. Observational studies, like the Framing-ham Heart Study and the Nurses' Health Study, have found lower rates of a number of degenerative diseases in people who take nonsteroidal anti-inflammatory drugs (NSAIDs) regularly—usually for pain or arthritis. High levels of C-reactive protein (CRP), a marker for inflammation, are associated with several illnesses.

But for the most part, our ideas about disease are organized by organ system, so scientists have tended to focus on the inflammatory process in particular organs or tissues. They are beginning to work out how inflammation lays the groundwork for the following:

Coronary artery disease. Cardio-vascular research indicates that inflam-mation acts in concert with an excess of "bad" LDL cholesterol to create ath-erosclerosis. At high blood levels, LDL cholesterol becomes oxidized. That makes it recognizable to the immune system and marks it for ingestion by macrophages. The lipid-loaded macro-phages trigger complement activity that damages the vascular endothelium— the layer of cells that lines the inside of blood vessels. Macrophages and their fatty cargo slip through the resulting cracks and lodge next to the arterial wall, where they are encased in a shell of fibrin and form arterial plaque.

W

As the plaque grows and its fibrin coat is stressed, it may rupture, forming a clot that blocks a coronary artery supplying oxygen to the heart muscle. Heart tissue nourished by the artery then dies, causing a heart attack.

Studies have determined that people whose CRP levels rank in the top third. are twice as likely to have a heart attack as those with CRPs in the lowest third. The risk is even greater if a person also has high cholesterol. More doctors are adding a CRP test to the battery of routine screening tests for adults.

Diabetes. Several large observational studies have shown that people with high levels of CRP are more likely to develop insulin resistance, a precursor to full-fledged diabetes in which cells rebuff insulin and therefore don't properly metabolize glucose circulating in the blood. Researchers have also found that people who ultimately develop diabetes have high levels of inflammatory molecules, including TNF-a, a molecule produced by macrophages, and T cells.

TNF-a seems to increase the liver's production of glucose and triglycerides and interfere with insulin's duties as a blood sugar escort. Moreover, insulin has anti-inflammatory effects of its own. Thus inflammation not only sets the stage for insulin resistance but accelerates as insulin resistance sets in, which may further hasten the onset of diabetes.

Cancer. Nearly 150 years ago, the pathologist Rudolf Virchow termed cancer a "wound that doesn't heal." He noticed that tissue from malignant tumors contained high concentrations of inflammatory cells and hypothesized that the tumors often formed at sites of chronic inflammation. Recent evidence suggests that he was right. About 15% of cancers—including cancers of the liver, cervix, and stomach—are closely linked to infectious diseases. Cigarette smoke and asbestos contain inflammatory substances. Exposure to cigarette smoke is a notorious cause of lung cancer, and exposure to asbestos is linked to mesothelioma, a cancer of the tissue lining the chest.

Moreover, laboratory research has shown that products of inflammatory reactions, such as reactive oxygen species, damage cellular DNA, creating mutant genes that lead to cancer. Macrophages, the mop-up molecules in the inflammatory process, churn out numerous tumor growth factors and appear to spur on angiogenesis, the growth of new blood vessels that nurture tumor cells with a fresh supply of blood. In short, malignant tissues seem to commandeer many of the inflammatory weapons sent out to vanquish them.

Alzheimer's disease. Doctors once thought the central nervous system was outside the reach of the immune system. The blood/brain barrier, formed by tightened capillaries, acts like a bouncer, screening out inflammatory cells and molecules so they can’t enter the brain. Yet observational studies have found links between NSAIDs (aspirin, ibuprofen, and naproxen), COX-2 inhibitors, and other anti-inflammatory medications and a lower risk of Alzheimer's disease. In addition, the brain may have its own branch of the immune system. Cells inside the brain called microglia, the counterparts to macrophages, swarm and engulf foreign substances and release TNF-a and other inflammatory molecules. Excess production of a molecule called beta-amyloid appears to play an important, and perhaps initiating, role in Alzheimer's disease, but the immune response may also be involved. Once microglia ingest beta-amyloid, they become enshrouded in fibrin and form the plaques characteristic of the disease.

Preventing inflammation Inflammation is now a fertile field for

basic research. The recently discovered

gene for selenoprotein S, a protein that

plays a pivotal role in controlling

inflammation, may lead to a test

predicting who is at high risk for

inflammatory disorders, and to the

development of new drugs for chronic

inflammation.

There are already scores of anti-

inflammatory agents on the market, ranging

from plain old aspirin to high-tech bio-

engineered molecules for treating asthma,

rheumatoid arthritis, and multiple sclerosis.

Long-term use of NSAIDs is a balancing act,

because while it may keep the fires of

inflammation burning low, it can also cause

stomach bleeding and liver and kidney

damage. The COX-2 inhibitors, especially

rofecoxib (Vioxx), have been linked to

increased heart attack risk. Still, the daily 81-

mg dose of aspirin recommended for people

at high risk for heart attack is a safe bet.

Commonsense health practices may also help. Keep regular dental appointments to spot and treat periodontal disease; the evidence is mixed, but some research has sketched a possible link between gum disease and coronary artery disease. Take the full prescribed dose of antibiotics to prevent lingering infection and re-infection with resistant bacterial strains.

Low-calorie diets and moderate exercise

remain the surest thing for preventing

degenerative inflammatory disease. Obesity

is linked to high CRP levels, as are "bad" fats

and refined carbohydrates. Saturated and

trans fats tend to stoke the immune response,

while omega-3 fatty acids (in fish oils) and

monounsaturated fats (such as olive and

canola oils) may dampen it. Highly

processed carbohydrates may promote

inflammation by aiding the formation of free

radicals, so whole grains with unrefined

carbs are more healthful. Alcohol — in

moderation only — also cools off

inflammation.

So, for now, it looks as though the recognition of inflammation's role in disease doesn't alter the standard prevention dogma—see a doctor regularly for checkups, follow a sensible diet, exercise routinely, avoid cigarettes, imbibe but with restraint, and take a baby aspirin if you've had a heart attack or you fall into a high-risk category for heart disease. Those practices may hold the dreaded horsemen at bay by keeping their steeds in the stable. ®

www.health.harvard.edu April 2006 Harvard Health Letter | 5

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Alzheimer's Disease Linked to InflammationAlzheimersupport.com

07-05-2005 Source: University of Southern California

Early exposure to inflammatory disease multiplies Alzheimer's risk, say researchers

A new study of dementia in identical twins suggests that exposure to inflammation early in life quadruplesone's risk of developing Alzheimer's disease.

Margaret Gatz, lead author and professor of psychology in the USC College of Letters, Arts and Sciences, isstated to present her findings at the first Alzheimer's Association International Conference on Prevention ofDementia, to be held June 18-21 in Washington, D.C.

If confirmed, the link would add inflammatory burden to the short list of preventable risk factors forAlzheimer's.

Previous studies by Gatz and others have shown that Alzheimer's is strongly genetic: If one twin has thedisease, his or her identical twin has a 60 percent chance of developing it'

Stroke and a short period of formal education both increase the odds of dementia, but not of Alzheimer'sspecifically, the new study found.

Dementia is an umbrella term for many conditions, including Alzheimer's,

"People can plan a life span that will alter dementia risk," Gatz said. "And these aren't risk factors that areunique to dementia. Many of these are also risk factors for other disorders. This is good news."

Gatz's team, which included researchers from the Karolinska Institute in Stockholm. Sweden, sifted the20,000 participants in the Swedish Twin Registry for the 109 "discordant" pairs where only one twin hadbeen diagnosed with dementia.

Information about participants' education, activities and health history came from surveys they completed inthe 1960s, when the reglstry was created, and from hospital discharge records.

The survcys included questions about loose or missing teeth. Gatz and colleagues used the answe6 to builda crude indicator of periodontal disease.

'We're talking about gum disease, but it was measured by teeth lost or loose," Gatz said. "It's not perfect.Given it's not perfect, it's even more striking that it's such a solid risk factor."

The conclusion is not that good oral health can prevent Alzheimer's, but that an inflammatory burden earlyin life, as represented by chronic gum disease, may have sevene consequences later'

Gatz was inspired to focus on inflammation by the work of USC aerontologists Caleb Finch and EileenCrimmins, who pubtished a pap€r in the journal Science linking today's record life spans to lower rates ofchildhood infectious diseases, such as gum disease, flu, rheumatic fever, tuberculosis and other illnesses.

Such diseases are often preventable, raising hope for prevention of Alzheimer's.

"If what we're indexing with periodontal disease is some kind of inflammatory burden, then it is probablyspeaking to general health conditions," Gatz said. 'There was in our twins quite a lot of periodontal disease,

-l

and at that time in Sweden there was a lot of poverty."

The study, titled "Potentially Modifiable Risk Factors From Dementia: Evidence From ldentical Twins,'alsofound that mental activities at age 40, such as reading or attending cultural events, did not seem to lowerthe risk of developing Alzheimer's.

Participants who had more education than their twins were at slightly lower risk of developing dementia, butthe influence of education on Alzheimer's risk was statistically negligible.

"Once one controls for genes, the level of education is not a huge risk factor," said Gatz, who questionedpopular attitudes linking Alzheimer's or dementia to mental inactivity.

"We go around saying, 'Well, it can't hurt to do crossword puzzles.'There is a way it can hurt," she said."The way it can hurt is if we start blaming the people who are demented for not exercising their brainsenough, or overselling activities that could make a difference where it's really unsubstantiated. I think wehave got to be real careful in our messages about risk reduction."

The research for this study was supported by Erants from the Alzheimer's Association and the NationalInstitute on Aging.

@2006 ProHealth, rnc. Copvriqht PolicyBy: http z I / www.alzheimersuppott.com

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You don't have to planaround your arthrit is pain.Is it the bags you carry? The gates you rush to?Or is it lifting your luggage into the overhead? Ifyou have osteoarthritis, it colors everything you do.But you shouldn't have to miss out on the importantthings. Ask your doctor about prescriptionCELEBREX. It was designed to target the sourceof your pain, stiffness, and inflammation.

Just one CELEBREX provides 24-haw, all dayand all night relief.

CELEBREX is one of the most studied arthritismedicines on the market. But you should know thatCELEBREX, like all medicines, has both risks andbenefits. It's important to talk to your doctorabout treatment options to find out which one isright for you. Your doctor may also recommendother kinds of treatments.

Important Information: CELEBREX, like allprescription NSAIDsT ffiay increase the chanceof a heart attack or stroke that can lead to death.It should not be used right before or aftercertain heart surgeries.Serious skin reactions or stomach and intestineproblems such as bleeding and ulcers can occurwithout warning and may cause death.

Patients taking aspirin and the elderly are atincreased risk for stomach bleeding and ulcers.

Tell your doctor if you:.Are pregnantn Have a history of ulcers or bleeding

in the stomach or intestines. Have high blood pressure or heart failureo F{ave kidney or liver problems

People with aspirin-sensitive asthma or allergicreactions due to aspirin or other arthritismedicines or certain drugs called sulfonamidesshould nor rake CELEBREX.

Prescription CELEBREX should be used exactly asprescribed at the lowest dose possible and for theshortest time needed.

For more information, call 1-8BB-CELEBREX{1-BBB-23 5-3273) or visit www. CELEBREX. com

Please see important information about CELEBREXand other NSAIDS on next page.

ffiHtHtsREK(CELECCXI B CAPSU LES) I88fr8

Uninsured? Need help paying for medicine? Pfizer has programs that can help,no matter your age or income. You may even qualify for free Pfizer medicines.Call I " & # * " ? S S - 3 4 # f"t. Or visit wvwv.pfizerhelpfulanswers. com.

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CELEBREX@{celecoxib capsules)

Medication Guidefor Non -Steroida I Anti -l nftammatory Dru gs (NSAI Ds)

{see the end of this Medication Guide for a list of prescription NSAID medicines,)

what is the most important information I should know about medicinescalled llon-Steroidal Anti-lnflammatory Drugs {NSAlDs}?FISAID medicines may increase the chance of a heart attack or strokethat can lead to death.This chance increases:r with longer use of NSAID medicines. in people who have heart disease

NSAID medicines should never be used right before or after a heartsurgery called a "coronary artery hypass grafi (CABG).',NSAID medicines can cause ulcers and bleeding in the stomach andintestines at any time during treatment, Ulcers and bleeding:o can happen without warning symptomsr moV cause death

The chance of a person getting an ulcer or bleeding increases with:. taking medicines called "corticosteroids" and "anticoagulants". longer use. smoking. drinking alcoholr older age. having poor health

tlSAlD medicines should only be used:. exactly as prescribed. at the lowest dose possible for your treatmentr for the shortest time needed

U[hat are l'lon-Steroida I Anti- Inf lammatory Dru gs (llSAlDs] ?NSAID medicines are used to treat pain and redness, swelling, and heat(inflammation) from medical conditions such as:. different types of arthritisr menstrual cramps and other types of shortterm pain

Who should not take a f{on-$leroidalAnti-lnflammatory Drug {NSAID}?Do not lake an NSAID medicine:. if you had an asthma attack, hives, or other allergic reaction with aspirin

or any other NSAID medicine. for pain right before or after heart bypass surgery

Tell your healthcare provider:r about all of your medical conditions,. about all of the medicines you take. NSAIDs and some other medicines

can interact with each other and cause serious side effects, Keep a list ofy0ur medicines to shourl to your health care provider and pharmacist.

. if you are pregnant. NSAID medicines should not be used by pregnantTuomen late in fteir pregnancy.

' if you are breastfeeding, Talk to your doctor.What are the possible side effects of Non-$teroidal Anti-lnflammatoryDrugs (ilSAlDs)?

Get emergency help righl away if you have any ol the following symptoms:r shortness of breath or trouble . sluned speech

breathing . swelling of the face or throat. chest paino weakness in one part or side of

your bodystop. your l'lsAlD medicine and call your healthcare provider right away ifyou have any of the following symptoms:' nausea r there is blood in Vour bowelI more tired or weaker than usual movement or it id black and stickvr itching like iaro lour skin or eyes look yellow. stomach pain. flu-like symptoms. vomit blood

. skin rash or blisters wfthfever

. unusual weight gain

. swelling of the arms and legs,hands and feet

These are not all the side effects with NSAID medicines. Talk io vourhealthcare provider or pharmacist for more information aboutNSAID medicines,0ther inlormation about Non-steroidal Anti-lnflammatory Drugs {llsAl0s}. Aspirin is an NSAID medicine but it does not increase the chance of aheart attack. Aspirin can cause bleeding in the brain, stomach, and intestines.Aspirin can also cause ulcers in the stomach and intestines.' Some of these NSAID medicines are sold in lower doses without a

presuiption (over-the-counter), Talk to your healthcare provider before usingover-the-counter NSAIDS for more than 10 days.

ilSAID medicines that need a prescription

Distributed by

G.D. Searle LLCDivision of ffizer Inc. Ny. Ny 10017

Serious side effects include: | Other side etfects include:r heart attack | " stomach pain.stroke l.constipation. high blood pressure | . diarrhea. heart failure from body swelling I o gas

(fluidretention) I . heartburn. kidney problems including kidney | . nausea

failure | . vomiting. bleeding and ulcers in the I . dizzinesl

stomach and intestine I. low red blood cells (anemia). life{hreatening skin reactionsr life{hreatening allergic reactions. liver problems including liver failure' asthma attacks in people who have

asthma

Generic NameTradename

Celecoxib Celebrex

Diclofenac Cataflam, Voltaren, Arthrotec (combined withmisoprostol)

Diflunisal Dolobid

Etodolac Lodine, Lodine XL

Fenoprofen Nalfon, Nalfon 200

Flurbiprofen Ansaid

lbuprofen Motrin, Tab-Profen, Vicoprof en (combi ned withhydrocodone), Combunox (combined with oxycodone)

Indomethacin lndocin, Indocin SR, lndo-Lemmon, Indomethagan

Ketoprofen 0ruvail

Ketorolac Toradol

Mefenamic Acid Ponstel

Meloxicam Mobic

Nabumetone Helafen

Naproxen Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn,Naprelan, Naprapac (copackaged with lansoprazole)

0xaprozin Daypro

Piroxicam Feldene

Sulindac Clinoril

Iolmetin Tolectin, Tolectin DS, Tolectin 600

This Medication 0ruide has been approved by the lJ.s. Food and Drug Adninistratian.

LAB-0315-1,0 o2006 ffizer Inc.Allrights reserved, cL26419BcJ lssued July 2005

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Press Release Source: Research and Markets Ltd.

This Year the Analgesic Market is Expected to Be Worth $50 Billion, withPredictions Saying the Market Will Reach $105 Billion By 2015Wednesday December 14, 2:30 am ET

The worldwide analgesic market is estimated to be worth $50 billion during the year 2005 and is expected toincrease to $75 billion by the year 2010 and $105 billion by the year 2015. Calculations are based on theepidemiology of various painful conditions and the development of analgesic drugs and devices. Unfulfilledneeds for analgesics are identified and strategi€s are outlined to develop markets for analgesic drugs. Thereport is supplemented with 53 tables 15 figures, and 460 selected references to the literature.

Over 500 companies have been identifted to be involved in developing or marketing pain therapeutics and 122of these are profil€d in the report along with '105 collaborations. These are a mix of pharmaceutical companiesand biotechnology companies.

This report describes the latest concepts of pathomechanisms of pain as a basis for management anddevelopm€nt of n6w pharmacotherapies for pain. Major segments of the pain market are arthritis, neuropathicpain and cancer pain. Because pain is a subjective sensation, it is difficult to evaluate objectively in clinicaltrials. Various tools for pain measurement are described, including brain imaging.

Most of the currently used analgesic drugs fall into the categories of opioids and nonsteroidal antiinflammatorydtugs (NSAlDs) such as COX-2 inhititors. Non-opioid analgosics include ketamine, a N-methyl-D-aspartatereceptor antagonist. Adjwant analgesics include antidepressants and antiepileptic drugs used for thetreatment of neuropathic pain. Management of pain is multidisciplinary and includes both pharmacological andnon-pharmacological methods such as acupuncture, transcutaneous eleclrical nerve stimulation and surgery.Varioug pain syndrom€s r€quire differ€nt approaches in managoment, for example, the main category of drugsfor migraine are triptans such as sumatriptan.

