As many as 18.2 million Americans (6.3 percent of the population) have diabetes.
Each year about one million more aged 20 or older are diagnosed with the disorder.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
Antidiabetic activity of a xanthone compound, mangiferin.
Phytomedicine. 2001 Mar;8(2):85-7. Miura T, Ichiki H, Hashimoto I, Iwamoto N, Kato M, Kubo M, Ishihara E, Komatsu Y, Okada M, Ishida T, Tanigawa K. Suzuka University of Medical Science, Mie, Japan.
Mangiferin, a xanthone, lowered the blood glucose (sugar) level in type II diabetic mice. From these findings, it seems likely that mangiferin exerts its antidiabetic
activity by decreasing insulin resistance.
--------------------------------------------------------------------------------------
Effect of mangiferin on hyperglycemia and atherogenicity in streptozotocin diabetic
rats
S. Muruganandana, , , K. Srinivasanb, S. Guptaa, P.K. Guptaa and J. Lala
aDivision of Pharmacology and Toxicology, Indian Veterinary Research Institute,
Izatnagar 243 122, UP, India bDepartment of Pharmacology and Toxicology, National Institute of PharmaceuticalEducation and Research, Mohali, Punjab, India Received 8 March 2004; revised 3November 2004; accepted 7 December 2004. Available online 5 February 2005.
In the present study, the effect of mangiferin (a xanthone glucoside, isolated from
the leaves of Mangifera indica) on the atherogenic potential of streptozotocin (STZ)-
diabetes was investigated. In addition, the effect of mangiferin on oral glucose tolerance in glucose-loaded normal rats was also determined. The chronic administration of mangiferin (10 and 20 mg/kg, i.p.) for 14 days significantly as well as markedly improved oral glucose tolerance in glucose-loaded normal rats suggesting its potent antihyperglycemic activity. The accumulating evidences suggest that both pancreatic and extrapancreatic mechanisms might be involved in its antidiabetic or antihyperglycemic action. In conclusion, the present study demonstrates that mangiferin possesses significant anti-diabetic, anti-hyperlipidemic and anti-atherogenic properties thus suggesting its beneficial effect in the treatment of diabetes mellitus associated with hyperlipidemia and related cardiovascular complications.
Saturday, July 28, 2007
Friday, July 27, 2007
Mangosteen for Heart Disease and Stroke
Heart disease and stroke
1st and 3rd leading causes of death in U.S.
•About 950,000 Americans die of cardiovascular disease each year, which amounts to one death every 33 seconds.
•About 61 million Americans (almost one-fourth of the population) have some form of cardiovascular disease.
•Stroke alone accounts for the disability of more than 1 million Americans.
Independent Research From Across the World Regarding Mangosteen’s impact on Heart Disease & Stroke.
------------------------------------------------------------------------------
Chiral 2-amino-1-butanol xanthone derivatives as potential antiarrhythmic and hypotensive agents.
Acta Pol Pharm. 1999 Jan-Feb;56(1):87-90. Librowski T, Czarnecki R, Jastrzebska M. Department of Pharmacodynamics, Collegium Medicum Jagiellonian University, Krakow, Poland.
------------------------------------------------------------------------------
Synthesis and antithrombotic effect of xanthone derivatives. J Pharm Pharmacol. 1996 Sep;48(9):887-90.
Lin CN, Hsieh HK, Liou SJ, Ko HH, Lin HC, Chung MI, Ko FN, Liu HW, Teng CM.
School of Pharmacy, Department of Internal Medicine, Kaohsiung Medical College, Taiwan,
R.O.C.
Researchers studied several xanthone derived compounds and found them to possess potent antithrombotic (anti clotting) activities.
------------------------------------------------------------------------------
Mechanism of vasorelaxation of thoracic aorta caused by xanthone.
Eur J Pharmacol. 1997 Oct 1;336(1):23-8. Cheng YW, Kang JJ. Institute of Toxicology, College of Medicine, National Taiwan University, Taipei.
The researchers showed vasorelaxation (relaxing of blood vessels, which lowers blood pressure) activity of the xanthones studied.
------------------------------------------------------------------------------
Antiplatelets activity of some xanthone derivatives.
Acta Pol Pharm. 1999 Jul-Aug;56(4):319-24. Rajtar G, Zolkowska D, Kleinrok Z, Marona H. Department of Pharmacology and Toxicology, Medical University School, Lublin, Poland.
Researchers studied the effects of twelve xanthone derived compounds on platelet aggregation. They found five of them inhibited thrombin-induced platelet aggregation (clot formation).
------------------------------------------------------------------------------
Antihypertensive and vasorelaxing activities of Synthetic xanthone derivatives.
Bioorg Med Chem. 2002 Mar;10(3):567-72. Wang LW, Kang JJ, Chen IJ, Teng CM, Lin
CN. School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan 807, ROC.
The researchers studied a series of xanthones and related compounds. The antihypertensive (against high blood pressure) and vasorelaxing (relaxing of the blood vessels to prevent high blood pressure) activity of compounds on cardiovascular system was evaluated. All the compounds tested exhibited effective hypotensive (lower blood pressure) activity in anesthetized rats.
------------------------------------------------------------------------------
Relationship between protective effect of xanthone on endothelial cells and endogenous nitric oxide synthase inhibitors.
Bioorg Med Chem. 2003 Nov 17;11(23):5171-7. Jiang DJ, Hu GY, Jiang JL, Xiang HL, Deng HW, Li YJ. Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Cha ngsha 410078, China.
The researchers found that xanthone preserved endothelial cells inhibited the increased adhesion of monocytes to endothelial cells induced by oxidized LDL. This is especially important in preventing plaque formation and the subsequent blockage of arteries and heart disease.
------------------------------------------------------------------------------
Inhibition of lipoprotein oxidation by prenylated xanthones derived from mangostin.
Free Radic Res. 2000 Nov;33(5):643-59. Mahabusarakam W, Proudfoot J, Taylor W, Croft K.
Chemistry Department, Prince of Songkla University, Hat Yai, Thailand.
Oxidative damage is thought to play a critical role in cardiovascular and other chronic diseases.
This has led to considerable interest in the antioxidant activity of dietary compounds. The researchers have previously shown that the xanthone, mangostin (found in mangosteen fruit), can inhibit the oxidation of LDL, low density lipoprotein (bad cholesterol). Researchers studied more xanthone derived compounds and found enhanced antioxidant
activities.
Note: If the oxidation of LDL cholesterol can be prevented or inhibited, then the LDL-cholesterol cannot exert its “bad” effect and cause heart disease.
------------------------------------------------------------------------------
Mangostin inhibits the oxidative modification of human low density lipoprotein.
Free Radic Res. 1995 Aug;23(2):175-84. 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. The researchers investigated the possible antioxidant effects of mangostin,
isolated from Garcinia mangostana (found in mangosteen fruit), on the oxidation of human LDL (bad cholesterol). From these results, it is concluded that mangostin is acting
as a free radical scavenger (“mop up” sponge) to protect the LDL from oxidative damage in this in vitro system. In other words, it is a potent antioxidant.
1st and 3rd leading causes of death in U.S.
•About 950,000 Americans die of cardiovascular disease each year, which amounts to one death every 33 seconds.
•About 61 million Americans (almost one-fourth of the population) have some form of cardiovascular disease.
•Stroke alone accounts for the disability of more than 1 million Americans.
Independent Research From Across the World Regarding Mangosteen’s impact on Heart Disease & Stroke.
------------------------------------------------------------------------------
Chiral 2-amino-1-butanol xanthone derivatives as potential antiarrhythmic and hypotensive agents.
Acta Pol Pharm. 1999 Jan-Feb;56(1):87-90. Librowski T, Czarnecki R, Jastrzebska M. Department of Pharmacodynamics, Collegium Medicum Jagiellonian University, Krakow, Poland.
------------------------------------------------------------------------------
Synthesis and antithrombotic effect of xanthone derivatives. J Pharm Pharmacol. 1996 Sep;48(9):887-90.
Lin CN, Hsieh HK, Liou SJ, Ko HH, Lin HC, Chung MI, Ko FN, Liu HW, Teng CM.
School of Pharmacy, Department of Internal Medicine, Kaohsiung Medical College, Taiwan,
R.O.C.
Researchers studied several xanthone derived compounds and found them to possess potent antithrombotic (anti clotting) activities.
------------------------------------------------------------------------------
Mechanism of vasorelaxation of thoracic aorta caused by xanthone.
Eur J Pharmacol. 1997 Oct 1;336(1):23-8. Cheng YW, Kang JJ. Institute of Toxicology, College of Medicine, National Taiwan University, Taipei.