Drug delivery is an important consideration in pain treatment. Controlted Glease preparations provide a steadydelivery of analgesics. Well-knom non-injection methods such astransdermal, pulmonary and intranasalapplication have been used. Topical analgesics and local anesthetics are also available. Devices such asimplanted pumps are used for delivery of drugs such as opioids intrathecally (introducdion into spinalsubaractinoid space by lumbar punc{ure) in patients with cancer pain.

The wide variety of drugs in development includes opioid receptor ligands, bradykinin antagonists, newer COXinhibitors, glutamate receptor antagonists, substance P and neurokinin receptor antagonists, P2X2 neuronr€ceptor antagonists and nitric oxide-based analgesics. A number of cannabinoids are also in development forpain. Fishderived tetrodotoxin was initially focused on indication of opiate addiction withdrawal but is found tohave an analg€sic action as well. Cone shells contain therapeutically useful peptides including the conotoxins,and one such peptide, ziconolide, has been approved. Various cell and gene therapies are also beingdeveloped for the management of pain.

Advances in molecular and biological techniques ar€ markedly advancing our undestanding of pain.Understanding the pathophysiology of pain is an important factor in discovery of rational therapies for pain.Advences in pharmacogenomics and pharmacogenetics are enabling the development of personalizedapproaches to the management of pain.

httpr/ibiz.vahoo.com/bil05 I 2 l4l2005 12 I 3006257.html?.v:l

There is no natural source in the world that has more to offer thanthe mangosteen whole fruit, Recent research shows thatMangosteen has significant quantities of:

Xanthones:(over 40 xanthones are identified in the Mangosteen fruit and are listed to date) that are unique to theMangosteen Fruit (Xanthones ire powerful anti-oxidant, anti-inflammatory, and immune systemboosters),(273,000 papers have been written on xanthones). Dr. James W. Duke's ethnobotanicaldatabase lists 202 health benefits associated with xanthones.

Catechins:Mangosteen contains 9 times the catechins that green tea has. Catechins are the most powerfulantioxidants known to science. Mangosteen is l47o catechins, by weight. (517,000 papers have beenwritten on this phytochemical)

Sterols:(protect the cardiac system), (1,870,000 papers have been written on this phytochemical) Sterols havebeen scientifically proven to significantly lower LDL Cholesterol.

Scnogenol:(1,850 papers have been written on this phytochemical). Pycnogenol is 20 times more powerful thanVitamin C and 50 times more powerful than Vitamin E. Pycnogenol is water soluble.

Polysaccharides:(The main component of Aloe Vera. There are more polysaccharides in Mangosteen than in AloeVera.)

Polyphenols:(1,920,0ffi papers have been written on this phytochemical)

Proanthocyanidins:(446,ff)0 papers have been written on this phytochemical)

Epigallocatechin Gallate :(EGCG). (433,(n0 papers have been written on this phytochemical)

Epigallocatechin:Studies show anti-tumor effects. (1,180 papers have been wriffen on this phytochemical)

"Mangosteen will, without a doubto be the most successful

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food supplement ever.tt - J Frederic Templemflrr M.f).

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Mangosteen Juice

Other common name(s): xango, mangostan, queen of fruits, numerous brand names

Scientific/medical name(s): Garcinia mangostana

Description

Mangosteen is a tropical fruit native to Southeast Asia that is touted for its antioxidants, especially xanthones, a type of chemical in certain plants. Its fruit, including the rind and pulp, can be pureed together and is sometimes sold as a drink. Mangosteen juice products may also be mixed with other types of juice. Its rind may be dried and made into a powder, and substances are also extracted from its bark. Mangosteen products are also available in capsule and tablet form. They are sold in health food stores, on the Internet, and through individual independent distributors.

Despite the name, mangosteen is not related to the mango.

Overview

Although there is no reliable evidence that mangosteen juice, puree, or bark is effective as a treatment for cancer in humans, its fruit has been shown to be rich in anti-oxidants. Very early laboratory studies suggest it may have promise as a topical treatment for acne. Early small laboratory and animal studies suggest that further research should be done to determine whether it can help to prevent cancer in humans.

How is it promoted for use?

Mangosteen is promoted to support microbiological balance, help the immune system, improve joint flexibility, and provide mental support. Some proponents claim that it can help diarrhea, infections, tuberculosis, and a host of other illnesses. In countries where the tree grows, various parts of the plant are used by native healers.

What does it involve?

In the United States, mangosteen is consumed as a juice or purèe or taken by mouth in capsule or tablet, often along with other herbs, fruits, or plants. In Asia and the Philippines, the rind may be steeped in water to make tea. Some folk healers prepare an ointment or salve to apply to the skin for conditions such as eczema, injuries, and infections. Others boil the leaves and bark of the tree to make a medicinal drink or to mix with other herbs to apply to wounds. The roots may be boiled to make a drink for women with menstrual problems.

What is the history behind it?

Parts of the mangosteen tree, including the fruit and bark, have been used in folk medicine in Asian

 countries for many years. In the mid-1800s, a compound in mangosteen, mangostin, was identified as a xanthone, a type of anti-oxidant. Mangostin was found to have anti-inflammatory effects in rats in the late 1970s. Today, mangosteen is sold in the United States mainly through a network marketing system, in which independent distributors, rather than stores, buy and sell mangosteen juice. Many mangosteen products are also available from health food stores and on the Internet.

In 2006, the U.S. Food and Drug Administration (FDA) warned one mangosteen vendor that the product was being illegally marketed. The FDA observed that the product was being promoted to treat illness, for which it had not been proved safe and effective.

What is the evidence?

Like many other plants, mangosteen extracts have shown in laboratory tests that they can stop certain bacteria and fungi from growing. One laboratory study suggested that mangosteen extract inhibits the growth of acne-causing bacteria. It has not been tested on people to determine whether it can help acne. In the laboratory, it also slowed the growth of certain cancer cells. A small study in rats suggested that the rind of the mangosteen may reduce the risk of cancer cell growth in the bowel. However, the ability of mangosteen to inhibit cancer growth has not been tested in humans.

Are there any possible problems or complications?

This product is sold as a dietary supplement in the United States. Unlike drugs (which must be tested before being allowed to be sold), the companies that make supplements are not required to prove to the Food and Drug Administration that their supplements are safe or effective, as long as they don't claim the supplements can prevent, treat, or cure any specific disease.

Some such products may not contain the amount of the herb or substance that is written on the label, and some may include other substances (contaminants). Actual amounts per dose may vary between brands or even between different batches of the same brand.

Most such supplements have not been tested to find out if they interact with medicines, foods, or other herbs and supplements. Even though some reports of interactions and harmful effects may be published, full studies of interactions and effects are not often available. Because of these limitations, any information on ill effects and interactions below should be considered incomplete.

Only one case of a serious adverse event possibly related to mangosteen juice has been reported. Doctors described a daily user of mangosteen juice who developed lactic acidosis (acidic blood due to buildup of a byproduct of sugar metabolism). Because mangosteen juice is quite popular and most users do not develop lactic acidosis, the doctors suggest that this problem may have resulted from an interaction of this supplement with other drugs he was taking.

No other ill effects have been reported to date. As with all plants, allergies may be possible. Because of its antioxidant effects, mangosteen supplements may make radiation therapy or chemotherapy less effective. While this concern is based largely on theories of how cancer treatments work, it is supported by some recent studies. For this reason, people being treated for cancer should speak with their doctors before taking this supplement. Other interactions are not well described. Always talk with your doctor and pharmacist about all the supplements and herbs you are taking.

Relying on this type of treatment alone, and avoiding or delaying conventional medical care for cancer, may have serious health consequences.

 Additional Resources

More information from your American Cancer Society

The following information on complementary and alternative therapies may also be helpful to you. These materials may be found on our Web site (www.cancer.org) or ordered from our toll-free number (1-800-ACS-2345).

Guidelines for Using Complementary and Alternative Methods

How to Know What Is Safe: Choosing and Using Dietary Supplements

The ACS Operational Statement on Complementary and Alternative Methods of Cancer Management

Complementary and Alternative Methods for Cancer Management

Placebo Effect

Learning About New Ways to Treat Cancer

Learning About New Ways to Prevent Cancer

References

Chomnawang MT, Surassmo S, Nukoolkarn VS, Gritsanapan W. Antimicrobial effects of Thai medicinal plants against acne-inducing bacteria. J Ethnopharmacol. 2005 Jul 8.

Lawenda BD, Kelly KM, Ladas EJ, Sagar SM, Vickers A, Blumberg JB. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? J Natl Cancer Inst. 2008;100:773-783.

Memorial Sloan-Kettering Cancer Center. Mangosteen, Clinical Summary. Accessed at: http://www.mskcc.org/mskcc/html/69295.cfm on June 11, 2008.

Moongkarndi P, Kosem N, Luanratana O, Jongsomboonkusol S, Pongpan N. Antiproliferative activity of Thai medicinal plant extracts on human breast adenocarcinoma cell line. Fitoterapia. 2004; 75:375-377.

Nabandith V, Suzui M, Morioka T, et al. Inhibitory effects of crude alpha-mangostin, a xanthone derivative, on two different categories of colon preneoplastic lesions induced by 1, 2-dimethylhydrazine in the rat. Asian Pac J Cancer Prev. 2004;5:433-438.

Mangosteen. Accessed at: www.quackwatch.org/01QuackeryRelatedTopics/DSH/hm.html on June 11, 2008.

US Food and Drug Administration. Cyber letters. Accessed at: http://www.fda.gov/foi/warning_letters/g6031d.pdf. on July 13, 2007. Content no longer available.

Wong LP, Klemmer PJ. Severe lactic acidosis associated with juice of the mangosteen fruit Garcinia

 mangostana. Am J Kidney Dis. 2008;51:829-833.

Note: This information may not cover all possible claims, uses, actions, precautions, side effects or interactions. It is not intended as medical advice, and should not be relied upon as a substitute for consultation with your doctor, who is familiar with your medical situation.

Last Medical Review: 11/01/2008 Last Revised: 11/01/2008  

---:.'--...--

ffiELSHIIER

Lih-Geeng Chen n, Ling-Ling Yang b, Ching-Chiung Wang b'n

o Gracluate Institute of Biomedical ancl Biophannaceutical tiirllit;rrri,i:::"It{;sciences, National Chiayi Uniuersity, 300 Uniuersity Road,

t' School oJ'Phurmacy, College of Pharmacy, Taipei Medical (Jniuersity,250 Wu-Hsing Street, Taipei 110, Taiwan, ROC

Received 5 May 2006; accepted l7 September 2007

Abstract

The fruit hull of G4rcinio mqngostana Linn (Guttiferae) is used as an anti-inflammatory drug in Southeast Asia, Two xanthones, ct-and y-mangostins, w€re isolated from the fmit hull of G mengostana, and both significantly inhibited nitric oxide (NO) and PGE2 pro-

duction from lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. The IC5s values for the inhibition ofNO production by q- and 1-mangostins were 12.4 and 10.1 pM, respectively. After iNOS enzyme activity was stimulat€d by LPS for 12 h, treatment with either q- or

T-mangostin at 5 pglml (12.2 and 12.6 ttM, respectively) for 24 h did not significantly inhibit NO production. The data show tlat the

inhibitory activiti€s of o- and 1-mangostins are not due to diroct inhibition of iNOS enzyme activity. On the other hand, expressionof iNOS was inhibited by a- and y-mangostius in LPS-stimulated RAW 264.7 cels, but not by COX-2. However, the level of PGE2 pro'

duction was reduc€d by the two xanthones. In an r'l ,rro study, cl-mangostid significandy inhibited mice carrageenan-induced paw edema.In conclusion, q- and y-mangostins from G. mangoslsna are bioactive substances with anti-inflammatoty etrects

@ 200? Elsevier Ltd. All dghts reserved.

Keywords: lndllicible nitric oxide synthase: Garcinia mangostMa Linn: Outtiferae; c[- and Y-mangostins; COX-2; RAW 264.7 mudne rnaorophag€s

Available online at www.sciencedirect.com.:," " ltr '';J

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Anti-inflammatory activtty of mangostins from

Food and Chemical Toxicology xxx (2007) xxx-xxx q#ffiwww. el sevier. com/locate/fo odchemtox

/-1Garctnta mangostana

1. Introduction

Mangoste en, Garcinia mangostana Linn (Guttiferae), isimported from Thailand and cultivated in Taiwan to pro-

duce a popular refreshing juicy fruit in the summer. More-

over, the rinds of the fruit have been used as a traditionalmedicine in Thailand for the treatment of trauma, diarrhea,and skin infections (Nakatani et a1., 2002). The xanthones,s- and y-mangostins, are major bioactive eompounds found

in the fruit hulls of the mangosteen (Jirrsart et erl., 1992;Chainrngsrilerd et u1., 1996a,b,c). The biological activities

of u-mangostin have been confirmed to consist of a compet-

itive antagonism of the histamine H1 receptor (Chairungsr-

ilerd et al., 1996a; Iikubo el al., 2002), antibacterial activityagainst Helicobacter pylori, anti-inflammatory activities,

-:-" Corresponding author. Tel . : +886 2 27361661x6161; fax: *886 2

2',1329368.E-mu il a tldr ess : c:rystal (Dtnru.edu. trv (C. -C. Wan g).

02'18-6915/$ - see front matter @ 2007 Elsevier Ltd. All rights reserved.

doi: I 0. 1 0 1 6 I i.fct.200'l .09.09 6

inhibition of oxidative damage by human low-density lipo-proteins (LDL) (Iikubo et al., 2002), antimicrobial activityagainst methicillin-resistant Staphylococcus aureus (Iinuma

et al., 1996), and weak antioxidant activity (Chairungsrilerd

et al., 1996a). The other xanthone derivative, Y-mangostinhas also been reported to have several pharmacological

activities, such as being a potent inhibitor of animal Cdk-activating kinases (Cak), plant Ca2+-dependent protein

kinases (CDPK) (Jinsart et a1.,1992), and a selective antag'onist for 5-HT24 receptors in smooth muscle cells and plate-

lets (Chairungsrilerd et al., 1996b,1998). Moreover, o- andy-mangostins can inhibit both human immunodeficiencyvirus (HIV) infection (Chen et a1., 1996; Vlietinck et al.,1998), and topoisomerases I and II (Tosa et a1., 1997).The mangosteen has long been widely used as an anti-inflammatory, anti-diarrhea, and anti-ulcer agent in South-east Asia (Lu et al., 1998; Harbborne and Baxter, 1993).However, the actual mechanism of the anti-inflammatoryaction of xanthones remains unclear. The possibility thatxanthones exhibit their biological effects by blocking

Please cite this articlef-hern Tnvinnl /?0n7\

in press as: Chen, L -G. et al.,r ln i '1 O 1 O1 6/ i fa. t ) f iA1'0g 096

Anti-infl ammatory activity' of 'mangostins'from Gat cinia mango s t ana, Food

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Physician Replaces Prescription Drugs With Natural Mangosteen J. Fredric Templeman, M.D.

I use Mangosteen as a first-line therapy in the following conditions:

Gastro-esophageal reflux disease Acid dyspepsia or gastritis Hiatal hernia Arthritis Fibromyalgia Fatigue or low energy states Mild depression or dysthymia Mild to moderate anxiety states

Mild to moderate asthma Irritable bowel disease Recurrent urinary tract infection Diverticulitis Allergic rhinitis Eczema Seborrhea Non-arthritis muscle or joint pain

I use Mangosteen as an adjunctive therapy in the following conditions

Rheumatic or connective tissue diseases Degenerative disc disease Chronic pain syndrome Peripheral neuropathy Migraine headache Stomach and duodenal ulcers Diabetes Cystic Fibrosis Moderate to severe depression

Ulcerative Colitis and Crohn's disease Cancer Cardiovascular disease and hypertension Post-menopausal mood disorder and PMS Viral infections Bacteria infections Fungal infections Hemorrhoids Psoriasis Severe allergic reaction

In my opinion, the Mangosteen equals or outperforms the following prescription drugs and over-the-counter drugs:

Nexium, Prevacid, Aciphex Zantac, Pepcid, other H2 blockers Allegra, Zyrtec, Claritin, other antihistamines Singulair Prednisone Lotrisone, Topicort, Cutivate, other topical corticosteroids Valium, Xanax, other minor tranquilizers Tegretol, Neurontin, other anti-epileptic drugs Anusol, other hemorrhoid preparations

Prozac, Zolort, Paxil, Lexapro, other anti-depressants Vicodin, Percocet, Duragesic patches, other narcotics Celebrex, Vioxx, Bextra, Naproxen, Arthrotec, Ibuprofen, other anti-inflammatories Ultram, Talwin, other non-opiod pain preparations Midrin, Fioricet, Imitrex, Amerge, Maxalt, Zomig, other migraine preparations Lipitor, Zocor, Pravacol, other lipid-lowering agents Valtrex Aricept, Cognex, other Alzheimer's preparations

www.MangosteenMD.com www.phytoresearch.com

_I

Mangosteen, Mayo Clinic and Potential Breakthroughs

Over the past seven-plus years, our not-so-small-anymore former startup company has made some

amazing breakthroughs and reached unprecedented successes. Who before XanGo knew what a

mangosteen was? Did you?

lt seems that in 2014, the queen of fruits has arrived. She's taking her place in the upper echelon of

must-have ingredients. So thought this month's People magazine when it named mangosteen as one

of the "Hot Food Trends of 2010." We're glad they finally caught up to us, because we've known this foryears.

So it came as no surprise that ABC News recently featured a segment on some fascinating research

we're doing together with the Mayo Clinic. Be sure to click the link below to see what Dr. Brent Bauer,

M.D., Associate Professor of Medicine, Director, Complementary and Integrative Medicine Program,

Mayo Clinic thinks about this research project (boy, that title was a mouthful, eh?). We think you'll l ike

it. Oh, and if you do, be sure to share it with your upline, downline, prospects, neighbors . . . you know

the dri l l .

Here's to a wonderfully productive 2010!

-lII

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r i t -Yov r5:t tn

Asian Pac J Cancer Prev. 2004 Oct-Dec;5(4):433-8. Related Articles, Links

Inhibitory effects of crude alpha-mangostin, a xanthone derivative, on two different categories of colon

preneoplastic lesions induced by 1, 2-dimethylhydrazine in the rat.

Nabandith V, Suzui M, Morioka T, Kaneshiro T, Kinjo T, Matsumoto K, Akao Y, Iinuma M, Yoshimi N.