The researchers showed vasorelaxation (relaxing of blood vessels, which lowers blood pressure) activity of the xanthones studied.
------------------------------------------------------------------------------
Antiplatelets activity of some xanthone derivatives.
Acta Pol Pharm. 1999 Jul-Aug;56(4):319-24. Rajtar G, Zolkowska D, Kleinrok Z, Marona H. Department of Pharmacology and Toxicology, Medical University School, Lublin, Poland.
Researchers studied the effects of twelve xanthone derived compounds on platelet aggregation. They found five of them inhibited thrombin-induced platelet aggregation (clot formation).
------------------------------------------------------------------------------
Antihypertensive and vasorelaxing activities of Synthetic xanthone derivatives.
Bioorg Med Chem. 2002 Mar;10(3):567-72. Wang LW, Kang JJ, Chen IJ, Teng CM, Lin
CN. School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan 807, ROC.
The researchers studied a series of xanthones and related compounds. The antihypertensive (against high blood pressure) and vasorelaxing (relaxing of the blood vessels to prevent high blood pressure) activity of compounds on cardiovascular system was evaluated. All the compounds tested exhibited effective hypotensive (lower blood pressure) activity in anesthetized rats.
------------------------------------------------------------------------------
Relationship between protective effect of xanthone on endothelial cells and endogenous nitric oxide synthase inhibitors.
Bioorg Med Chem. 2003 Nov 17;11(23):5171-7. Jiang DJ, Hu GY, Jiang JL, Xiang HL, Deng HW, Li YJ. Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Cha ngsha 410078, China.
The researchers found that xanthone preserved endothelial cells inhibited the increased adhesion of monocytes to endothelial cells induced by oxidized LDL. This is especially important in preventing plaque formation and the subsequent blockage of arteries and heart disease.
------------------------------------------------------------------------------
Inhibition of lipoprotein oxidation by prenylated xanthones derived from mangostin.
Free Radic Res. 2000 Nov;33(5):643-59. Mahabusarakam W, Proudfoot J, Taylor W, Croft K.
Chemistry Department, Prince of Songkla University, Hat Yai, Thailand.
Oxidative damage is thought to play a critical role in cardiovascular and other chronic diseases.
This has led to considerable interest in the antioxidant activity of dietary compounds. The researchers have previously shown that the xanthone, mangostin (found in mangosteen fruit), can inhibit the oxidation of LDL, low density lipoprotein (bad cholesterol). Researchers studied more xanthone derived compounds and found enhanced antioxidant
activities.
Note: If the oxidation of LDL cholesterol can be prevented or inhibited, then the LDL-cholesterol cannot exert its “bad” effect and cause heart disease.
------------------------------------------------------------------------------
Mangostin inhibits the oxidative modification of human low density lipoprotein.
Free Radic Res. 1995 Aug;23(2):175-84. 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. The researchers investigated the possible antioxidant effects of mangostin,
isolated from Garcinia mangostana (found in mangosteen fruit), on the oxidation of human LDL (bad cholesterol). From these results, it is concluded that mangostin is acting
as a free radical scavenger (“mop up” sponge) to protect the LDL from oxidative damage in this in vitro system. In other words, it is a potent antioxidant.
Tuesday, July 24, 2007
Special NOTE to Chiropractors & Health Professionals prescribing Vioxx, Celebrex, or Bextra
Xanthones are proven* to provide natural relief via direct inhibition of
the COX II enzymes.
In general (especially in Chiropractic medicine), most musculo-skeletal conditions are a result of one or two types of injuries -- either a traumatic condition or a repetitive condition such as carpal tunnel...
But all musculo-skeletal conditions have one thing in common --inflammation.
The inflammatory process comes at a time when tissues are going through the
natural process of disrepair. Cells have been damaged, and the end result of that
damage is the production of hormone-like molecules called prostaglandins, which
cause pain and inflammation.
The intermediate of this process is an enzyme called Cox II. The Cox II enzyme is what actually starts the inflammation, swelling and pain.
Good News... we now have XANTHONES!
In Chiropractic, the NUMBER-ONE course of action is the restoration of joint and nerve stability by the use of manipulation.
While the reduction of interim and chronic pain and inflammation can contribute to
successful treatment, this must be accomplished without harm or stress to the
liver or other body systems.
Xanthones are naturally occurring biochemically active agents found in high
concentration in the mangosteen fruit.
These Xanthones have been INDEPENDENTLY researched for decades with
direct* evidence of their profound and diverse health giving properties.
*Over 40 Xanthones have been identified in the fruit and pericarp of the
mangosteen!
the COX II enzymes.
In general (especially in Chiropractic medicine), most musculo-skeletal conditions are a result of one or two types of injuries -- either a traumatic condition or a repetitive condition such as carpal tunnel...
But all musculo-skeletal conditions have one thing in common --inflammation.
The inflammatory process comes at a time when tissues are going through the
natural process of disrepair. Cells have been damaged, and the end result of that
damage is the production of hormone-like molecules called prostaglandins, which
cause pain and inflammation.
The intermediate of this process is an enzyme called Cox II. The Cox II enzyme is what actually starts the inflammation, swelling and pain.
Good News... we now have XANTHONES!
In Chiropractic, the NUMBER-ONE course of action is the restoration of joint and nerve stability by the use of manipulation.
While the reduction of interim and chronic pain and inflammation can contribute to
successful treatment, this must be accomplished without harm or stress to the
liver or other body systems.
Xanthones are naturally occurring biochemically active agents found in high
concentration in the mangosteen fruit.
These Xanthones have been INDEPENDENTLY researched for decades with
direct* evidence of their profound and diverse health giving properties.
*Over 40 Xanthones have been identified in the fruit and pericarp of the
mangosteen!
Monday, July 23, 2007
Mangosteen: A Powerful Anti-Inflammatory
The mangosteen, while definitely one of the most powerful natural antioxidants yet discovered, contains a host of other benefits that in some ways are even more exciting.
The mangosteen's anti-inflammatory xanthones are probably responsible for providing more immediate relief than any other phytonutrients found in the fruit.
Dr. Kenneth J. Finsand has this to say:
"This is probably the most famous use of all the qualities found in the mangosteen: it is by far the most powerful anti-inflammatory I have ever seen in 30 years of practice. Research has proven this to be true, along with folk medicine history."
Dr. Frederic Templeman tells us that the anti-inflammatory properties of mangosteen have been compared in strength to one of the most potent anti-inflammatory prescription drugs, Dexamethasone. In his words, "this drug knocks the socks off Vioxx in terms of potency." The following excerpt taken from the audio "The Miracle Mangosteen" is available at http://www.mangosteentools.com.
[NOTE: Since making the above statement about Vioxx (Dexamethasone), that drug was pulled from the market as of September 30, 2004, due to its possible adverse side effects, see below.]
Just look at this list of possible adverse side effects from the above mentioned drug (Dexamethasone)!
- upset stomach
- stomach irritation
- vomiting
- headache
- dizziness
- insomnia
- restlessness
- depression
- anxiety
- acne
- increased hair growth
- easy bruising
- irregular or absent menstrual periods
If you experience any of the following symptoms when using prescriptions, call your doctor immediately:
- skin rash
- edema (swollen face, lower legs, or ankles)
- vision problems
- persistent cold or infection
- muscle weakness
- black or bloody stool
The Mangosteen has NONE of those side effects!
Do you realize what this means?
Inflammation plays a huge role in an incredible array of common ailments:
- Arthritis
- Back pain
- Heart attack
- Headache
- Multiple Sclerosis
- Circulatory Impairment
- any kind of infection
- and many more
While inflammation can affect all tissues in the body, it is the primary mechanism underpinning diseases which attack muscles, joints and connective tissue.
Inflammation is the PRIMARY cause of PAIN!
What are the qualities of an ideal health supplement?
- Effective, it works!
- Safe, no adverse side affects
- No contraindications with medications
- Prevention
- Has broad applications
Take a closer look and you will find that the mangosteen measures up in ALL categories.
How Safe is Mangosteen?
Toxicity studies were done in the laboratory with rats, using the human equivalent of 3 liters of mangosteen juice per day, with no adverse behavioral or tissue effects noted.
Also, there are no historical records of any folk medicine warnings after centuries of medicinal use of the plant in SouthEast Asia.
It is always recommended that you consult your physician, if you have a known medical condition or allergy before using any food supplement. Mangosteen is safe for use by children and adults under almost any condition.
The mangosteen's anti-inflammatory xanthones are probably responsible for providing more immediate relief than any other phytonutrients found in the fruit.