Tumor Pathology Division, Faculty of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan.

The purpose of this study was to examine whether crude alpha-mangostin (a major xanthone derivative in mangosteen pericarp

(Garcinia mangostana)) has short-term chemopreventive effects on putative preneoplastic lesions involved in rat colon

carcinogenesis. The crude preparation was obtained by simple recrystallization of an ethylacetate extract of mangosteen pericarps.

A total of 33 five-week-old male F344 rats were randomly divided into 5 experimental groups. Rats in groups 1-3 were given a

subcutaneous injection of 1,2-dimethylhydrazine (DMH)(40 mg/kg body weight) once a week for 2 weeks. Starting one week

before the first injection of DMH, rats in groups 2 and 3 were fed a diet containing 0.02% and 0.05% crude alpha-mangostin,

respectively, for 5 weeks. Rats in group 4 also received the diet containing 0.05% crude alpha-mangostin, while rats in group 5

served as untreated controls. The experiment was terminated 5 weeks after the start. Dietary administration of crude alpha-

mangostin at both doses significantly inhibited the induction and/or development of aberrant crypt foci (ACF) (P<0.05 for 0.02%

crude alpha-mangostin, P<0.01 for 0.05% crude alpha-mangostin), when compared to the DMH-treated group (group 1).

Moreover, treatment of rats with 0.05% crude alpha-mangostin significantly decreased dysplastic foci (DF) (P<0.05) and beta-

catenin accumulated crypts (BCAC) (P<0.05), to below the group 1 values. The proliferating cell nuclear antigen (PCNA) labeling

indices of colon epithelium and focal lesions in groups 2 and 3 were also significantly lower than in group 1 and this effect

occurred in a dose dependent manner of the crude alpha-mangostin. This finding that crude alpha-mangostin has potent

chemopreventive effects in our short-term colon carcinogenesis bioassay system suggests that longer exposure might result in

suppression of tumor development.

PMID: 15546251 [PubMed - indexed for MEDLINE]

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J Ethnopharmacol. 2004 Jan;90(1):161-6. Related Articles, Links

Antiproliferation, antioxidation and induction of apoptosis by Garcinia mangostana (mangosteen) on

SKBR3 human breast cancer cell line.

Moongkarndi P, Kosem N, Kaslungka S, Luanratana O, Pongpan N, Neungton N.

Department of Microbiology, Faculty of Pharmacy, Mahidol University, Sri Ayudthaya Road, Rajdhevee, Bangkok 10400,

Thailand. pypmk@mahidol.ac.th

This study was designed to determine the antiproliferative, apoptotic and antioxidative properties of crude methanolic extract

(CME) from the pericarp of Garcinia mangostana (family Guttiferae) using human breast cancer (SKBR3) cell line as a model

system. SKBR3 cells were cultured in the presence of CME at various concentrations (0-50 microg/ml) for 48 h and the percentage

of cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-di phenyl tetrazolium bromide (MTT) assay. CME showed a

dose-dependent inhibition of cell proliferation with ED(50) of 9.25+/-0.64 microg/ml. We found that antiproliferative effect of

CME was associated with apoptosis on breast cancer cell line by determinations of morphological changes and oligonucleosomal

DNA fragments. In addition, CME at various concentrations and incubation times were also found to inhibit ROS production.

These investigations suggested that the methanolic extract from the pericarp of Garcinia mangostana had strong antiproliferation,

potent antioxidation and induction of apoptosis. Thus, it indicates that this substance can show different activities and has potential

for cancer chemoprevention which were dose dependent as well as exposure time dependent.

PMID: 14698525 [PubMed - indexed for MEDLINE]

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Nat Prod Res. 2005 Apr;19(3):239-43. Related Articles, Links

A geranylated biphenyl derivative from Garcinia malvgostana.

Dharmaratne HR, Piyasena KG, Tennakoon SB.

Natural Products Programme, Institute of Fundamental Studies, Kandy 20000, Sri Lanka. hrwd@ifs.ac.lk

Extracts of root bark, stem bark and the latex collected from the green fruits of Garcinia mangostana gave alpha-mangostin, beta-

mangostin, gamma-mangostin, garcinone-E, methoxy-beta-mangostin and a new geranylated biphenyl derivative 3-hydroxy-4-

geranyl-5-methoxybiphenyl. The latex of G. mangostana consists of more than 75% of xanthones which have strong antibacterial

(anti-MRSA and -VRE), anti-inflammatory, antifungal and a number of other biological activities. Hence the presence of the

above highly bioactive compounds in large quantities should be the causative factor for G. mangostana's medicinal value in

indigenous medicine.

PMID: 15702637 [PubMed - indexed for MEDLINE]

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Bioorg Med Chem. 2004 Nov 15;12(22):5799-806. Related Articles, Links

Preferential target is mitochondria in alpha-mangostin-induced apoptosis in human leukemia HL60

cells.

Matsumoto K, Akao Y, Yi H, Ohguchi K, Ito T, Tanaka T, Kobayashi E, Iinuma M, Nozawa Y.

Gifu International Institute of Biotechnology, 1-1 Naka-Fudogaoka, Kakamigahara, Gifu 504-0838, Japan. kmatsumo@giib.or.jp

Our previous study has shown that alpha-mangostin, a xanthone from the pericarps of mangosteen, induces caspase-3-dependent

apoptosis in HL60 cells. In the current study, we investigated the mechanism of apoptosis induced by alpha-mangostin in HL60

cells. Alpha-mangostin-treated HL60 cells demonstrated caspase-9 and -3 activation but not -8, which leads us to assume that

alpha-mangostin may mediate the mitochondrial pathway in the apoptosis. Parameters of mitochondrial dysfunction including

swelling, loss of membrane potential (deltapsim), decrease in intracellular ATP, ROS accumulation, and cytochrome c/AIF

release, were observed within 1 or 2 h after the treatment. On the other hand, alpha-mangostin-treatment did not affect expression

of bcl-2 family proteins and activation of MAP kinases. These findings indicate that alpha-mangostin preferentially targets

mitochondria in the early phase, resulting in indication of apoptosis in HL60 cells. Furthermore, we examined the structure-activity

relationship between xanthone derivatives including alpha-mangostin and the potency of deltapsim-loss in HL60 cells.

Interestingly, replacement of hydroxyl group by methoxy group remarkably decreased its potency. It was also shown that the

cytotoxicity substantially correlated with deltapsim decrease. These results indicate that alpha-mangostin and its analogs would be

candidates for preventive and therapeutic application for cancer treatment.

PMID: 15498656 [PubMed - indexed for MEDLINE]

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J Nat Prod. 2003 Aug;66(8):1124-7. Related Articles, Links

Induction of apoptosis by xanthones from mangosteen in human leukemia cell lines.

Matsumoto K, Akao Y, Kobayashi E, Ohguchi K, Ito T, Tanaka T, Iinuma M, Nozawa Y.

Gifu International Institute of Biotechnology, 1-1 Naka-Fudogaoka, Kakamigahara, Gifu 504-0838, Japan. kmatsumoto@giib.or.jp

We examined the effects of six xanthones from the pericarps of mangosteen, Garcinia mangostana, on the cell growth inhibition of

human leukemia cell line HL60. All xanthones displayed growth inhibitory effects. Among them, alpha-mangostin showed

complete inhibition at 10 microM through the induction of apoptosis.

PMID: 12932141 [PubMed - indexed for MEDLINE]

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Fitoterapia. 2004 Jun;75(3-4):375-7. Related Articles, Links

Antiproliferative activity of Thai medicinal plant extracts on human breast adenocarcinoma cell line.

Moongkarndi P, Kosem N, Luanratana O, Jongsomboonkusol S, Pongpan N.

Department of Microbiology, Faculty of Pharmacy, Mahidol University, Rajdhevee, Sri Ayudthaya Rd, Bangkok 10400, Thailand.

pypmk@mahidol.ac.th

Ethanolic extracts of selected nine Thai medicinal plants were tested for antiproliferative activity against SKBR3 human breast

adenocarcinoma cell line using MTT assay. Garcinia mangostana showed the most potent activity. However, all plant extracts

showed activity in potential range for further investigation on cancer cells. Copyright 2004 Elsevier B.V.

PMID: 15158999 [PubMed - indexed for MEDLINE]

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Chem Pharm Bull (Tokyo). 2003 Jul;51(7):857-9. Related Articles, Links

Antimycobacterial activity of prenylated xanthones from the fruits of Garcinia mangostana.

Suksamrarn S, Suwannapoch N, Phakhodee W, Thanuhiranlert J, Ratananukul P, Chimnoi N, Suksamrarn A.

Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok, Thailand. sunit@swu.ac.th

Prenylated xanthones, isolated from the fruit hulls and the edible arils and seeds of Garcinia mangostana, were tested for their

antituberculosis potential. Alpha- and beta-mangostins and garcinone B exhibited strong inhibitory effect against Mycobacterium

tuberculosis with the minimum inhibitory concentration (MIC) value of 6.25 microg/ml. Tri- and tetra-oxygenated xanthones with

di-C5 units or with a C5 and a modified C5 groups are essential for high activities. Substitution in the A and C rings has been

shown to modify the bioactivity of the compounds.

PMID: 12843596 [PubMed - indexed for MEDLINE]

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Planta Med. 2002 Nov;68(11):975-9. Related Articles, Links

Garcinone E, a xanthone derivative, has potent cytotoxic effect against hepatocellular carcinoma cell

lines.

Ho CK, Huang YL, Chen CC.

Department of Medical Research & Education, Veterans General Hospital, Taipei, ROC.

Treatment of hepatocellular carcinomas (HCCs) with chemotherapy has generally been disappointing and it is most desirable to

have more effective new drugs. We extracted and purified 6 xanthone compounds from the rinds (peel) of the fruits of Garcinia

mangostana L., using partitioned chromatography and then tested the cytotoxic effects of these compounds on a panel of 14

different human cancer cell lines including 6 hepatoma cell lines, based on the MTT method. Several commonly used

chemotherapeutic agents were included in the assay to determine the relative potency of the potential new drugs. Our results have

shown that one of the xanthone derivatives which could be identified as garcinone E has potent cytotoxic effect on all HCC cell

lines as well as on the other gastric and lung cancer cell lines included in the screen. We suggest that garcinone E may be

potentially useful for the treatment of certain types of cancer.

PMID: 12451486 [PubMed - indexed for MEDLINE]

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Biol Pharm Bull. 2002 Sep;25(9):1137-41. Related Articles, Links

Inhibitions of histamine release and prostaglandin E2 synthesis by mangosteen, a Thai medicinal

plant.

Nakatani K, Atsumi M, Arakawa T, Oosawa K, Shimura S, Nakahata N, Ohizumi Y.

Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai,

Japan.

The fruit hull of mangosteen, Garcinia mangostana L. has been used as a Thai indigenous medicine for many years. However, its

mechanism of action as a medicine has not been elucidated. The present study was undertaken to examine the effects of

mangosteen extracts (100% ethanol, 70% ethanol, 40% ethanol and water) on histamine release and prostaglandin E2 synthesis.

We found that the 40% ethanol extract of mangosteen inhibited IgE-mediated histamine release from RBL-2H3 cells with greater

potency than the water extract of Rubus suavissimus that has been used as an anti-allergy crude drug in Japan. All extracts of

mangosteen potently inhibited A23187-induced prostaglandin E2 synthesis in C6 rat glioma cells, while the water extract of Rubus

suavissimus had no effect. The 40% ethanol extract of mangosteen inhibited the prostaglandin E2 synthesis in a concentration-

dependent manner with relatively lower concentrations than the histamine release. In addition, passive cutaneous anaphylaxis

(PCA) reactions in rats were significantly inhibited by this ethanol extract as well as by the water extract of Rubus suavissimus.

These results suggest that the 40% ethanol extract of mangosteen has potent inhibitory activities of both histamine release and

prostaglandin E2 synthesis.

PMID: 12230104 [PubMed - indexed for MEDLINE]

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Biochem Pharmacol. 2002 Jan 1;63(1):73-9. Related Articles, Links

Inhibition of cyclooxygenase and prostaglandin E2 synthesis by gamma-mangostin, a xanthone

derivative in mangosteen, in C6 rat glioma cells.

Nakatani K, Nakahata N, Arakawa T, Yasuda H, Ohizumi Y.

Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba,

Aramaki, Aoba-ku, 980-8578, Sendai, Japan.

The fruit hull of mangosteen, Garcinia mangostana L., has been used for many years as a medicine for treatment of skin infection,

wounds, and diarrhea in Southeast Asia. In the present study, we examined the effect of gamma-mangostin, a tetraoxygenated

diprenylated xanthone contained in mangosteen, on arachidonic acid (AA) cascade in C6 rat glioma cells. gamma-Mangostin had a

potent inhibitory activity of prostaglandin E2 (PGE2) release induced by A23187, a Ca2+ ionophore. The inhibition was

concentration-dependent, with the IC50 value of about 5 microM. gamma-Mangostin had no inhibitory effect on A23187-induced

phosphorylation of p42/p44 extracellular signal regulated kinase/mitogen-activated protein kinase or on the liberation of [14C]-AA

from the cells labeled with [14C]-AA. However, gamma-mangostin concentration-dependently inhibited the conversion of AA to

PGE2 in microsomal preparations, showing its possible inhibition of cyclooxygenase (COX). In enzyme assay in vitro, gamma-

mangostin inhibited the activities of both constitutive COX (COX-1) and inducible COX (COX-2) in a concentration-dependent

manner, with the IC50 values of about 0.8 and 2 microM, respectively. Lineweaver-Burk plot analysis indicated that gamma-

mangostin competitively inhibited the activities of both COX-1 and -2. This study is a first demonstration that gamma-mangostin,

a xanthone derivative, directly inhibits COX activity.

PMID: 11754876 [PubMed - indexed for MEDLINE]

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J Med Assoc Thai. 1997 Sep;80 Suppl 1:S149-54. Related Articles, Links

Immunopharmacological activity of polysaccharide from the pericarb of mangosteen garcinia:

phagocytic intracellular killing activities.

Chanarat P, Chanarat N, Fujihara M, Nagumo T.

Department of Clinical Microscopy, Faculty of Associated Medical Sciences, Chiang Mai University, Thailand.

Polysaccharides from the pericarbs of mangosteen, Garcinia mangostana Linn., was obtained by treating the dried ground

pericarbs with hot water followed by ethanol precipitation (M fraction). The extract was fractionated by anion exchange

chromatography on a DEAE-cellulose column as MDE1-5 fractions. The fractions of MDE3 and MDE4 composed of mainly D-

galacturonic acid and a small amount of neutral sugar (L-arabinose as the major one and L-rhamnose and D-galactose as the minor

ones) were studied for immunopharmacological activities by phagocytic test to intracellular bacteria (Salmonella enteritidis) and

nitroblue tetrazolium (NBT) and superoxide generation tests. The results showed that the number of S. enteritidis in cultured

monocyte with extract of pericarb of mangosteen (MDE3) was killed. Activating score (mean +/- SD) of NBT test of 100

polymorphonuclear phagocytic cells were 145 +/- 78, 338 +/- 58, 222 +/- 73, 209 +/- 77, 211 +/- 63, 372 +/- 19, 369 +/- 20, 355

+/- 34 in normal saline control, phorbol myristate acetate (PMA), MDE3, MDE4, indomethacin (I), PMA + MDE3, PMA + MDE4

and PMA + I, respectively. Superoxide generation test was also done by color reduction of cytochrome c. Both MDE3 and MDE4

stimulate superoxide production. The number of S. enteritidis in cultured monocyte with extract of pericarb of mangosteen was

killed. This paper suggests that polysaccharides in the extract can stimulate phagocytic cells and kill intracellular bacteria (S.

enteritidis).

PMID: 9347663 [PubMed - indexed for MEDLINE]

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J Ethnopharmacol. 2005 Oct 3;101(1-3):330-3. Links

Antimicrobial effects of Thai medicinal plants against acne-inducing bacteria.

Chomnawang MT, Surassmo S, Nukoolkarn VS, Gritsanapan W.

Department of Microbiology, Faculty of Pharmacy, Mahidol University, 447 Sri Ayudthaya Road, Rachathevi, Bangkok 10400,

Thailand. scmtd@mahidol.ac.th

Propionibacterium acnes and Staphylococcus epidermidis have been recognized as pus-forming bacteria triggering an

inflammation in acne. The present study was conducted to evaluate antimicrobial activities of Thai medicinal plants against these

etiologic agents of acne vulgaris. Crude extracts were tested for antimicrobial activities by disc diffusion and broth dilution

methods. The results from the disc diffusion method showed that 13 medicinal plants could inhibit the growth of

Propionibacterium acnes. Among those, Senna alata, Eupatorium odoratum, Garcinia mangostana, and Barleria lupulina had strong

inhibitory effects. Based on a broth dilution method, the Garcinia mangostana extract had the greatest antimicrobial effect. The

MIC values were the same (0.039 mg/ml) for both bacterial species and the MBC values were 0.039 and 0.156 mg/ml against

Propionibacterium acnes and Staphylococcus epidermidis, respectively. In bioautography assay, the Garcinia mangostana extract

produced strong inhibition zones against Propionibacterium acnes. Antimicrobial activity from fractions of column

chromatography revealed one of the active compounds in Garcinia mangostana could be mangostin, a xanthone derivative. Taken

together, our data indicated that Garcinia mangostana had a strong inhibitory effect on Propionibacterium acnes and

Staphylococcus epidermidis. Therefore, this plant would be an interesting topic for further study and possibly for an alternative

treatment for acne.

PMID: 16009519 [PubMed - indexed for MEDLINE]

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J Nat Prod. 1997 May;60(5):519-24. Related Articles, Links

Evaluation of the antifungal activity of natural xanthones from Garcinia mangostana and their

synthetic derivatives.

Gopalakrishnan G, Banumathi B, Suresh G.

Centre for Agrochemical Research, SPIC Science Foundations, Madras, India.

The antifungal activity of several xanthones isolated from the fruit hulls of Garcinia mangostana and some derivatives of

mangostin against three phytopathogenic fungi, Fusarium oxysporum vasinfectum, Alternaria tenuis, and Dreschlera oryzae, has

been evaluated. The natural xanthones showed good inhibitory activity against the three fungi. Substitution in the A and C rings

has been shown to modify the bioactivities of the compounds.

PMID: 9213587 [PubMed - indexed for MEDLINE]

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Clin Microbiol Infect. 2005 Jun;11(6):510-2. Related Articles, Links

Activity of medicinal plant extracts against hospital isolates of methicillin-resistant Staphylococcus

aureus.

Voravuthikunchai SP, Kitpipit L.

Department of Microbiology, Faculty of Science, Prince of Songkla University, Hatyai, Songkla, Thailand. supayang.v@psu.ac.th

Aqueous and ethanolic extracts of ten traditional Thai medicinal plants were investigated for their ability to inhibit 35 hospital

isolates of methicillin-resistant Staphylococcus aureus (MRSA). Nine medicinal plants displayed activity against all isolates tested.

Ethanolic extracts of Garcinia mangostana, Punica granatum and Quercus infectoria were most effective, with MICs for MRSA

isolates of 0.05-0.4, 0.2-0.4 and 0.2-0.4 mg/mL, respectively, and for S. aureus ATCC 25923 of 0.1, 0.2 and 0.1 mg/mL,

respectively. MBCs for MRSA isolates were 0.1-0.4, 1.6-3.2 and 0.4-1.6 mg/mL, and for S. aureus ATCC 25923 were 0.4, 3.2 and

1.6 mg/mL, respectively.

PMID: 15882206 [PubMed - in process]

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Planta Med. 1996 Oct;62(5):471-2. Related Articles, Links

Histaminergic and serotonergic receptor blocking substances from the medicinal plant Garcinia

mangostana.

Chairungsrilerd N, Furukawa K, Ohta T, Nozoe S, Ohizumi Y.

A crude methanolic extract of the fruit hull of Mangosteen, Garcinia mangostana L. inhibited the contractions of isolated thoracic

rabbit aorta induced by histamine and serotonin. The extract of the fruit hull has been fractionated by silica gel chromatography,

monitoring the pharmacological activity to give alpha- and gamma-mangostin. On the basis of pharmacological data, it is

suggested that alpha-mangostin and gamma-mangostin are a histaminergic and a serotonergic receptor blocking agent,

respectively.

PMID: 8923814 [PubMed - indexed for MEDLINE]

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Phytochemistry. 1992 Nov;31(11):3711-3. Related Articles, Links

Inhibition of wheat embryo calcium-dependent protein kinase and other kinases by mangostin and

gamma-mangostin.

Jinsart W, Ternai B, Buddhasukh D, Polya GM.

Department of Chemistry, La Trobe University, Bundoora, Victoria, Australia.

The hull of the fruit of the mangosteen tree (Garcinia mangostana) contains four inhibitors of plant Ca(2+)-dependent protein

kinase. Two of these inhibitors have been purified and identified as the xanthones 1,3,6-trihydroxy-7-methoxy-2,8-bis(3-methyl-2-

butenyl)-9H- xanthen-9-one (mangostin) and 1,3,6,7-tetrahydroxy-2,8-bis(3-methyl-2-butenyl)- 9H-xanthen-9-one (gamma-

mangostin). Both xanthones also inhibit avian myosin light chain kinase and rat liver cyclic AMP-dependent protein kinase. This is

the first report of inhibition of plant and animal second messenger-regulated protein kinases by plant-derived xanthones.

PMID: 1368866 [PubMed - indexed for MEDLINE]

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Mol Pharmacol. 2004 Sep;66(3):667-74. Related Articles, Links

gamma-Mangostin inhibits inhibitor-kappaB kinase activity and decreases lipopolysaccharide-induced

cyclooxygenase-2 gene expression in C6 rat glioma cells.

Nakatani K, Yamakuni T, Kondo N, Arakawa T, Oosawa K, Shimura S, Inoue H, Ohizumi Y.

Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba,

Aramaki, Aoba-ku, Sendai 980-8578, Japan.

We investigated the effect of gamma-mangostin purified from the fruit hull of the medicinal plant Garcinia mangostana on

spontaneous prostaglandin E(2) (PGE(2)) genase release and inducible cyclooxy-2 (COX-2) gene expression in C6 rat glioma

cells. An 18-h treatment with gamma-mangostin potently inhibited spontaneous PGE(2) release in a concentration-dependent

manner with the IC(50) value of approximately 2 microM, without affecting the cell viability even at 30 microM. By

immunoblotting and reverse-transcription polymerase chain reaction, we showed that gamma-mangostin concentration-

dependently inhibited lipopolysaccharide (LPS)-induced expression of COX-2 protein and its mRNA, but not those of constitutive

COX-1 cyclooxygenase. Because LPS is known to stimulate inhibitor kappaB (IkappaB) kinase (IKK)-mediated phosphorylation

of IkappaB followed by its degradation, which in turn induces nuclear factor (NF)-kappaB nuclear translocation leading to

transcriptional activation of COX-2 gene, the effect of gamma-mangostin on the IKK/IkappaB cascade controlling the NF-kappaB

activation was examined. An in vitro IKK assay using IKK protein immunoprecipitated from C6 cell extract showed that this

compound inhibited IKK activity in a concentration-dependent manner, with the IC(50) value of approximately 10 microM.

Consistently gamma-mangostin was also observed to decrease the LPS-induced IkappaB degradation and phosphorylation in a

concentration-dependent manner, as assayed by immunoblotting. Furthermore, luciferase reporter assays showed that gamma-

mangostin reduced the LPS-inducible activation of NF-kappaB-and human COX-2 gene promoter region-dependent transcription.

gamma-Mangostin also inhibited rat carrageenan-induced paw edema. These results suggest that gamma-mangostin directly

inhibits IKK activity and thereby prevents COX-2 gene transcription, an NF-kappaB target gene, probably to decrease the

inflammatory agent-stimulated PGE(2) production in vivo, and is a new useful lead compound for anti-inflammatory drug

development.

PMID: 15322259 [PubMed - indexed for MEDLINE]

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J Pharm Pharmacol. 1996 Aug;48(8):861-5. Related Articles, Links

Antibacterial activity of xanthones from guttiferaeous plants against methicillin-resistant

Staphylococcus aureus.

Iinuma M, Tosa H, Tanaka T, Asai F, Kobayashi Y, Shimano R, Miyauchi K.

Department of Pharmacognosy, Gifu Pharmaceutical University, Japan.

Extracts of Garcinia mangostana (Guttiferae) showing inhibitory effects against the growth of S. aureus NIHJ 209p were

fractionated according to guidance obtained from bioassay and some of the components with activity against methicillin-resistant

Staphylococcus aureus (MRSA) were characterized. One active isolate, alpha-mangostin, a xanthone derivative, had a minimum

inhibitory concentration (MIC) of 1.57-12.5 micrograms mL-1. Other related xanthones were also examined to determine their

anti-MRSA activity. Rubraxanthone, which was isolated from Garcinia dioica and has a structure similar to that of alpha-

mangostin, had the highest activity against staphylococcal strains (MIC = 0.31-1.25 micrograms mL-1), an activity which was

greater than that of the antibiotic vancomycin (3.13-6.25 micrograms mL-1). The inhibitory effect against strains of MRSA of two

of the compounds when used in conjunction with other antibiotics was also studied. The anti-MRSA activity of alpha-mangostin

was clearly increased by the presence of vancomycin; this behaviour was not observed for rubraxanthone. The strong in-vitro

antibacterial activity of xanthone derivatives against both methicillin-resistant and methicillin-sensitive Staphylococcus aureus

suggests the compounds might find wide pharmaceutical use.

PMID: 8887739 [PubMed - indexed for MEDLINE]

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J Pharmacol Sci. 2004 May;95(1):33-40. Related Articles, Links

Alpha-mangostin induces Ca2+-ATPase-dependent apoptosis via mitochondrial pathway in PC12

cells.

Sato A, Fujiwara H, Oku H, Ishiguro K, Ohizumi Y.

Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai,

Japan.

We investigated the cell death effects of eight xanthones on PC12 rat pheochromocytoma cells. Among these compounds, alpha-

mangostin, from the fruit hull of Garcinia mangostana L., had the most potent effect with the EC(50) value of 4 microM. Alpha-

mangostin-treated PC12 cells demonstrated typical apoptotic DNA fragmentation and caspase-3 cleavage (equivalent to

activation). The flow cytometric analysis indicated that this compound induced apoptosis in time-and concentration-dependent

manners. Alpha-mangostin showed the features of the mitochondrial apoptotic pathway such as mitochondrial membrane

depolarization and cytochrome c release. Furthermore, alpha-mangostin inhibited the sarco(endo)plasmic reticulum Ca(2+)-

ATPase markedly. There was a correlation between the Ca(2+)-ATPase inhibitory effects and the apoptotic effects of the xanthone

derivatives. On the other hand, c-Jun NH(2)-terminal kinase (JNK/SAPK), one of the signaling molecules of endoplasmic

reticulum (ER) stress, was activated with alpha-mangostin treatment. These results suggest that alpha-mangostin inhibits Ca(2+)-

ATPase to cause apoptosis through the mitochondrial pathway.

PMID: 15153648 [PubMed - indexed for MEDLINE]

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Phytomedicine. 2005 Mar;12(3):203-8. Related Articles, Links

Antibacterial activity of alpha-mangostin against vancomycin resistant Enterococci (VRE) and

synergism with antibiotics.

Sakagami Y, Iinuma M, Piyasena KG, Dharmaratne HR.

Osaka Prefectural Institute of Public Health, Osaka, Japan. sakagami@iph.pref.osaka.jp

alpha-Mangostin, isolated from the stem bark of Garcinia mangostana L., was found to be active against vancomycin resistant

Enterococci (VRE) and methicillin resistant Staphylococcus aureus (MRSA), with MIC values of 6.25 and 6.25 to 12.5 microg/ml,

respectively. Our studies showed synergism between alpha-mangostin and gentamicin (GM) against VRE, and alpha-mangostin

and vancomycin hydrochloride (VCM) against MRSA. Further studies showed partial synergism between alpha-mangostin and

commercially available antibiotics such as ampicillin and minocycline. These findings suggested that alpha-mangostin alone or in

combination with GM against VRE and in combination with VCM against MRSA might be useful in controlling VRE and MRSA

infections.

PMID: 15830842 [PubMed - indexed for MEDLINE]

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Planta Med. 1996 Aug;62(4):381-2. Related Articles, Links

Active constituents against HIV-1 protease from Garcinia mangostana.

Chen SX, Wan M, Loh BN.

The ethanol extract of Garcinia mangostana L. (Guttiferae) showed potent inhibitory activity against HIV-1 protease. The activity-

guided purification of the extract resulted in the isolation of two active, known compounds. The chemical structures of the isolated

compounds were established by spectroscopic analyses as mangostin (IC50 = 5.12 +/- 0.41 microM) and gamma-mangostin (IC50

= 4.81 +/- 0.32 microM). The type of inhibition by both compounds is noncompetitive.

Publication Types:

Letter

PMID: 8792678 [PubMed - indexed for MEDLINE]

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Jpn J Pharmacol. 1996 Aug;71(4):337-40. Related Articles, Links

The mode of inhibitory action of alpha-mangostin, a novel inhibitor, on the sarcoplasmic reticulum

Ca(2+)-pumping ATPase from rabbit skeletal muscle.

Furukawa K, Shibusawa K, Chairungsrilerd N, Ohta T, Nozoe S, Ohizumi Y.

Department of Pharmaceutical Molecular Biology, Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.

alpha-Mangostin, the principal ingredient of the fruit hull of Garcinia mangostana, caused a concentration-dependent decrease in

the activities of both Ca(2+)-ATPase and Ca(2+)-transport of the sarcoplasmic reticulum from rabbit skeletal muscle with an IC50

value of 5 microM. Neither Ca2+ release nor other enzyme activities were affected by alpha-mangostin. Kinetic analysis of the

inhibitory effects of alpha-mangostin on Ca(2+)-ATPase suggests that the inhibition of the ATPase is a noncompetitive-type with

respect to ATP or Ca2+. alpha-Mangostin may become a useful pharmacological tool for clarifying the physiological functions of

Ca(2+)-pumping ATPase and sarcoplasmic reticulum.

PMID: 8886932 [PubMed - indexed for MEDLINE]

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Br J Pharmacol. 1998 Mar;123(5):855-62. Related Articles, Links

Effect of gamma-mangostin through the inhibition of 5-hydroxy-tryptamine2A receptors in 5-fluoro-

alpha-methyltryptamine-induced head-twitch responses of mice.

Chairungsrilerd N, Furukawa K, Tadano T, Kisara K, Ohizumi Y.

Department of Molecular Biology, Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.

1. Intracerebronventricular (i.c.v.) injection of gamma-mangostin (10-40 nmol/mouse), a major compound of the fruit hull of

Garcinia mangostana Lin., like ketanserin (10, 20 nmol/mouse, i.c.v.) inhibited 5-fluoro-alpha-methyltryptamine (5-FMT) (45 mg

kg(-1), i.p.)-induced head-twitch response in mice in the presence or absence of citalopram (a 5-hydroxytryptamine (5-HT)-uptake

inhibitor). 2. Neither the 5-FMT- nor the 8-hydroxy-2-(di-n-propylamino)tetralin (5-HT1A-agonist)-induced 5-HT syndrome (head

weaving and hindlimb abduction) was affected by gamma-mangostin or ketanserin. 3. The locomotor activity stimulated by 5-

FMT through the activation of alpha1-adrenoceptors did not alter in the presence of gamma-mangostin. 4. 5-HT-induced inositol

phosphates accumulation in mouse brain slices was abolished by ketanserin. Gamma-mangostin caused a concentration-dependent

inhibition of the inositol phosphates accumulation. 5. Gamma-mangostin caused a concentration-dependent inhibition of the

binding of [3H]-spiperone, a specific 5-HT2A receptor antagonist, to mouse brain membranes. 6. Kinetic analysis of the [3H]-

spiperone binding revealed that gamma-mangostin increased the Kd value without affecting the Bmax value, indicating the mode

of the competitive nature of the inhibition by gamma-mangostin. 7. These results suggest that gamma-mangostin inhibits 5-FMT-

induced head-twitch response in mice by blocking 5-HT2A receptors not by blocking the release of 5-HT from the central neurone.

Gamma-mangostin is a promising 5-HT2A receptor antagonist in the central nervous system.

PMID: 9535013 [PubMed - indexed for MEDLINE]

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Nippon Yakurigaku Zasshi. 1997 Oct;110 Suppl 1:153P-158P. Related Articles, Links

[Novel types of receptor antagonists from the medicinal plant Garcinia mangostana]

[Article in Japanese]

Furukawa K, Chairungsrilerd N, Ohta T, Nozoe S, Ohizumi Y.

Department of Pharmaceutical Molecular Biology, Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.

A crude methanolic extract of the fruit hull of Garcinia mangostana L. inhibited the contraction of the isolated rabbit aorta induced

by histamine and serotonin. The extract has been fractionated by silica gel chromatography, monitoring the pharmacological

activity to give active compounds. On the basis of physicochemical data, the active substances were identified as alpha-mangostin

and gamma-mangostin. To define the pharmacological properties of alpha-mangostin, the effect of alpha-mangostin on both

histamine H1 and H2 receptors were examined by monitoring the mechanical responses of smooth muscles and measuring the

radioligand binding to cultured vascular smooth muscle cells. The results suggest that alpha-mangostin acts as a selective and

competitive histamine H1 receptor antagonist. The pharmacological actions of gamma-mangostin on 5-HT receptors were also

investigated by using contractile response of vascular smooth muscle, platelet aggregation and radioligand binding studies. The

results provide the evidence that gamma-mangostin is a selective and competitive 5-HT2A receptor antagonist. It is of great

interest that the structures of alpha-mangostin and gamma-mangostin free from nitrogen atom are not resemble to the common

structures of histamine and serotonin receptor antagonists. alpha-Mangostin and gamma-mangostin may become novel types of

lead compounds for histamine and serotonin receptor antagonists.

PMID: 9503424 [PubMed - indexed for MEDLINE]

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Naunyn Schmiedebergs Arch Pharmacol. 1998 Jan;357(1):25-31. Related Articles, Links

Gamma-mangostin, a novel type of 5-hydroxytryptamine 2A receptor antagonist.

Chairungsrilerd N, Furukawa KI, Ohta T, Nozoe S, Ohizumi Y.

Department of Pharmaceutical Molecular Biology, Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.

Gamma-mangostin, purified from the fruit hull of the medicinal plant Garcinia mangostana caused a parallel rightwards shift of the

concentration/response curve for the contraction elicited by 5-hydroxytryptamine (5-HT) in the rabbit aorta (pA2 = 8.2) without

affecting the contractile responses to KCl, phenylephrine (alpha1) or histamine (H1). The perfusion pressure response of rat

coronary artery to 5-HT (5-HT2A) was reduced concentration dependently by gamma-mangostin (IC50 = 0.32 microM). 5-HT

amplified, ADP-induced aggregation of rabbit platelets (5-HT2A) was inhibited by gamma-mangostin (IC50 = 0.29 microM),

whereas that induced by thrombin was not affected, nor did gamma-mangostin affect 5-HT-induced contraction of the guinea-pig

ileum (5-HT3)in the presence of 5-HT1, 5-HT2 and 5-HT4 receptor antagonists. Furthermore, 5-HT-induced contraction of the rat

fundus (5-HT2B) and 5-HT-induced relaxation of the rabbit aorta in the presence of ketanserin (5-HT1) and carbachol-induced

contraction of the guinea-pig ileum (muscarinic M3) were not affected by gamma-mangostin (5 microM). Gamma-mangostin

inhibited [3H]spiperone binding to cultured rat aortic myocytes (IC50 = 3.5 nM). The Kd for [3H]spiperone binding was increased

by gamma-mangostin (3 nM) from 11.7 to 27.4 nM without affecting Bmax. These results suggest that gamma-mangostin is a

novel competitive antagonist, free from a nitrogen atom, for the 5-HT2A receptors in vascular smooth muscles and platelets.

PMID: 9459569 [PubMed - indexed for MEDLINE]

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Free Radic Res. 1995 Aug;23(2):175-84. Related Articles, Links

Mangostin inhibits the oxidative modification of human low density lipoprotein.

Williams P, Ongsakul M, Proudfoot J, Croft K, Beilin L.

University of Western Australia, Department of Medicine, Royal Perth Hospital, Australia.