Dr. Kenneth J. Finsand has this to say:
"This is probably the most famous use of all the qualities found in the mangosteen: it is by far the most powerful anti-inflammatory I have ever seen in 30 years of practice. Research has proven this to be true, along with folk medicine history."
Dr. Frederic Templeman tells us that the anti-inflammatory properties of mangosteen have been compared in strength to one of the most potent anti-inflammatory prescription drugs, Dexamethasone. In his words, "this drug knocks the socks off Vioxx in terms of potency." The following excerpt taken from the audio "The Miracle Mangosteen" is available at http://www.mangosteentools.com.
[NOTE: Since making the above statement about Vioxx (Dexamethasone), that drug was pulled from the market as of September 30, 2004, due to its possible adverse side effects, see below.]
Just look at this list of possible adverse side effects from the above mentioned drug (Dexamethasone)!
- upset stomach
- stomach irritation
- vomiting
- headache
- dizziness
- insomnia
- restlessness
- depression
- anxiety
- acne
- increased hair growth
- easy bruising
- irregular or absent menstrual periods
If you experience any of the following symptoms when using prescriptions, call your doctor immediately:
- skin rash
- edema (swollen face, lower legs, or ankles)
- vision problems
- persistent cold or infection
- muscle weakness
- black or bloody stool
The Mangosteen has NONE of those side effects!
Do you realize what this means?
Inflammation plays a huge role in an incredible array of common ailments:
- Arthritis
- Back pain
- Heart attack
- Headache
- Multiple Sclerosis
- Circulatory Impairment
- any kind of infection
- and many more
While inflammation can affect all tissues in the body, it is the primary mechanism underpinning diseases which attack muscles, joints and connective tissue.
Inflammation is the PRIMARY cause of PAIN!
What are the qualities of an ideal health supplement?
- Effective, it works!
- Safe, no adverse side affects
- No contraindications with medications
- Prevention
- Has broad applications
Take a closer look and you will find that the mangosteen measures up in ALL categories.
How Safe is Mangosteen?
Toxicity studies were done in the laboratory with rats, using the human equivalent of 3 liters of mangosteen juice per day, with no adverse behavioral or tissue effects noted.
Also, there are no historical records of any folk medicine warnings after centuries of medicinal use of the plant in SouthEast Asia.
It is always recommended that you consult your physician, if you have a known medical condition or allergy before using any food supplement. Mangosteen is safe for use by children and adults under almost any condition.
Inflammation - The Secret Killer
“Hardly a week goes by without the publication of yet another study uncovering a new way that chronic inflammation does harm to the body.” - Time Magazine, Feb 2004
Inflammation has been linked to these and other diseases: Alzheimer’s, kidney disease, Parkinson’s, uterine cancer, allergies, respiratory disease, heart disease, hypoglycemia, breast cancer, high cholesterol, degenerative arthritis, colon cancer, rheumatoid arthritis, infection, Crohn’s disease, and osteoporosis.
“One study showed mangosteen was a more potent anti-inflammatory agent than several prescription anti-inflammatory medications currently used for arthritis.” - Dr. Sam Walters, Tame the Flame
Monday, Feb. 23, 2004
The Fires Within
By Christine Gorman and Alice Park
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."
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 C-reactive 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 COX-2—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
*
*
* Click to Print
*
* Find this article at:
* http://www.time.com/time/magazine/article/0,9171,590682,00.html
Inflammation has been linked to these and other diseases: Alzheimer’s, kidney disease, Parkinson’s, uterine cancer, allergies, respiratory disease, heart disease, hypoglycemia, breast cancer, high cholesterol, degenerative arthritis, colon cancer, rheumatoid arthritis, infection, Crohn’s disease, and osteoporosis.
“One study showed mangosteen was a more potent anti-inflammatory agent than several prescription anti-inflammatory medications currently used for arthritis.” - Dr. Sam Walters, Tame the Flame
Monday, Feb. 23, 2004
The Fires Within
By Christine Gorman and Alice Park
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."
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 C-reactive 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 COX-2—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
*
*
* Click to Print
*
* Find this article at:
* http://www.time.com/time/magazine/article/0,9171,590682,00.html
Friday, July 20, 2007
Why Do Healthy People Drink Mangosteen?
According to professional journals such as Free Radical Research, Journal of Pharmacology, and the Indian Journal of Experimental Biology, these Xanthones...are some of the most powerful antioxidants to be found in nature.
While it’s true that most young people are healthy -- and thankfully so -- no matter how old you are, you're being exposed to free radicals by the millions each day.