The oxidation of low density lipoprotein (LDL) may play an important role in atherosclerosis. We investigated the possible

antioxidant effects of mangostin, isolated from Garcinia mangostana, on metal ion dependent (Cu2+) and independent (aqueous

peroxyl radicals) oxidation of human LDL. Mangostin prolonged the lagtime to both metal ion dependent and independent

oxidation of LDL in a dose dependent manner over 5 to 50 microM as monitored by the formation of conjugated dienes at 234 nm

(P < 0.001). There was no significant effect of mangostin on the rate at which conjugated dienes were formed in the uninhibited

phase of oxidation. Levels of thiobarbituric reactive substances (TBARS) generated in LDL were measured 4 and 24 hours after

oxidation with 5 microM Cu2+ in the presence or absence of 50 microM or 100 microM mangostin. We observed an inhibition of

TBARS formation with 100 microM mangostin at 4 hours (P = 0.027) but not at 24 hours (P = 0.163). Similar results were

observed in the presence of 50 microM mangostin. Mangostin, at 100 microM, retarded the relative electrophoretic mobility of

LDL at both 4 and 24 hours after Cu2+ induced oxidation. Mangostin (100 microM) significantly inhibited the consumption of

alpha-tocopherol in the LDL during Cu2+ initiated oxidation over a 75 minute period (P < 0.001). From these results, we conclude

that mangostin is acting as a free radical scavenger to protect the LDL from oxidative damage in this in vitro system.

PMID: 7581813 [PubMed - indexed for MEDLINE]

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Planta Med. 1983 May;48(1):59-60. Related Articles, Links

Antimicrobial activities of Garcinia mangostana.

Sundaram BM, Gopalakrishnan C, Subramanian S, Shankaranarayanan D, Kameswaran L.

PMID: 6611746 [PubMed - indexed for MEDLINE]

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Indian J Exp Biol. 1980 Aug;18(8):843-6. Related Articles, Links

Effect of mangostin, a xanthone from Garcinia mangostana Linn. in immunopathological &

inflammatory reactions.

Gopalakrishnan C, Shankaranarayanan D, Kameswaran L, Nazimudeen SK.

PMID: 7461736 [PubMed - indexed for MEDLINE]

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Arch Int Pharmacodyn Ther. 1979 Jun;239(2):257-69. Related Articles, Links

Pharmacological profile of mangostin and its derivatives.

Shankaranarayan D, Gopalakrishnan C, Kameswaran L.

Mangostin (M), a naturally occurring xanthone in the rinds of the fruits of Garcinia mangostana Linn. (Guttiferae) and its

derivatives such as 3-0-methyl mangostin (MM), 3,6-di-O-methyl mangostin (DM), 1-isomangostin (IM), mangostin triacetate

(MT), mangostin 3,6-di-O-(tetra acetyl) glucoside (MTG) and mangostin-6,6-di-O-glucoside (MOG) were screened for various

pharmacological effects in experimental animals. With the exception of DM all the test compounds produced CNS depression

characterised by ptosis, sedation, decreased motor activity, potentiation of pentobarbital sleeping time and ether anaesthesia in

mice and rats. None of the compounds exhibited analgesic, antipyretic and anticonvulsant effects. With the exception of MOG,

none of the test compounds produced significant effects on the cardiovascular system of frogs and dogs. MOG produced

myocardial stimulation and a rise in blood pressure which was partially blocked by propranolol. M, IM and MT produced

pronounced antiinflammatory activity both by intraperitoneal and oral routes in rats as tested by carrageenininduced hind paw

oedema, cotton pellet implantation and granuloma pouch techniques. Antiinflammatory activity for M, IM and MT was observed

even in bilaterally adrenalectomised rats. M, IM and MT did not produce any mast cell membrane stabilising effect and the

degranulation effect of polymyxin B, diazoxide and Triton X-100 on rat peritoneal mast cells in vitro was not prevented. M, IM

and MT did not alter the prothrombin time of albino rats. M alone produced significant antiulcer activity in rats.

PMID: 314790 [PubMed - indexed for MEDLINE]

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Chem Pharm Bull (Tokyo). 2006 Mar;54(3):301-5. Related Articles, Links

Cytotoxic Prenylated Xanthones from the Young Fruit of Garcinia mangostana.

Suksamrarn S, Komutiban O, Ratananukul P, Chimnoi N, Lartpornmatulee N, Suksamrarn A.

Department of Chemistry, Faculty of Science, Srinakharinwirot University.

Three new prenylated xanthones, mangostenones C (1), D (2), and E (3), together with 16 known xanthones 4-19, were isolated

from the young fruit (7-week maturity stage) of Garcinia mangostana. The structural elucidation of the new compounds was

mainly established on the basis of 1D and 2D NMR and HR-MS spectroscopic analysis. Compound 1 showed cytotoxic properties

against three human cancer cell lines, epidermoid carcinoma of the mouth (KB), breast cancer (BC-1), and small cell lung cancer

(NCI-H187), with IC(50) values of 2.8, 3.53, and 3.72 mug/ml, respectively. Among the isolates, alpha-mangostin (12), the major

metabolite, exhibited the most potent effects against the BC-1 cells with an IC(50) value of 0.92 mug/ml, an activity greater than

that of the standard drug ellipticine (IC(50)=1.46 mug/ml). Compound 12 also showed the highest activity against KB cells, while

gartanin (10) displayed the strongest activity against the NCI-H187 cells at the respective IC(50) values of 2.08 mug/ml and 1.08

mug/ml.

PMID: 16508181 [PubMed - in process]

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J Int Acad Periodontol. 2007 Jan;9(1):19-25. Links

Effects of herbal mouthwash containing the pericarp extract of Garcinia mangostana L on halitosis,

plaque and papillary bleeding index.

Rassameemasmaung S, Sirikulsathean A, Amornchat C, Hirunrat K, Rojanapanthu P, Gritsanapan W.

Department of Oral Medicine, Faculty of Dentistry, Mahidol University, Bangkok, Thailand. dtsrs@mahidol.ac.th

OBJECTIVES: To determine the effects of herbal mouthwash containing the pericarp extract of Carcinia mangostana L on volatile

sulfur compound (VSC) levels, plaque index (PI) and papillary bleeding index (PBI) in gingivitis subjects and the recurrence of

these parameters after periodontal treatment. METHODS: Sixty subjects who were diagnosed as having mild or moderate chronic

gingivitis were randomly distributed into herbal or placebo mouthwash groups. On day 1, all parameters were recorded. Subjects

rinsed with the assigned mouthwash and VSC was measured at 30 min and 3 h post-rinsing. For the following 2 weeks, subjects

practiced their usual oral hygiene and rinsed with the assigned mouthwash twice daily after tooth brushing. On day 15, parameters

were recorded. In the 4-week washout period that followed, subjects received scaling and polishing. After another baseline

examination, they were re-randomized into the herbal or placebo group and rinsed with mouthwash for 2 weeks. All parameters

were re-evaluated on day 15. RESULTS: All parameters were significantly different compared to baseline in both groups at 30

min, 3 h and day 15 (p < 0.05). When compared between groups, VSC was significantly different at day 15 (p < 0.05). After

scaling, poloshing and rinsing with mouthwash for 2 weeks, PI and PBI were significantly different compared to baseline (p <

0.05) while VSC was not (p > 0.05). When compared between groups, VSC was significantly different (p < 0.05).

CONCLUSION: Herbal mouthwash containing the pericarp extract of G. mangostana may be used as an adjunct in treating oral

malodor.

PMID: 17274236 [PubMed - indexed for MEDLINE]

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Bioorg Med Chem. 2007 Aug 15;15(16):5620-8. Epub 2007 May 18. Links

Characterized mechanism of alpha-mangostin-induced cell death: caspase-independent apoptosis with

release of endonuclease-G from mitochondria and increased miR-143 expression in human colorectal

cancer DLD-1 cells.

Nakagawa Y, Iinuma M, Naoe T, Nozawa Y, Akao Y.

Gifu International Institute of Biotechnology, 1-1 Naka-Fudogaoka, Kakamigahara, Gifu 504-0838, Japan.

alpha-Mangostin, a xanthone from the pericarps of mangosteen (Garcinia mangostana Linn.), was evaluated for in vitro

cytotoxicity against human colon cancer DLD-1 cells. The number of viable cells was consistently decreased by the treatment with

alpha-mangostin at more than 20 microM. The cytotoxic effect of 20 microM alpha-mangostin was found to be mainly due to

apoptosis, as indicated by morphological findings. Western blotting, the results of an apoptosis inhibition assay using caspase

inhibitors, and the examination of caspase activity did not demonstrate the activation of any of the caspases tested. However,

endonuclease-G released from mitochondria with the decreased mitochondrial membrane potential was shown. The levels of

phospho-Erk1/2 were increased in the early phase until 1h after the start of treatment and thereafter decreased, and increased again

in the late phase. On the other hand, the level of phospho-Akt was sharply reduced with the process of apoptosis after 6h of

treatment. Interestingly, the level of microRNA-143, which negatively regulates Erk5 at translation, gradually increased until 24h

following the start of treatment. We also examined the synergistic growth suppression in DLD-1 cells by the combined treatment

of the cells with alpha-mangostin and 5-FU which is one of the most effective chemotherapeutic agents for colorectal

adenocarcinoma. The co-treatment with alpha-mangostin and 5-FU, both at 2.5 microM, augmented growth inhibition compared

with the treatment with 5 microM of alpha-mangostin or 5 microM 5-FU alone. These findings indicate unique mechanisms of

alpha-mangostin-induced apoptosis and its action as an effective chemosensitizer.

PMID: 17553685 [PubMed - indexed for MEDLINE]

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FEMS Immunol Med Microbiol. 2006 Dec;48(3):367-72. Epub 2006 Oct 18. Links

Antimicrobial activity in cultures of endophytic fungi isolated from Garcinia species.

Phongpaichit S, Rungjindamai N, Rukachaisirikul V, Sakayaroj J.

Natural Products Research Unit and Department of Microbiology, Faculty of Science, Prince of Songkla University, Hat Yai,

Songkla, Thailand. souwalak.p@psu.ac.th

The aim of the present study was to screen for antimicrobial activity in endophytic fungi isolated from surface sterilized leaves and

branches of five Garcinia plants, G. atroviridis, G. dulcis, G. mangostana, G. nigrolineata and G. scortechinii, found in southern

Thailand. Fermentation broths from 377 isolated fungi were tested for antimicrobial activity by the agar diffusion method.

Minimum inhibitory concentrations (MICs) were obtained for crude ethyl acetate extracts. Seventy isolates (18.6%) displayed

antimicrobial activity against at least one pathogenic microorganism, such as Staphylococcus aureus, a clinical isolate of

methicillin-resistant S. aureus, Candida albicans and Cryptococcus neoformans. The results revealed that 6-10%, 1-2% and 18% of

the crude ethyl acetate extracts inhibited both strains of S. aureus (MIC 32-512 microg mL(-1)), Ca. albicans and Cr. neoformans

(MIC 64-200 microg mL(-1)), and Microsporum gypseum (MIC 2-64 microg mL(-1)), respectively. Isolates D15 and M76

displayed the strongest antibacterial activity against both strains of S. aureus. Isolates M76 and N24 displayed strong antifungal

activity against M. gypseum. Fungal molecular identification based on internal transcribed spacer rRNA gene sequence analysis

demonstrated that isolates D15 (DQ480353), M76 (DQ480360) and N24 (DQ480361) represented Phomopsis sp., Botryosphaeria

sp. and an unidentified fungal endophyte, respectively. These results indicate that some endophytic fungi from Garcinia plants are

a potential source of antimicrobial agents.

PMID: 17052267 [PubMed - indexed for MEDLINE]

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Fitoterapia. 2007 Sep;78(6):401-8. Epub 2007 Jun 2. Links

Effect of Garcinia mangostana on inflammation caused by Propionibacterium acnes.

Chomnawang MT, Surassmo S, Nukoolkarn VS, Gritsanapan W.

Department of Microbiology, Faculty of Pharmacy, Mahidol University, 447 Sri Ayudthaya Road, Rachathevi,Bangkok, 10400,

Thailand.

The present study was aimed to investigate the activity of Thai medicinal plants on inflammation caused by Propionibacterium

acnes in terms of free radical scavenging and cytokine reducing properties. P. acnes have been recognized as pus-forming bacteria

triggering an inflammation in acne. Antioxidant activity was determined by DPPH scavenging and NBT reduction assay. The

result showed that Garcinia mangostana possessed the most significant antioxidant activity and reduced reactive oxygen species

production. Houttuynia cordata, Eupatorium odoratum, and Senna alata had a moderate antioxidant effect. In addition, Garcinia

mangostana extracts could reduce the TNF-alpha production as determined by ELISA. Garcinia mangostana was highly effective

in scavenging free radicals and was able to suppress the production of pro-inflammatory cytokines. This study has identified the

promising source of anti-inflammatory agent which could be useful in treatment of acne vulgaris.

PMID: 17644272 [PubMed - in process]

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J Agric Food Chem. 2006 Mar 22;54(6):2077-82. Links

Antioxidant xanthones from the pericarp of Garcinia mangostana (Mangosteen).

Jung HA, Su BN, Keller WJ, Mehta RG, Kinghorn AD.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210,

USA.

As part of ongoing research on cancer chemopreventive agents from botanical dietary supplements, Garcinia mangostana L.

(commonly known as mangosteen) was selected for detailed study. Repeated chromatography of a CH2Cl2-soluble extract of the

pericarp led to the isolation of two new highly oxygenated prenylated xanthones, 8-hydroxycudraxanthone G (1) and

mangostingone [7-methoxy-2-(3-methyl-2-butenyl)-8-(3-methyl-2-oxo-3-butenyl)-1,3,6-trihydroxyxanthone, 2], together with 12

known xanthones, cudraxanthone G (3), 8-deoxygartanin (4), garcimangosone B (5), garcinone D (6), garcinone E (7), gartanin

(8), 1-isomangostin (9), alpha-mangostin (10), gamma-mangostin (11), mangostinone (12), smeathxanthone A (13), and

tovophyllin A (14). The structures of compounds 1 and 2 were elucidated by spectroscopic data analysis. Except for compound 2,

which was isolated as a minor component, the antioxidant activities of all isolates were determined using authentic and

morpholinosydnonimine-derived peroxynitrite methods, and compounds 1, 8, 10, 11, and 13 were the most active. Alpha-

mangostin (10) inhibited 7,12-dimethylbenz[alpha]anthracene-induced preneoplastic lesions in a mouse mammary organ culture

assay with an IC50 of 1.0 microg/mL (2.44 microM).

PMID: 16536578 [PubMed - indexed for MEDLINE]

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Med Princ Pract. 2006;15(4):281-7. Links

Antioxidative and neuroprotective activities of extracts from the fruit hull of mangosteen (Garcinia

mangostana Linn.).

Weecharangsan W, Opanasopit P, Sukma M, Ngawhirunpat T, Sotanaphun U, Siripong P.

Faculty of Pharmacy, Silpakorn University, Nakhonpathom, Thailand.

OBJECTIVE: The aim of this study was to investigate the antioxidative and neuroprotective activities of various extracts from the

fruit hull of mangosteen (Garcinia mangostana Linn., GM). MATERIALS AND METHODS: Four extracts: water, 50% ethanol,

95% ethanol and ethyl acetate, were used. The antioxidative activity was evaluated using 2,2-diphenyl-1-picrylhydrazyl free-

radical scavenging assay at extract concentrations of 1, 10, 50 and 100 microg/ml. Based on the free radical scavenging activity of

the extracts, two (water and 50% ethanol) were selected for their protective activity in NG108-15 neuroblastoma cells against

H(2)O(2)-induced oxidative stress and for cell viability using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.

RESULTS: All extracts exhibited antioxidative activity. The water and 50% ethanol extracts showed high free-radical scavenging

activity with IC(50) values of 34.98 +/- 2.24 and 30.76 +/- 1.66 microg/ml, respectively. Both water and 50% ethanol extracts

exhibited neuroprotective activity on NG108-15 cells. The highest activity was observed at the concentration of 50 microg/ml for

both the water and 50% ethanol extracts. For cytotoxicity test, none of the extracts was toxic to the cells except at the high

concentration of 100 microg/ml. CONCLUSIONS: These results suggest that the water and 50% ethanol extracts from the fruit

hull of GM may be potent neuroprotectants.

PMID: 16763395 [PubMed - indexed for MEDLINE]

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Planta Med. 2006 Aug;72(10):912-6. Epub 2006 Aug 10. Links

Prenylated xanthones as potential antiplasmodial substances.

Mahabusarakam W, Kuaha K, Wilairat P, Taylor WC.

Department of Chemistry, Prince of Songkla University, Hat Yai, Songkhla, Thailand. wilawan.m@psu.ac.th

Mangostin, the major xanthone of Garcinia mangostana, and a series of synthetic derivatives were investigated for their in vitro

antiplasmodial activity against Plasmodium falciparum. Mangostin itself showed moderate activity, but prenylated xanthones

containing alkylamino functional groups exhibited quite potent antiplasmodial activity. Some structure-activity relationships are

proposed.

PMID: 16902859 [PubMed - indexed for MEDLINE]

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J Agric Food Chem. 2007 Nov 28;55(24):9805-10. Epub 2007 Oct 26.

Assay-guided Fractionation Study of alpha-Amylase Inhibitors from Garcinia mangostana Pericarp.

Eng Kiat Loo A, Huang D.

chmhdj@nus.edu.sg.

alpha-Amylase inhibitor (alpha-AI) activity of Garcinia mangostana, commonly known as mangosteen, pericarp extracts was

studied by assay guided fractionations from lipophilic to hydrophilic using combined solvent extraction and Amberlite XAD2

adsorption chromatography. Neither the lipophilic, xanthone containing fraction, nor the highly polar fraction, which has no

affinity on Amberlite XAD2, showed any alpha-AI. The fraction that shows very high inhibitory activity contains primarily

polyphenols and can be adsorbed on Amberlite XAD2. The IC50 of 5.4 microg/mL of this fraction is comparable to that of

acarbose, a prescribed alpha-AI used in the control of type II diabetes, at 5.2 microg/mL. Total phenolic content (TPC) of each

fraction was measured and the TPC has no correlation with the alpha-AI activity. The lipophilic fraction contains mainly

xanthones as revealed by HPLC-MS analysis. Colorimetric analysis coupled with UV-vis and IR spectroscopic analysis

demonstrated that the fractions with high alpha-AI activity are primarily oligomeric proanthocyanidins (OPCs) with little gallate

moiety. There is also evidence to show that the alpha-AI by these OPCs is not purely by nonspecific protein complexation. Both

tannic acid and G. mangostana OPCs precipitate BSA equally well but G. mangostana OPCs are 56 times more effective in

inhibiting alpha-amylase.