"It has been estimated that each human cell undergoes ten thousand hits from free radicals each day... causing damage to cell proteins, DNA, fat lipids, and membranes through oxidation. This results in the generation of dysfunctional molecules
responsible for conditions as diverse as cancers, lung disease, dementia, cardio vascular disease and eye diseases." ~ 'The Wellness Options', Lillian Chan
It’s far easier to address serious health challenges BEFORE they begin -- with prevention -- than after they've already taken hold in your body.
If Mangosteen and its Xanthones are making this much visible difference in people's lives (testimonials), then how many more INVISIBLE differences may be going on?
Wouldn't it make logical sense for a healthy person -- of any age -- to begin drinking Mangosteen right away, in order to give the strong antioxidants within the fruit a chance to help PRESERVE their healthy well-being as much as possible?
"...the stage is set...to enhance the likelihood of older persons not only to avoid disease and disability, but to truly age successfully."~ Dr. John Rove
PREVENTION -- Mangosteen can be a key!.
• The medical properties of the Mangosteen juice are well-documented by empirical, laboratory, scientific, medical, and experiential methods.
• The Mangosteen fruit is not system-specific, but pan-systemic -- in other words, good for the WHOLE body.
• Over 40 different Xanthones have been found in the Mangosteen, which are chemically beneficial molecules, each having specific leading properties.
• These health promoting Xanthones help the body in so many ways -- healthy foods help us age more successfully.
• These free radical scavenger/fighters stop pain, reduce swelling and inflammation, and help in the body's healing process.
• The "strong" antioxidants strengthen cell walls.
• They kill bacteria, viruses, and fungus.
• They stop the attack in DNA and even have restorative properties.
• They help the body run as a complete, interrelated and integrated system.
• They help the mind think better, adapt better, and give a sense of well-being (anti-depressant).
• They stop the damage of brain cells so they grow and divide properly and help the cell walls and the neuro transmitters function properly.
• They aid with Alzheimers, and all forms of memory loss.
• They help in the battle against degenerative diseases like cancer, heart disease, diabetes, arthritis, and all forms of brain malfunctions.
• They help the VISION process: cataracts, macular degeneration, glaucoma, and other forms of vision loss may be prevented.
"By controlling free radicals, antioxidants can make the difference between life
and death, as well as influence how fast and how well we age."~ 'The Antioxidant Miracle', Lester Packer, Ph.D.
ALSO Visit MangosteenMD.com
Dr. Templeman, author of "Mangosteen, The X Factor", has designed this site to support product-orientated distributors, customers, and health professionals.
While it’s true that most young people are healthy -- and thankfully so -- no matter how old you are, you're being exposed to free radicals by the millions each day.
"It has been estimated that each human cell undergoes ten thousand hits from free radicals each day... causing damage to cell proteins, DNA, fat lipids, and membranes through oxidation. This results in the generation of dysfunctional molecules
responsible for conditions as diverse as cancers, lung disease, dementia, cardio vascular disease and eye diseases." ~ 'The Wellness Options', Lillian Chan
It’s far easier to address serious health challenges BEFORE they begin -- with prevention -- than after they've already taken hold in your body.
If Mangosteen and its Xanthones are making this much visible difference in people's lives (testimonials), then how many more INVISIBLE differences may be going on?
Wouldn't it make logical sense for a healthy person -- of any age -- to begin drinking Mangosteen right away, in order to give the strong antioxidants within the fruit a chance to help PRESERVE their healthy well-being as much as possible?
"...the stage is set...to enhance the likelihood of older persons not only to avoid disease and disability, but to truly age successfully."~ Dr. John Rove
PREVENTION -- Mangosteen can be a key!.
• The medical properties of the Mangosteen juice are well-documented by empirical, laboratory, scientific, medical, and experiential methods.
• The Mangosteen fruit is not system-specific, but pan-systemic -- in other words, good for the WHOLE body.
• Over 40 different Xanthones have been found in the Mangosteen, which are chemically beneficial molecules, each having specific leading properties.
• These health promoting Xanthones help the body in so many ways -- healthy foods help us age more successfully.
• These free radical scavenger/fighters stop pain, reduce swelling and inflammation, and help in the body's healing process.
• The "strong" antioxidants strengthen cell walls.
• They kill bacteria, viruses, and fungus.
• They stop the attack in DNA and even have restorative properties.
• They help the body run as a complete, interrelated and integrated system.
• They help the mind think better, adapt better, and give a sense of well-being (anti-depressant).
• They stop the damage of brain cells so they grow and divide properly and help the cell walls and the neuro transmitters function properly.
• They aid with Alzheimers, and all forms of memory loss.
• They help in the battle against degenerative diseases like cancer, heart disease, diabetes, arthritis, and all forms of brain malfunctions.
• They help the VISION process: cataracts, macular degeneration, glaucoma, and other forms of vision loss may be prevented.
"By controlling free radicals, antioxidants can make the difference between life
and death, as well as influence how fast and how well we age."~ 'The Antioxidant Miracle', Lester Packer, Ph.D.
ALSO Visit MangosteenMD.com
Dr. Templeman, author of "Mangosteen, The X Factor", has designed this site to support product-orientated distributors, customers, and health professionals.
Wednesday, July 18, 2007
FIRST LINE THERAPY
From: J. Frederic Templeman, MD*
108,000 people died last year from prescriptions PROPERLY prescribed and dispensed.
The following list of health issues, once diagnosed, are being addressed with the Mangosteen as Dr. Templeman's first-line therapy:
GERD (gastro-esophageal reflux disease)
Hiatal hernia
Arthritis
Fibromyalgia
Fatigue
Mild depression
Mild to Moderate Asthma
Irritable bowel disease (diarrheal type)
Recurrent unirary tract infections in the elderly
Diverticulitis
Sleep disorders
Allergic rhinitis
Neurodermatitis
Eczema
Seborrhea
Muscle or joint pain without evidence of Arthritis
Medications which Mangosteen has replaced in Dr. Templeman’s practice:
Nexium, Prevacid, Aciphex, & other proton pump inhibitors.
Zantac, Pepcid, & other H2 blockers.
Allegra, Zyrtec, Claritin, Clarinex, & other antihistamines.
Singulair, Prednisone
Lotrisone, Topicort, Cutivate, Diprolene, & other topical Cortico Steroids used for skin conditions (Eczema, Psoriasis, Seborrhea)
Valium, Xanax, & other minor tranqulizers.
Tegretol, Neurontin, & other anti-epileptic drugs used (off label) for chronic pain relief.
Prozac, Zoloft, Paxil, Lexapro, & other antidepressants when used for Dysthymia & anxiety states.
Vicodin, Percocet, Duragesic patch, Methadone, & other narcotics used for chronic pain control.
Celebrex, Vioxx, Bextra, Naproxen, Arthrotec, Ibuprofin, & other anti-inflammatories used for Musculo-Skeletal pain & inflammation.
Control of Menstrual pain.
Ultram, Talwin, & other non-Opiod pain preparations.
Midrin, Fioricet, Imitrex, Amerge, Maxalt, Zomig, & other Seretonergil Migraine headache preparations.
Lipitor, Zolor, Pravacol, & other Lipid-lowering agents.
Valtrex, & other anti-herpetic agents.
Aricept, Cognex, & other Alzheimer’s preparations.
Anusol, & other Hemorrhoid preparations
Why Would You Use A Drug When A Food Is An Option???
Excerpted from the DVD Presentation: “Mangosteen, Xanthones & the Human Body with Dr. J. Frederic Templeman” available at www.MangosteenTools.com
108,000 people died last year from prescriptions PROPERLY prescribed and dispensed.
The following list of health issues, once diagnosed, are being addressed with the Mangosteen as Dr. Templeman's first-line therapy:
GERD (gastro-esophageal reflux disease)
Hiatal hernia
Arthritis
Fibromyalgia
Fatigue
Mild depression
Mild to Moderate Asthma
Irritable bowel disease (diarrheal type)
Recurrent unirary tract infections in the elderly
Diverticulitis
Sleep disorders
Allergic rhinitis
Neurodermatitis
Eczema
Seborrhea
Muscle or joint pain without evidence of Arthritis
Medications which Mangosteen has replaced in Dr. Templeman’s practice:
Nexium, Prevacid, Aciphex, & other proton pump inhibitors.
Zantac, Pepcid, & other H2 blockers.
Allegra, Zyrtec, Claritin, Clarinex, & other antihistamines.
Singulair, Prednisone
Lotrisone, Topicort, Cutivate, Diprolene, & other topical Cortico Steroids used for skin conditions (Eczema, Psoriasis, Seborrhea)
Valium, Xanax, & other minor tranqulizers.