PMID: 17960880 [PubMed - as supplied by publisher]

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Bioorg Med Chem. 2008 Apr 15;16(8):4500-8. Epub 2008 Feb 21.

Inhibitory effect of xanthones isolated from the pericarp of Garcinia mangostana L. on rat basophilic

leukemia RBL-2H3 cell degranulation.

Itoh T, Ohguchi K, Iinuma M, Nozawa Y, Akao Y.

Gifu International Institute of Biotechnology, Bio-active Substances Research, 1-1 Naka-Fudogaoka, Kakamigahara, Gifu 504-

0838, Japan.

Mangostin, Garcinia mangostana L. is used as a traditional medicine in southeast Asia for inflammatory and septic ailments.

Hitherto we indicated the anticancer activity induced by xanthones such as alpha-, beta-, and gamma-mangostin which were major

constituents of the pericarp of mangosteen fruits. In this study, we examined the effect of xanthones on cell degranulation in rat

basophilic leukemia RBL-2H3 cells. Antigen (Ag)-mediated stimulation of high affinity IgE receptor (FcepsilonRI) activates

intracellular signal transductions resulting in the release of biologically active mediators such as histamine. The release of

histamine and other inflammatory mediators from mast cell or basophils is the primary event in several allergic responses. These

xanthones suppressed the release of histamine from IgE-sensitized RBL-2H3 cells. In order to reveal the inhibitory mechanism of

degranulation by xanthones, we examined the activation of intracellular signaling molecules such as Lyn, Syk, and PLCgammas.

All the xanthones tested significantly suppressed the signaling involving Syk and PLCgammas. In Ag-mediated activation of

FcepsilonRI on mast cells, three major subfamilies of mitogen-activated protein kinases were activated. The xanthones decreased

the level of phospho-ERKs. Furthermore, the levels of phospho-ERKs were observed to be regulated by Syk/LAT/Ras/ERK

pathway rather than PKC/Raf/ERK pathway, suggesting that the inhibitory mechanism of xanthones was mainly due to

suppression of the Syk/PLCgammas/PKC pathway. Although intracellular free Ca(2+) concentration ([Ca(2+)](i)) was elevated by

FcepsilonRI activation, it was found that alpha- or gamma-mangostin treatment was reduced the [Ca(2+)](i) elevation by

suppressed Ca(2+) influx.

PMID: 18328716 [PubMed - as supplied by publisher]

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Food Chem Toxicol. 2008 Feb;46(2):688-93. Epub 2007 Sep 26. Links

Anti-inflammatory activity of mangostins from Garcinia mangostana.

Chen LG, Yang LL, Wang CC.

Graduate Institute of Biomedical and Biopharmaceutical Sciences, College of Life Sciences, National Chiayi University, 300

University Road, Chiayi 600, Taiwan, ROC.

The fruit hull of Garcinia mangostana Linn (Guttiferae) is used as an anti-inflammatory drug in Southeast Asia. Two xanthones,

alpha- and gamma-mangostins, were isolated from the fruit hull of G. mangostana, and both significantly inhibited nitric oxide

(NO) and PGE(2) production from lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. The IC(50) values for the inhibition of

NO production by alpha- and gamma-mangostins were 12.4 and 10.1 microM, respectively. After iNOS enzyme activity was

stimulated by LPS for 12 h, treatment with either alpha- or gamma-mangostin at 5 microg/ml (12.2 and 12.6 microM, respectively)

for 24 h did not significantly inhibit NO production. The data show that the inhibitory activities of alpha- and gamma-mangostins

are not due to direct inhibition of iNOS enzyme activity. On the other hand, expression of iNOS was inhibited by alpha- and

gamma-mangostins in LPS-stimulated RAW 264.7 cells, but not by COX-2. However, the level of PGE(2) production was reduced

by the two xanthones. In an in vivo study, alpha-mangostin significantly inhibited mice carrageenan-induced paw edema. In

conclusion, alpha- and gamma-mangostins from G. mangostana are bioactive substances with anti-inflammatory effects.

PMID: 18029076 [PubMed - in process]

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Exp Toxicol Pathol. 2008 Aug;60(4-5):357-64. Epub 2008 Apr 18.

Ameliorative prospective of alpha-mangostin, a xanthone derivative from Garcinia mangostana

against beta-adrenergic cathecolamine-induced myocardial toxicity and anomalous cardiac TNF-alpha

and COX-2 expressions in rats.

Sampath PD, Vijayaragavan K.

Centre for Advanced Studies in Botany, University of Madras, Guindy Campus, Chennai, India.

Altered membrane integrity and inflammation play a key role in cardiovascular damage. We investigated the salubrious effect of

exogenously administered alpha-mangostin against beta-adrenergic cathecolamine-induced cardiovascular toxicity with special

reference to membrane ATPases, lysosomal hydrolases and inflammatory mediators TNF-alpha and Cyclooxygenase-2 (COX-2)

expressions in albino rats. Induction of rats with isoproterenol (150mg/kg body wt, i.p.) for 2 days resulted in a significant increase

in the activities of serum and cardiac lysosomal hydrolases (beta-d-glucuronidase, beta-d-galactosidase, beta-d-N-

acetylglucosaminidase, acid phosphatase and cathepsin-D). A significant increase in cardiac levels of sodium, calcium with a

decrease in the level of potassium paralleled by abnormal activities of membrane-bound phosphatases (Na(+)-K(+) ATPase,

Ca(2+) ATPase and Mg(2+) ATPase) were observed in the heart of ISO-administered rats. Cardiac TNF-alpha and COX-2

expressions were assessed by Western blotting. Cardiac TNF-alpha and COX-2 expressions were significantly elevated in ISO-

intoxicated rats. Pre-co-treatment with alpha-mangostin (200mg/kg body wt.) orally for 8 days significantly attenuated these

abnormalities and restored the levels to near normalcy when compared to ISO intoxicated group of rats. In conclusion, alpha-

mangostin preserves the myocardial membrane integrity and extenuates anomalous TNF-alpha and COX-2 expressions by

mitigating ISO-induced oxidative stress and cellular damage effectively. Restoration of cellular normalcy accredits the

cytoprotective role of alpha-mangostin.

PMID: 18424012 [PubMed - as supplied by publisher]

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J Asian Nat Prod Res. 2008 May;10(5):481-5.

Garcinia mangostana: a source of potential anti-cancer lead compounds against CEM-SS cell line.

Ee GC, Daud S, Izzaddin SA, Rahmani M.

Chemistry Department, Faculty of Science, Universiti Putra Malaysia, Serdang, Selangor, Malaysia.

Our current interest in searching for natural anti-cancer lead compounds from plants has led us to the discovery that the stem and

roots of Garcinia mangostana can be a source of such compounds. The stem furnished 2,8-dihydroxy-6-methoxy-5-(3-methylbut-

2-enyl)-xanthone (1), which is a new xanthone. Meanwhile, the root bark of the plant furnished six xanthones, namely alpha-

mangostin (2), beta-mangostin (3), gamma-mangostin (4), garcinone D (5), mangostanol (6), and gartanin (7). The hexane and

chloroform extracts of the root bark of G. mangostana as well as the hexane extract of the stem bark were found to be active

against the CEM-SS cell line. gamma-Mangostin (4) showed good activity with a very low IC(50) value of 4.7 mug/ml, while

alpha-mangostin (2), mangostanol (6), and garcinone D (5) showed significant activities with IC(50) values of 5.5, 9.6, and 3.2

mug/ml, respectively. This is the first report on the cytotoxicity of the extracts of the stem and root bark of G. mangostana and of

alpha-mangostin, mangostanol, and garcinone D against the CEM-SS cell line.

PMID: 18464091 [PubMed - in process]

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J Biochem Mol Toxicol. 2007;21(6):336-9.

Cardioprotective effect of alpha-mangostin, a xanthone derivative from mangosteen on tissue defense system against isoproterenol-induced myocardial infarction in rats.

Devi Sampath P, Vijayaraghavan K.

Centre for Advanced Studies in Botany, University of Madras, Guindy Campus, Chennai, India.

Increased oxidative stress and antioxidant deficit have been suggested to play a major role in isoproterenol-induced myocardial

infarction. The present study was designed to evaluate the effect of alpha-mangostin on the antioxidant defense system and lipid

peroxidation against isoproterenol-induced myocardial infarction in rats. Induction of rats with ISO (150 mg/kg body weight, ip)

for 2 days resulted in a marked elevation in lipid peroxidation, serum marker enzymes (LDH, CPK, GOT, and GPT) and a

significant decrease in the activities of endogenous antioxidants (SOD, CAT, GPx, GST, and GSH). Pre-treatment with alpha-

mangostin (200 mg/kg of body weight per day) orally for 6 days prior to the ISO administration and 2 days along with ISO

administration significantly attenuated these changes when compared to the individual treatment groups. These findings indicate

the protective effect of alpha-mangostin on lipid peroxidation and antioxidant tissue defense system during ISO-induced

myocardial infarction in rats.

PMID: 17994576 [PubMed - indexed for MEDLINE]

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J Ethnopharmacol. 2008 Nov 14. [Epub ahead of print]

Effects of compounds from Garcinia mangostana on inflammatory mediators in RAW264.7

macrophage cells.

Tewtrakul S, Wattanapiromsakul C, Mahabusarakam W.

Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Prince of Songkla University,

Hat-Yai, Songkhla 90112, Thailand.

ETHNOPHARMACOLOGICAL RELEVANCE: The fruit hull of Garcinia mangostana Linn. has been used in Thai traditional

medicine for treatment of abscess and skin infection. AIM OF THE STUDY: The mangosteen fruit hull and its compounds were

carried out to investigate for anti-inflammatory activity. MATERIAL AND METHODS: The extract of Garcinia mangostana

together with alpha- and gamma-mangostins were tested for anti-inflammatory effect against lipopolysaccharide (LPS)-induced

nitric oxide (NO), prostaglandin E(2) (PGE(2)), tumor necrosis factor alpha (TNF-alpha) and interleukin-4 (IL-4) releases as well

as their mechanisms in transcriptional levels using RAW264.7 macrophage cells. RESULTS: Mangosteen extract possessed potent

NO inhibitory effect with an IC(50) value of 1.0mug/ml. The isolated compounds from the extract including alpha-mangostin and

gamma-mangostin, possessed marked inhibitory effect against NO release with IC(50) values of 3.1 and 6.0muM, respectively.

The extract exhibited potent inhibitory effect on PGE(2) release (IC(50)=6.0mug/ml), whereas those of alpha- and gamma-

mangostins were 13.9 and 13.5muM, respectively. However, mangostins possessed only moderate effects towards TNF-alpha and

IL-4 releases with IC(50) values ranging from 31.8 to 64.8muM. Both extract and alpha-mangostin suppressed transcription of

gene encoding inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in dose-dependent manners, whereas

gamma-mangostin had only an inhibitory effect on transcription of iNOS. CONCLUSION: The present study may support the

Thai traditional use of Garcinia mangostana fruit hull for treatment of inflammatory-related diseases through the inhibition of NO

and PGE(2) releases, but moderate effect through TNF-alpha and IL-4.

PMID: 19056479 [PubMed - as supplied by publisher]

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J Nat Prod. 2008 Jul;71(7):1161-6. Epub 2008 Jun 18.

Xanthones from the Botanical Dietary Supplement Mangosteen (Garcinia mangostana) with

Aromatase Inhibitory Activity.

Balunas MJ, Su B, Brueggemeier RW, Kinghorn AD.

kinghorn.4@osu.edu.

Twelve xanthone constituents of the botanical dietary supplement mangosteen (the pericarp of Garcinia mangostana) were

screened using a noncellular, enzyme-based microsomal aromatase inhibition assay. Of these compounds, garcinone D ( 3),

garcinone E ( 5), alpha-mangostin ( 8), and gamma-mangostin ( 9) exhibited dose-dependent inhibitory activity. In a follow-up

cell-based assay using SK-BR-3 breast cancer cells that express high levels of aromatase, the most potent of these four xanthones

was gamma-mangostin ( 9). Because xanthones may be consumed in substantial amounts from commercially available mangosteen

products, the consequences of frequent intake of mangosteen botanical dietary supplements require further investigation to

determine their possible role in breast cancer chemoprevention.

PMID: 18558747 [PubMed - as supplied by publisher]

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Phytochemistry. 2008 Feb;69(3):754-8. Epub 2007 Nov 7.

Xanthones with quinone reductase-inducing activity from the fruits of Garcinia mangostana

(Mangosteen).

Chin YW, Jung HA, Chai H, Keller WJ, Kinghorn AD.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210,

USA.

Bioactivity-guided fractionation of a dichloromethane-soluble extract of Garcinia mangostana fruits has led to the isolation and

identification of five compounds, including two xanthones, 1,2-dihydro-1,8,10-trihydroxy-2-(2-hydroxypropan-2-yl)-9-(3-

methylbut-2-enyl)furo[3,2-a]xanthen-11-one (1) and 6-deoxy-7-demethylmangostanin (2), along with three known compounds,

1,3,7-trihydroxy-2,8-di-(3-methylbut-2-enyl)xanthone (3), mangostanin (4), and alpha-mangostin (5). The structures of compounds

1 and 2 were determined from analysis of their spectroscopic data. All isolated compounds in the present study together with

eleven other compounds previously isolated from the pericarp of mangosteen, were tested in an in vitro quinone reductase-

induction assay using murine hepatoma cells (Hepa 1c1c7) and an in vitro hydroxyl radical antioxidant assay. Of these,

compounds 1-4 induced quinone reductase (concentration to double enzyme induction, 0.68-2.2microg/mL) in Hepa 1c1c7 cells

and gamma-mangostin (6) exhibited hydroxyl radical-scavenging activity (IC50, 0.20microg/mL).

PMID: 17991497 [PubMed - indexed for MEDLINE

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Fitoterapia. 2008 Nov 5. [Epub ahead of print]

Antibacterial Activity of Thai Medicinal Plants against Methicillin-resistant Staphylococcus aureus.

Chomnawang MT, Surassmo S, Wongsariya K, Bunyapraphatsara N.

Department of Microbiology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial pathogen which causes severe morbidity and mortality

worldwide. Seventeen Thai medicinal plants were investigated for their activity against MRSA. Garcinia mangostana was

identified as the most potent plant, and its activity was traced to the prenylated xanthone, alpha-mangostin (MIC and MBC values

of 1.95 and 3.91 microg/ml, respectively).

PMID: 19022354 [PubMed - as supplied by publisher]

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Food Chem Toxicol. 2008 Oct;46(10):3227-39. Epub 2008 Aug 6.

Medicinal properties of mangosteen (Garcinia mangostana).

Pedraza-Chaverri J, Cárdenas-Rodríguez N, Orozco-Ibarra M, Pérez-Rojas JM.

Facultad de Química, Departamento de Biología, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510

Mexico, DF, Mexico. pedraza@servidor.unam.mx

Many tropical plants have interesting biological activities with potential therapeutic applications. Garcinia mangostana Linn.

(GML) belongs to the family of Guttiferae and is named "the queen of fruits". It is cultivated in the tropical rainforest of some

Southeast Asian nations like Indonesia, Malaysia, Sri Lanka, Philippines, and Thailand. People in these countries have used the

pericarp (peel, rind, hull or ripe) of GML as a traditional medicine for the treatment of abdominal pain, diarrhea, dysentery,

infected wound, suppuration, and chronic ulcer. Experimental studies have demonstrated that extracts of GML have antioxidant,

antitumoral, antiallergic, anti-inflammatory, antibacterial, and antiviral activities. The pericarp of GML is a source of xanthones

and other bioactive substances. Prenylated xanthones isolated from GML have been extensively studied; some members of these

compounds possess antioxidant, antitumoral, antiallergic, anti-inflammatory, antibacterial, antifungal and antiviral properties.

Xanthones have been isolated from pericarp, whole fruit, heartwood, and leaves. The most studied xanthones are alpha-, beta-, and

gamma-mangostins, garcinone E, 8-deoxygartanin, and gartanin. The aim of this review is to summarize findings of beneficial

properties of GML's extracts and xanthones isolated from this plant so far.

PMID: 18725264 [PubMed - indexed for MEDLINE]

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J Drugs Dermatol. 2007 Nov;6(11):1141-8.

Evaluating the efficacy in improving facial photodamage with a mixture of topical antioxidants.

Hsu J, Skover G, Goldman MP.

University of California, San Diego, USA.

This study evaluates the efficacy and tolerability of an investigational study cream composed of 3 ingredients (green and white

teas, mangosteen, and pomegranate extract), Vitaphenol Skin Cream (La Jolla Spa MD, La Jolla CA), as compared to a placebo

cream in rejuvenating facial skin. Twenty healthy females between the ages of 35 and 65 with demonstrable facial wrinkling,

achieving a Rao-Goldman wrinkle scale score of 2 or above, applied either Vitaphenol Skin Cream or placebo cream to a

randomized half of their face twice daily for 60 days and returned for follow-up after 2 weeks. Twice as many subjects indicated

an enhancement of skin texture (eg, reduction in pore size, roughness, and touch) with the usage of Vitaphenol versus placebo. In

all, 41% of the study subjects preferred the half of their face that had been receiving Vitaphenol, while only 0.06% of the subjects

favored the placebo side. PRIMOS images from periorbital skin treated with Vitaphenol demonstrated an average improvement in

skin smoothness of 1 mm3, whereas skin treated with placebo showed an average decrease in smoothness or an increase in skin

roughness of 0.9 mm3. The addition of 3 antioxidants, green and white teas, mangosteen, and pomegranate, have an additive effect

to enhance the improvement of age-related changes in the skin.

PMID: 18038502 [PubMed - indexed for MEDLINE]

Mangosteen Testimonial: Peter Tedesco My background is in Facility Maintenance, with some experience in Nutrition Medicine, and my wife is a nurse. I’m 62 years old and have a family history of heart problems. Parents both died from heart attacks, grandfather on my dad’s side and grandmother, along with grandfather on Mom’s side, also died from heart attacks. The only medicine I took was a multi vitamin & an aspirin each day. A lady from our church told us about [Mangosteen]. With a history of family heart conditions we decided to try [Mangosteen], started with 2 ounces 3 times a day. Later that week I also had an appointment to see my physician, Dr Basa, an Internist. He was raised in the Philippines and graduated from Johns Hopkins University and is aware of mangosteen. We did blood tests on November 10th and he ordered a C-Reactive Protein (CRP) test. That next week the doctor gave me some very distributing news, CRP level reading came back at 9.9. My doctor told me I was a walking heart attack ready to happen. With a CRP level under 1, your risk is low. I was considered a high risk for future cardiovascular event. Not a good sign given the family history. Without taking any other medication and continuing to take [Mangosteen] over the next 37 days my CRP test on December 16th came in at 0.8. I believe [Mangosteen] reduced my CRP to a low risk level, see charts below. Dr Basa did a Quant. CRP the second time…more sensitive results.

From: Carolyn Johnson [mailto:carolyn@OnXanGo.com] Sent: Thursday, September 23, 2004 8:34 AM To: Carolyn Subject: FW: Wonderful Xango Story

Subject: Wonderful Xango Story Parkinson's, Congestive Heart Failure, High Blood Pressure, High Cholesterol, Diabetes, COPD, Angina, Kidney Failure. Jerry Smith - Lacey, WA. This is a my story about Xango and the mangosteen fruit. I was 59 years old when I was released from a hospital at the end of October 2003 with the some serious health problems. The doctors had told me that I had Parkinson's, rapid eye movement disorder associated with Parkinson's, congestive heart failure, high blood pressure, high cholesterol, diabetes, COPD (Chronic Obstructive Pulmonary Disease), angina, and renal problems. I was sent home on four liters of oxygen and a suit case full of drugs. These are medications that I was on: Atenolol 25mg, Candesartan Cilexetil 16mg, Nitroglycerin 0.4mg tab., Nitroglycerin 0.4mg/hr patch, Lovastatin 20mg, Carbidopa 25/Levodopa 250mg, Entacone 200mg, Clonazepam 1mg, Hydrochlorothiazide 25mg, Glyburide 8mg, Albuterol 90mcg., Advair 500mg. Foradil Aerolizer, Albuterol Sulfate Inhalation Solution 0.083%. I would wake up every morning and walk from my bedroom to the couch, a distance of about 30 feet. I literally fell to the couch because I was completely out of breath. My skin color was turning to an ashen color and the skin under my finger nails was dark blue. A friend came over to see me and brought me a case of Xango™ containing the mangosteen. He told me to take it and said that it might help me. He was telling me all the helpful things that this product would or could do. I was very skeptical at first because how could a fruit have so much healing power and work on all the organs in the body at the same time. I asked my doctors about it and they never heard of the fruit. They told me that it would not hurt me to try. I started taking three ounces three times a day and was hoping for an instant cure. It did not happen! I did not feel anything at all until I had finished my third bottle. I noticed that I was sleeping the whole night through and that a little energy was coming back. I could walk from the bedroom to the couch and was not huffing and puffing.

After a month on mangosteen juice, my blood sugar was back down into the 140-150s which was not bad since a month before it was in the 300s. My blood pressure was dropping from 180/90 to 120/70 and my tremors had stopped! I was also checking my oxygen absorption rate everyday and noticed that it was climbing up which is a good thing. I would be getting readings of 88-89 at rest and when I moved around the level dropped to 80-81 before any mangosteen. At the end of a month on mangosteen, my readings were 94-95% at rest and when moving the level stayed the same!! I began cutting back on all my medication gradually and was taking readings from all my machines. I noticed that when I was cutting back on my medications that I was feeling less and less fatigued. By Christmas time, I was off ALL my medication and oxygen and I had reduced my mangosteen to only two ounces three times a day. I am still taking two ounces three times a day. To me this is a miracle fruit and I tell everybody about it. I will be glad to talk to anybody about this product. You can call or e-mail me. Sincerely, Jerry Smith jesmith92003@yahoo.com

To whom it may concern:

My name is Barbara Gjnbalaj. I am aago one of our residents' daughters brougfifd

mother who has Alzheime/s disease. This

ow. after

our other i6tlE outstanding results.

I have now gon

ol W h e n l b e g i n t o f e e l t h e s y m p t o m s o f a M i g r a i n e , j d o u b | e u p ,do not have Migraines. My energy leveltas also increased since being on "[\4e!]ggslesn_

en I Degln to

A few nronthsre home to try

Res ident1 : isa72yea|o lmat ientwhopr ior to tak ing ' ,MangoteenJu ice. ,wass|eep inga l lday, would not communicate and coTlilTtt feed herself. Now after two months on "Mangosteen Juice"she does not sleep al l day,

Resident 2: is an 86 year old Alzheime/s patient, is blind, has very stiff muscles, she has not tatked oropened her eyes for several years and is bed bound. After being on "Mangosteen Juice" for approximatelytwo months she now talks at times, moves her a"rns and leqs oqgasionally and communicates withoutscreamrng.

Resident 3: is a76 year old who has Prior to taking "Mangostggdgpq'was veryuiet, stayed in her room all Now after two mo s on "Mangosteen Juice" s

Resident 4: is ag4 year old wl'ro is very frail, has transfusions every tffiee mognd is anemic tlqw.g&fleing on Mangosteen Juice" for almost two months,

After q wonderful results that the resid-e.nlF were experienciry | slartgd taking "Mangosteen Juice"elf.

Juice". I am also glyjng Mangosteen Juice" toAfter taking "Mangosteen JLiffiffi

n f lares up I double the dosage of "Ma

Also, my tour year old niece had no appetite, would vomit at the site of food, was very skinny and pale.She has been on "Mangosteen Juice" for several months. She is now eating very well, has gained weight, hasrosy cheeks, and less sinus infections."Mangosteen Juice" has truly been a miracle in a short period of time for nry family and for the residentsat the hcility I manage.

Sincerely,

Gfiorlllr.lruprAdultc*rc i{ooaArimnr

rs old. The resg,lts were aln'azilg.i and it wasl

in two to three days.

Prostate Cancer, Cancer Side Effects, Energy

I was diagnosed with stage 4 prostate cancer and given 3-6 month to live:

In February of 2005, I was given 3-6 month to live after being diagnosed with prostate cancer. My PSAscore was 1500. (See graph below)

I started chemotherapy and became very ill, unbearable hiccups; bad breath; pain; fatigue; weaknessand I could not walk without a walker. In March of 2005, I learned about the Mangosteen Juice withXanthones. I wanted to believe everything that I heard and read but was afraid to take it with thechemotherapy. I got too sick after three chemotherapy treatments, I was getting weaker and weaker. Ifelt and I could not get up, I went to the hospital and they told me I would had to start injecting myselfda i |yandtha t themedica t ionwou|dcos t@.onehosp i ta lb i | |a |onewasover 946,000. I had no medical insurance. I was left for dead. I turned to God. I prayed for a healingand then I decided to give the Mangosteen Juice a serious try in March 2005.

My prayers were answered immediately. The first day I had more energy that I could remember andmy horrific bad breath went away. In two days the pain was subsided and I did not need the walkeranymore. I started to feel stronger and stronger. I drank a 25 once bottle [Mangosteen Juice] a day.On May 1, 2005 my PSA score had gone from 1500 to 3. I am now cancer FREE. I feel terrific. I am sothankful to be alive and well. I will drink lMangosteen Juice] for the rest of my life and encourageeveryone who wants to restore his health to do the same.

I thank God for [Mangosteen Juice] and so will you..

The Best of Health to You,

Love Fentress

Love Fentress 31 3-228-21 05

Patient: E'ENTRESS, LO\IEMRN: E-367502392

Flowsheet GraphPrinted by: EEjATB, BLISABEIS I

Pr inted on: 5/4/2OOS 11:32 AI ' t

Prostate $pecific Antigen1500

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2t20t2005 3t20t2005 4t17t2005 5/112005 5115/2005

May 23,2005Hi - My name is Evan and I 'm 4 months o ld.

For few months or half my life, I have battled eczema on my cheeks and jawline (see first 2 pictures below).

The Dr. prescribed a steroidal cream that my mom put on for a few weeksbut it did nothing for my very itchy and sore face.

My mom thought she might share some of her Mangosteen Juice with meand since I have not been introduced to fruit, she started slowly.

On May 23,2005 my mom started me on 5cc (1 tsp) 3 times a day. She alsorubbed some on my face with a cotton ball.

After only 3 days on Mangosteen Juice, I have had remarkable results ( seepictures 3 & 4).

I could not help but want to share my results with you. lf you know someonethat has eczema, please share my story and pictures with them.

Thanks to Mangosteen Juice, lam a much happier l i t t le boy.

Evan

1$ili:

'.:,..;l

't,li.:'

t!.,

Three Days Later! !!

f h f s i s r h e F f r s f F h o r o f a k e n A $ g u s t 2 9 r f i , . ? 0 0 5

j u ice ' on my face and on ly

Wayne is a s ingle father of two youngboys and the owner of a custom paint

and body shop. He suffered 2nd degreeburns f rom an accidental workshop ex-

p los ion .

These Photos are done as a sequence. Thef i rs t photo is August 29th, 2005 and the

17th photo is September 5th, 2005. As youcan see, f f iy hand was not burned as badlyas my face. I decided to use 'mangosteen

do what the hospi ta l and Doctor instructed,fo r my hand.

Photo 17 c lear ly shows the d i f fe rent speeds o f recovery , my facehea led so much fas te r w i th the 'mangos teen j u i ce ' .

I was to ld in i t ia l ly that recovery cou ldto get used to the idea o f a fu l l beard

be as l ong as 4 - 6 mon ths , andfo r a l ong wh i l e . . . I shaved ex -act ly 7 days af ter the accident.

Wayne ELangley, nC.

T h i s i s a ' M a n g o s t e e n J u i c e ' s o a k e d c l o t h p l a c e d o v e r t h e b u r n .

:,1:.

MfcEno Cricftrsn - $epfambe r e*f{.

A wife's 'Mangosteen Juice' Story,

About s ix months ago my husband became i l l , h is whole body and jo ints were racked wi th pain. Some mornings h is hands wereso swollen that they were useless until he massaged them for hours. He had no energy or appetite and he was drastically losingweight. The doctors were doing blood tests, lung x-rays and prostate exams. They ruled out cancer, but they could not find what

was wrong. They said that it was possibly rheumatoid arthritis. They prescribed an anti inflammatory drug called NAPROXEN.That re l ieved a lo t o f the swel l ing and pain.

After a several months the situation was getting worse instead of better. The medication was affecting his stomach so he wasprescr ibed an over the counter drug cal led Zantax. He, a lso s tar ted tak ing some wel l known dry v i tamins as wel l as a l iqu id v i ta-

m t n .

The doctors decided to do a test that would require that he be off of all drugs (except for over the counter pain relievers) forseven days. My husband was in sheer agony!

My f r iend had spoken about 'Mangosteen Ju ice ' severa l t imes prev ious . We were skept ica l , bu t we dec idedt r y . S o s h e p r o v i d e d u s w i t h a b o t t l e a n d h e i m m e d i a t e l y b e g a n t a k i n g 2 o u n c e s i n t h e m o r n i n g a n d t w o

About a week la te r he had h is co lo r back ! He had a lo t more energy , some o f h is appet i te and he was ab leN a p r o x e n a d a y !

tha t i t was wor th ao u n c e s a t n i g h t .

to cu t back to one

He was just about out of the 'Mangosteen lu ice ' but , he st i l l had the dry v i tamins as wel l as the l iqu id v i tamins. So we d idn ' t getanother bottle.

I t wasn ' t very manyback . He was lack ing

Need less to say(December 2004)

d a y s a f t e r h e f i n i s h e d t h e ' M a n g o s t e e n J u i c e ' b e f o r e t h e p a i n a n d s w e l l i n g w e r eenergy and he had to s ta r t tak ing the fu l l dose o f Naproxen and Zantec AGAIN!

w e h u r r i e d t o g e t m o r e ' M a n g o s t e e n J u i c e ' . A t t h i s w r i t i n g i n t h e l a s t m o n t hm y h u s b a n d h a s o n l y h a d t o t a k e a t o t a l o f 3 N a p r o x e n p i l l s - I N T H E W H O L E

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my energy has inc reased beyond be l ie f . I now s inge v e r y o n e I k n o w a n d m e e t ! ! ! ! ! ! !

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Before After 

Brenda used Glimpse for 5 weeks on her face and neck.

Notice the neck area, especially under her chin and around her mouth.

The after pictures show the firming and tightening of the skin.

-Note-

The after pictures are lighter because she stopped tanning right after the before pictures were taken

Before After 

Before Glimpse   Only 4 days after starting Glimpse!   

 

 

 

 

 

 

 

For the past 8 years acne has had a grip on my life. I've tried glycolic acid, lactic acid, salicylic acid, chemical peels, facials, microdermabrasion, masks, serums, creams, pastes and powders( just to name a few). I earned a license in Esthetics, removed all metal fillings from my mouth and have drastically changed my diet numerous times in hopes of uncovering the secret to my skin problems. Thousands of dollars and many years later my breakouts are still persistent and unpredictable. Social isolation, a feeling of hopelessness and many tears are just a few of the side effects associated with chronic acne.

The first time I tried Glimpse was on a day like most others. I examined a moderate breakout around my mouth and jaw line along with very dry cheeks. I started using the product on a Friday morning and to my amazement started seeing results within the first 24 hours. My skin felt calm, nourished and for the first time in a long time...it felt GOOD! Today my skin has no flaky dryness and my breakouts have cleared by approximately 85%. It has only been 4 DAYS!!! That's right, today is Tuesday and I am filled with joy and excitement. I am thrilled with my results and simply can't wait to see what the future weeks and months will hold for me and my skin. Thank you Xango for keeping health in mind while providing the most effective skin care product that I have ever used! Jadyn McLeod, San Diego CA November 11, 2008

Marsha Levine Photos after 3 weeks of Glimpse use.She treated only one side of her face with glimpse.

Wow! Look at the difference.She gets so many comments on her face that she st i l l has not gl impsed

the other side.

More Than A Check For XanGo by Heidi roth - utah Daity Herald

February 26,2010 - Giving is more than just writing a check.

That part is good, and XanGo, a Lehi-based nutritional beverage company, haswritten its share of dedrs for all sorts of good causes. But tre founders wantmore than that, so they also have written a philanthropic gene into the c,orporateDNA.

Employees can take a couple of hours a month off - paid * to volunteer for thecause of their choice. They can participate in any number of projects XanGodoes, or go find a cause they want to support.

The reason this is such a focus, said public relations manager Jeff Chandler, is because the founders realized that one ofthe key principles to success was in giving back to the community. They started making charitable donations immediately,even before they made a profit. And they passed that on.'l think ultimately when people feel like that they have more of a dedication to what they do in their regular job functionbecause they see how it contributes to making the world a better place," Chandler said.

SCERA theaterFour years ago, the company committed $1 million throughout the course of the next five years. Much of that funding went torenovate the 750-seat theater, now named after the company, into a performing arts stage.

The financial infusion came when SCEM's supporters were desperate for help. XanGo's donation also sent a message toother local corporations who then donated to SCEM for education, training, facility upgrades and other opportunities for thecultural arts organization.

Now that partnership has almost reached an end to the stated terms, and SCERA recently recognized XanGo with a StarAward for corporate sponsorship. They're also hoping SCERA will want to continue the partnership.*l don't know where we'd be without XanGo," SCEM CEO Adam Robertson said.

XanGo Meal Pack programJust rnore than two years after launching the Meal Pack prqram, XanGo hit the 1-million-meal milestone. The meals, whichare made for people so close to starving to death that they cannot eat solid food, contain all the fats, minerals and vitaminsneeded to keep a person alive, Some of those meals have gone to Cambodia, Malawi, Kenya, Zimbabwe, Ghana, Myanmar,Haiti and El Salvador.

Operation SmileThe company has sponsored several trips to Mexico in 2008 and 2009 as part of Operation Smile, which provides cleft lipand cleft palate surgeries to children. Several local distributors acted as interpreters and provided care and comfort."lt's really amazing that in a matter of an hour or less, not only is their face healed, and smiles upon their faces, but reallythere's a change in a sense that it's opening up new opportunities,' Chandler said. "lt's an amazing transformation that takesplace in a pretty short time."

At its October convention, XanGo raised about $70,000 for an Openation Smile mission to Thailand to help the children ofworkers who pick the mangosteen fruit. Both Mexico and Thailand are important markets for XanGo.

Best BuddiesEvery year, a few dozen Utah high school students who have mental disabilities gather at XanGo's property to play games,job shadow and get to know a XanGo employee. lt's called Best Buddies Day, and the employees who participate love it.The company also regularly donates to the organization and raises money for it.

*From Best Buddies' perspective, we have programs that would not exist without XanGo's contribution," said Nicole Tatom, aprogram manager from Best Buddies Utah.

http:lirvr,vw.heraldextra.com/special-sec$ory'?rticle_a2015ba{-3025-5775-ac96-d8622bbf5e28.html

To learn more about XanGo please contact the person who shared this article with you.

Joe Morton, Co-Founder of XanGo

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Masters of lJr-rsiness Administral,ion anci a ialv

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Maybe they overheard the cheering. Perhaps it was the fact the Salt Palace was draped in brightorange banners this weekend or that a crowd of 6/500+ was scouring the Salt Lake Citydowntown area with bright orange bags in tow. Whatever it was, two of the area's largestnewspapers couldn't help but take notice of Xanco's third annual Convention; both The Salt LakeTribune and the Deseret Morning News gave enthusiastic coverage to Xanco Saturday morning.Linda Fantin, Tribune reporter, wrote, "Is Xanco the next Google? The iPod of dietarysupplements? Rosa Parks in a bottle? Yes, yes and yes ..."

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Eptrepreneur of the Ye4r AwaqdXanGo hlamed Winner of lItah's 2006 Ernst & Youn

Award Recognizes Catogory Creator's Rapid Growth and Success in GlobalMarketplrce

LEHI, UT- Ime 19, 2006 -Xanco LLC, recognized creator of the mangosEen supplementcategory, today announced that Gary Hollister, CEO and Aamo Garrity, Prcsiden! have received theprestigious Ernst & Young Entepreneur ofthe Yeaf Award for 2006 in thc "Emerging" category forthe Utah region.