Tegretol, Neurontin, & other anti-epileptic drugs used (off label) for chronic pain relief.
Prozac, Zoloft, Paxil, Lexapro, & other antidepressants when used for Dysthymia & anxiety states.
Vicodin, Percocet, Duragesic patch, Methadone, & other narcotics used for chronic pain control.
Celebrex, Vioxx, Bextra, Naproxen, Arthrotec, Ibuprofin, & other anti-inflammatories used for Musculo-Skeletal pain & inflammation.
Control of Menstrual pain.
Ultram, Talwin, & other non-Opiod pain preparations.
Midrin, Fioricet, Imitrex, Amerge, Maxalt, Zomig, & other Seretonergil Migraine headache preparations.
Lipitor, Zolor, Pravacol, & other Lipid-lowering agents.
Valtrex, & other anti-herpetic agents.
Aricept, Cognex, & other Alzheimer’s preparations.
Anusol, & other Hemorrhoid preparations
Why Would You Use A Drug When A Food Is An Option???
Excerpted from the DVD Presentation: “Mangosteen, Xanthones & the Human Body with Dr. J. Frederic Templeman” available at www.MangosteenTools.com
Saturday, July 14, 2007
Mangosteen and Inflammation
Mangosteen and Pain & Inflammation
1 out of 6 Americans suffering from pain
Chronic daily headaches 4 to 5 percent of the population
Migraines 28 to 30 million people suffer (70% are women)
Arthritis 41 million Americans Suffer *
Fibromyalgia 3 affects 3-- 6 million (80% are women) *
$8 Billion+ spent on over-the-counter pain relievers
$30 Billion + prescription pain relievers
*American College of Rheumatology (ACR)
“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.”TIME Feb 23rd, 2004
Independent Research From Across the World
Regarding Mangosteen’s impact on Inflammation.
Synthesis and anti-inflammatory effects of xanthone derivatives.
J Pharm Pharmacol. 1996 May;48(5):532-8. Lin CN, Chung MI, Liou SJ, Lee TH, Wang JP. School of Pharmacy, Kaohsiung Medical College, Taiwan, R.O.C.
The researchers studied 18 xanthone derived compounds and found that some of these compounds possessed strong anti-inflammatory properties.
Inhibition of cyclooxygenase and prostaglandin E2 synthesis by gamma-mangostin, a xanthone derivat ive in mangosteen, in C6 rat glioma cells.
Biochem Pharmacol. 2002 Jan 1;63(1):73-9. 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 fruit, 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, the investigators studied the effect of
gamma-mangostin, a xanthone contained in the mangosteen fruit, and showed it had a potent inhibitory activity of prostaglandin E2 (PGE2) release.
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. Mol Pharmacol. 2004 Sep;66(3):667-74.
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 reversetranscription 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. 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.
1 out of 6 Americans suffering from pain
Chronic daily headaches 4 to 5 percent of the population
Migraines 28 to 30 million people suffer (70% are women)
Arthritis 41 million Americans Suffer *
Fibromyalgia 3 affects 3-- 6 million (80% are women) *
$8 Billion+ spent on over-the-counter pain relievers
$30 Billion + prescription pain relievers
*American College of Rheumatology (ACR)
“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.”TIME Feb 23rd, 2004
Independent Research From Across the World
Regarding Mangosteen’s impact on Inflammation.
Synthesis and anti-inflammatory effects of xanthone derivatives.
J Pharm Pharmacol. 1996 May;48(5):532-8. Lin CN, Chung MI, Liou SJ, Lee TH, Wang JP. School of Pharmacy, Kaohsiung Medical College, Taiwan, R.O.C.
The researchers studied 18 xanthone derived compounds and found that some of these compounds possessed strong anti-inflammatory properties.
Inhibition of cyclooxygenase and prostaglandin E2 synthesis by gamma-mangostin, a xanthone derivat ive in mangosteen, in C6 rat glioma cells.
Biochem Pharmacol. 2002 Jan 1;63(1):73-9. 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 fruit, 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, the investigators studied the effect of
gamma-mangostin, a xanthone contained in the mangosteen fruit, and showed it had a potent inhibitory activity of prostaglandin E2 (PGE2) release.
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. Mol Pharmacol. 2004 Sep;66(3):667-74.
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 reversetranscription 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. 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.
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