Sinc€ its founding just 3% years ago, XanGo has gpwn inlo an intemational company with more +hen600 employees at its Lehi headquarters. Its flagship product, Xancoo Juice, is sold by more thnn500,000 independent distributon in 14 inrernational markets. 'XanGo has surrounded itselfwithpeople that continue to take us to new h€ights," said Ganity.

"I do not accept this award on my own, this award really belongs to all of my partners for their visionin bringing this category-creating product to a worldwide markel" said Grrity as he accepted theaward at the annual gala event held oa Friday, June 16, 2006 at the Salt Palacc Convention Center. Hespecifically singled out XanGo Co-Fouder and EVP Joe Morton who "discover€d" the mingosteenfruit wilile living in Malaysia a decade ago, recognizing it as a fruit with propetties that would benefitpeople all over thc world. "Wc dedicdc tonight to Joe Morbn who startcd it all and I'ho bcgm thiscompany with a dream, and we are grateful to hin1" he said.

According to Emst and Young, itr amual awards program reognizas outstanding entepreneurs whoare building and leading dynamic and gmwing businesses. Amual winn€rs are selected by a paml ofind€pendeirt judges. This year marks the 20th anniversay of lhis nqtionql avruds program vhich hasgrown into thd most prestigious award of its kind ia thc U,S, "For two decadcs, this aunrds programhas bonorcd entrcpreneus who have demonsbated excellence and exbaordinry success in such areasas innovatioq finmcial performmoc, and personal commifuent to tbeir businc$€s and companies,"said David Jolley, Emst & Yomg Estsproneur of tbe Year menaging padncr for Utah.

As a Utah award recipient XanGo is now eligible fo'r consideration for the Ernst & Yormg's nstionalEuteprmeur of thc Year progrm, which will be namsd ldot this yer. Thc overall national recipient isthen considaed for the world Event held in Monte Carlo by ycar;-end"

Garrity conchrded his acccp@cc speech by observing th* "XanCro will coatinup to expand into newmartcts md lead thc mmgosteen cetegory through responsible science aod social responsibility."

Abont the Ernst & Young Entrcprcnsur Of The Y€rr Awrrds

lte Entcprenem OfThc Yeaf awardg program u,as crcdcd and ir produccd by profcesional scrviceofirm Ernst & Young LLP. As the first award of its kin4 the Emst & Yormg Entepreneur Of The Yearawrd rcognins or$hoding eqbepmrerrs lr&o arc buildiog awl lceding dyrcic and grcwinghrsincsces. The program honors eofepenorrrs tlrcugb regionat ndional aud global award programsin over 100 cities aad 35 coufiies

{}glgrnde: XanGo's Ever-Expanding HQ

Since November 2003, XANGO has expanded from 2,000 to 7,000 to 18,000 to 60,000 to 140,000 square-footquarters. Now we're seeing two 120,000 sq. ft. edifices near completion. A whole XanGo campus is comingtogether. Ask any employee and they'll tell you: lt's nice to have everyone back home---no more spread outoperations. Building C is already the office to hundreds of XanGo workers. And, wonder of wonders. this newbuilding is not only huge; it's beautifut with futuristic features:

Starl wilh lhe ground source heal pump system-friend to the environment and friend to the pocketbool(, itworks inexpensively with Mother Earth for all its heating and cooling needs. Next, fancy the backup powersystems that will keep us cot'nfortable, operable and reliable through even the worst of grid power problems.Those two features alone mean we can basically run the buildings without the utility companies.

And that's just the outside. Inside, the rooms-small, medium, large-have the plug-ins, wiring and AN foranything thrown at them. The founders have created a very welcome work environment. lt's bright, professionaland fun.

The breaurecreation room rests atop the five-story structure, an anomaly to lhe industry. lt's a glonous mergerof eating, exercising, playing and resting. Smooth cement floors and exposed metal beams give tne space aparty-warehouse feel. Ten total showers accompany the locker room and fitness center. Booths and bistroseating offer respite reminiscent of a nice sit{own joint. Vending machines have taken it one step ctoser totaking over servers'jobs everywhere. Ping pong, foosball, air hockey and arcade games beckon fun-seekers.Savor that thought.

The landscape is in progress, already a far cry from the dusty hills that once resided lhere. Trees are olanted.Lampposts are lighted. The soil is groomed. parking is curbed and painted. And by .painted,', we mean, thedetached parking struclure has XANGO painted across its top in 60 foot high orange lettering for pitots' andpassengers' viewing pleasure.

A Compensation Plan Comparison

There is no perfect model for oomparing marketing plans. A model generally can be selected to favorone plan: a side by side conparison, howwer, is the only objective and practical m€ans to drrw a comparisonand illustrate a plan's strengths and weakresses.

The following is a dircct comparison between the Amway aad XanGo markefing plans. A frve wi<te, sixdeep sfuchrre with $100.ffi units will be used. Not€ ftat firther width will not affect the resuft--6, l0 or 15wide. Additional depth would dramatically favor tho XanGo plan. Further, to keep ihe number simple andm4n'geable we will ignore the PV/BV cost reldionship in Amway--for we are all paid on commissionablevolume.

Model:

You - $200 VolumeLevel # People Volumels Level 5 People generating $100 commissionable volume each $5002nd Level 25 People genetating $100 commissionable volume each $2,5003'd Level 125 People generating $100 commissionable volume each $12,5004th Level 625 Peopte generating $100 commissionable volume each $62,5005tr Level 3 ,125 People generating $100 commissionable volume each $312,5006tr Level 15,600 People generating $100 commissionable volume each $1.560"000

Total $1,950,500

Amway Proiected fncome XanGo Proiected IncomeYou - $2fi) Volume1"'LcYel - $sfi' Volume $?fi) x 9Vo * $72 - (5 x $3) * $48 prolit $5fi) x Sa/o = $25 residual2* I-evel - $2"500 Volume $5{X} + $2,500 * $3$ffi Volume x l87o = $540

$540- (5 x $54) = $270 nrolit$:l'500 x56/s = $125$125 + $25 = $150 residual

3* Level - $12F00 Volume $Sfrt + $z'flX) + $12'5fi1= $15,5fi1Yolume x27o/o = ${,1E5$4,185 - (5 x $558) = $1J95 profit

$12500 xlOo/o = $1150$1250 + $150 = $1.4(Xl residual

4- Level - $62,flm Volume $500 + $2,5[n + $12,5{X} + $62,500 = $78,0(X} Volume$7E 000 Vslumc x4Ya (you broke 5 Directs) = $J,120$3,120 - $460 pass-up = S2,66) profit

$62,500 xSo/o = ff1,125$3,1,25 + $1,400 = $i41525 residual

5'" Lcvcl - $3l2SO0 Volume $StlXl + Sl,gm + $f2S{X} + $62,500 + $312,500 = &190,5fi}4olo Pass-up on 5 Directs = $2J0028/al*allership Bonus on $;130,0fi) = t$6,flX1$2J00 + $6,6m = $8,9(X) profit

$f2,500x57e=$15,625$15'625 + $4525 = $20,150 residual

6'q l*vol - $IrS60,0Ul Volume $500 + $2"500 + $12,ff10 + $52,5{Xl + tr}12$00 + S1n560,fr)0$f850'500 Volume47o Pass-up on 5 Direets = $2J0027o Pass-up on 25 Directs = $51750

$2Joo + $s,?so = $8rL50 profit

$l'ffi'000 x$o/o = $78,(X)0$7E,000 + $2O15{l =

$98,150 residual

The difforenco grows lAo with added depth lovels. This is why Amway lsadsrs w€rc forc€d to cng@ a toolvev€nt'syst6m' to pay ft€m in depft; overpiced tools 8ad €vents g€derare rnoga profits for Emoakls md above. Delh Yeager,himse$ told me persoully in 1989 tlc ho figrned ealy on there was no real nonEr for high producers in thecompensation plan

Iayrlty:A ryecial note io those blindly loyal folks who like io e)plain away ftcts.., Y€s you could rgue to 'build nder 5 or l0legs and there is no pass-up,' In reality, you ne doubling or tripling the problem. More of smething terribly flewed justworsens the restrlt,

"Charging more then $2,00 fm a cassete or $5.fi) for a vftleo is abusing the little guf- Richard Poe. Tave 3

A Mary Kay record r $1 mill ion in year

Star sales rep will be honored as convention kicks off in Dallas

10:00 AM CDT on Monday, July L7, 2A06

By VICTOR GODINEZ I The Dallas Morning News

Anne Newbury never dreamed of becoming a millionaire when she joined Mary Kay Inc. as an independent salesrepresentative 37 years ago.

"I didn't want anything full time," said Ms, Newbury, a Dallas resident, 'Just give me 950 a week. If I could bring inthat kind of money, that was significant."

But today, Ms. Newbury will be feted as the finst-€ver Mary Kay independent national sales director to eam morethan $1 million in commissions in a single year,

She'll rec€ive the accolades on the opening day of Mary Kay's annual convention, which runs through Aug. 2 at theDallas Convention Center,

More than 42,000 Mary l(ay sales representatives will visit the area over the @urse of the convention, and morethan 1,100 ofthe famous pink Cadillacs will be awarded to the top sellers,

There are more than 1.6 million Mary Kay'independent beauty consultants" worldwide, up 17 percent from lastyear.

The company estimates that the massive convention, which is focused mostly on the U.S. sates force, will injectabout $100 million into the Dallas economy,

While Mary Kay is now known as a global beauty powerhouse with $2.2 billion in sales last year, Ms. Newburyjoined the company when it was just getting started under the stewardship of the legendary Mary l<ay Ash.

Ms. Ash died in 2001, but Rhonda Shasteen, senior vice president of marketing at Mary Kay, said there was nodoubt the cosmetics company would continue to prosper.

"For those of us who are involved with th€ company and knew Mary Kay, I would say no, thet€ was no concem,'she said. "tulary Kay knew early on that what she built was going to surpass her lifetime.'

Ms, Newbury, 65, is retiring this year and has earned nearly $11 million over the cours€ of her career whileoverseeing roughly 30,000 independent Mary Kay representatives in eight countries. She said she hopes to pass onthe things she's learned to upcoming generations.

And she's thrilled to be ending her career with a record that Ms. Ash herself encouraged salespeople to aim for.

"Mary Kay used to talk about it in her speeches, saying 'Some day this will happen,' " Ms. Newbury said. 'I'm moreexcited about lt than I can probably express rlght now,"

Anne Newbury,

Terrified of hees, snakesand swimming pools?Thousands of Americans die in accidents every year,but the odds are extremely high that you won't beone of them. A look at what killed Americans in2003, the most recent year for which data areavailable, shows that just 4o/o of fatalities wereaccidental. So go ahead and take that plane tripor swim in the ocean. Just be careful out there

Maybe you should worrymorc about your heart

-Even if you exercise regularly and don't snor drink, you will probably die of a disease.Two ailments-heart disease and cancer-cause half of all deaths in the U.S. Exoticbugs like avian flu and mad cow diseasemight grab a lot of headlines, but so far thelhaven't killed a single person in the U.S.

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biasl'the thing that makes usglower when we see someone driving errat-ically while talking on a cell phone, even ifwdve done the very same thing perhaps onthe very same day. We tell ourselves wdredifferent, because our call was shorter orour business was urgent or we were ableto pay attention to the road even as wetalked. What optimism bias comes down to,however, is the convenient belief that risks

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theres the irrational way we react to riskybehavior that also confers some benefit. ftwould be a lot easier to aclcrowledge theperils of smoking cigarettes or eating toomuch ice cream if they weren't such pleas-ures. Drinking too much confers certainbenefits too, as do risky sex, recreationaldrugs and uncounted other indulgences.This is especially true since, in most cases,the gratification is immediate andthe penal-ty, if itcomesatall, comeslater. Withenough

lfi#dl.md enougtr temptation, we can tur-ourselves into ignoring almost any long-term costs. "These things are fun or hip,even if they can be lethalj' says Ropeik. 'And

that pleasure is a benefit we weighi'If these reactions are true for all of us-

and they are-then you might think that allof us would react to risk in the same wav. Butthat's clearly not the case. Some p"opi"

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joy roller coasters; others wort't go nearthem. Some skydive; others can'timagine it.Not onlyare thrill seekers notputoffbyris(but they're drawn to it, seduced by the mor-tal frisson that would leave many of us cold."There's an internal thermostat that seemsto control thisj'says risk expertJohn Adams

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your ability to sell it? Do you think ,someone t"ight track you down laterto complain about it?who have the

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reports; you may want to go to the sitewhere that person is supposedly doingbusiness. Be suspicious if he or shewont disclose the location.

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youll be paid a cnrtain amount for eachperson you bring into the system.

$USC[$$: ,Is ftad+ag.,a corapany wi-th agood prodlaot enough?'BR0llER: No. Last year we sued aCalifornia company called FtrtureNet.It sold a legitimate product calledWebTV. The only problem was thatthe [version of the] product it wasselling was al'most obsolete by thetirne the cornpan)z started selling it. Italso would have cost someone moreto buy the product through thisprogram than if hcd just gone straightto Circuit City. Although some people

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Beware when youre asked to spend alot of rnoney up front on expensiveinventory. That's a clenx red flag thatyoure *uil.ing toward a pyrarrlidschenne destined to collapse.

$USGE$$:,[,&w do, ssls@-4s.@ee&*e?BR0DER; Let me tell vou about onecase I prosecuted in iong Beach,Calif. A comparqr called CreditDeveloprnent International invitedpeople to join a progr.am describbd as a"fiaternal orgm;wation of people.h.lpi"g 1reople," In less than a year, ithad recruited more than 3o,ooornembers. People were pronrisedresidual incomes of $r8,ooo a mont"hand aVisa or MasterCard credit cardwith a $5,ooo line of credit. When wewent to court, we came with affidavitsfrorn Visa and MasterCard, as well asftom the banla that the cornpanyclairned to be affiliated with, thatdenied any relationship with CDI.

SUCCI$$: Whom can you call to help'you distinguish the legit players frorrrtl-re unscrupulous ones? ,.:

EROEER: Our Web site, Iglg&gggy,and unvw.consumer.gov are one-stop-shops lor consumer protection. Youcan also check out your local BetterBusiness Bureau.@

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ffi$Y&L F&CT$#ru$The competition will be fi.erce.Everyone craves a chunk of the sr5obillion U.S. market for health- andbody-related products, a fi.gure thatincludes the aforementioned s85 billionin prescription rnedications artd $zzbillion in over-the-counter medicines.MerckMedco Managed Care is in theWeb-csmmerce garne, and, to varyingdegrees, so are the retail chains RiteAid and Walgreens. Amazoncom isrurnored to be backing anotherprescri,ption-drug venture,Drug$tore.com. What sets PlanetRxapffi Besides beiqg the first to takeprescriptions online, says Schear,PlanetRx will offer a number of value-added innorzations. Among these areautortutic prescription refills (a freshbotde of pills will be sent to you at the'begin'ning of each month, for example),personalized service (the site can

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rernind you via e-mail when yourprescription has expired), andovernight delivery. Also, in its quest tobecorne a resource center, PlanetRxwill provide free disease-treatrnentinf,onnation, pricing cornparisons,resea.rch repofts on prescriptionmedicines, and an'Ask the Pharmacist"area which will be accessible z4 hoursa iJuiy.Orders will be taken via e-mail,fax, phone, or regular mail, anddoctors can contact PlanetRx directlywith prescription information.

Schear declines to disclose thefirm's financial goals for 1999 andbeyond Profitabilicy is important, butnot in the near tenn. "If you look atthe Amazon.com model," stle says, "itpays to spend aggressively earlv on,acquire customers, and get it right." Shethinks that the groups idealism is itssrrongest asset. "We really believe wecan do well by doing good."o

Santa Cruz County Stories Lorri Lockyer: In work or at play, she rides high on life

Ann Parker - Sentinel Correspondent Article Launched: 10/27/2008 01:33:37 AM PDT

Lorri Lockyer finds herself on the receiving end of a bit of affection... (Shmuel Thaler/Sentinel)

In 2016, Lorri Lockyer hopes to be at Olympic qualifying level with her tall, dark and handsome partner.

Make that very tall. At 16.2 hands high and around 1,500 pounds, Lockyer's horse Zelvius is big even for a Friesian, his handsome Netherlands breed that once carried knights in armor. "He loves food," laughs Lorri, who bought Zelvius in 2005. "Especially peppermints."

Despite her petite size, Lockyer seems well-matched with Zelvius. Her enthusiastic energy complements the huge horse, whose sociable yet mellow temperament and jet-black coat typify his breed. The two train about 1-1/2 hours daily in dressage, sometimes called "horse ballet," a highly demanding form of horsemanship that demonstrates riding performance and athletic ability.

An athlete in her own right, Lorri has competed in two Hobie catamaran world championships with her boyfriend, John; she practices yoga and Pilates and was an aerobics instructor and lifeguard in college. After college, she flexed her muscles in bodybuilding competitions. She also admits, infectious laugh pealing, to mud wrestling once for a Humboldt State fundraiser.

Lockyer always wanted to be a vet, an ambition that led to 20 years of working for veterinary hospitals. Early on, she groomed horses and milked goats; during high school, she took care of baby wildlife at Lion Country Safari in Irvine. "Bears, a lion, cheetah, hippo, chimps -- I have great stories from that job."

Now a nutritional biochemist, Lorri has been a global clinical project manager since 2000, overseeing test projects for pharmaceutical companies across the globe. "My clinical trials have included people with diabetes, Parkinson's, non-Hodgkin's Lymphoma and several oncology trials. It can be so rewarding."

While fighting her own battle with a cervical cancer-causing virus in 2005, Lockyer heard about a mangosteen juice-based product called Xango that reportedly boosted immunity. "It seemed at least like another way to be proactive," she recalls. "I'm a scientist so I did some research, including on www.pubmed.org, which called it 'promising.' Then I tried it." Three months later, the cervical virus was gone; Lorri became such a believer that she's now a distributor for Xango. Describing it as "a natural anti-inflammatory, broad spectrum health beverage," she says she gives Zelvius two ounces of Xango twice a day to benefit his joints and muscle recovery from their workouts.

Lockyer brushes back her ginger curls and plants a kiss on Zelvius' soft ebony muzzle. "He likes kisses," she chuckles and resumes brushing his rippling black mane. The regal horse ducks his long neck and gently nuzzles her, looking for peppermints.