New research continues to link tart cherries, one of today’s hottest “Super Fruits,” to lowering risk factors for heart disease. In addition to lowering cholesterol and reducing inflammation, the study being presented by University of Michigan researchers at next week’s American Dietetic Association annual meeting, found that a cherry-enriched diet lowered body weight and fat – major risk factors for heart disease.In the study, at-risk, obese rats that were fed a cherry-enriched diet saw significant decreases in body weight and fat (especially the important “belly” fat with known risk for heart disease) while maintaining lean muscle mass. After twelve weeks, the cherry-fed rats had 14 percent lower body fat compared to the other rats who did not consume cherries (cherry-fed rats were approximately 54% body fat; rats eating the Western diet alone were 63% body fat). The researchers suggested cherry consumption could have an effect on important fat genes and genetic expression. According to the American Heart Association, being overweight or obese, in particular when the weight is concentrated in the middle, is a major risk factor for heart disease . Nearly two out of three Americans are overweight.

The animals were fed a “Western diet,” characterized by high fat and moderate carbohydrate – in line with the typical American diet – with or without added whole tart cherry powder, as 1 percent of the diet. The study was funded by the Cherry Marketing Institute, which provided an unrestricted grant to the University of Michigan to conduct the research and was not directly involved in the design, conduct or analysis of the project.

“Heart disease is the number one killer of Americans today, so it’s important we continue researching ways people can improve their diet to help reduce key risk factors,” said study co-author Dr. Steven F. Bolling, a cardiac surgeon at the University of Michigan Cardiovascular Center who also heads the U-M Cardioprotection Research Laboratory, where the study was performed. “We know excess body fat increases the risk for heart disease. This research gives us one more support point suggesting that diet changes, such as including cherries, could potentially lower heart disease risk.”

Cherry-enriched diets in the study also reduced total cholesterol levels by about 11 percent and two known markers of inflammation – commonly produced by abdominal fat and linked to increased risk for heart disease. Inflammation marker TNF-alpha was reduced by 40 percent and interleukin 6 (IL-6) was lowered by 31 percent. In their genetic analysis, the researchers found that the cherry-enriched diets reduced the genes for these two inflammation compounds, suggesting a direct anti-inflammation effect. While inflammation is a normal process the body uses to fight off infection or injury, according to recent science, a chronic state of inflammation could increase the risk for diseases and may be especially common for those who are overweight or obese, at least in part because of excess weight around the middle. Researchers say the animal study is encouraging and will lead to further clinical studies in humans to explore the link between diet, weight, inflammation and lowering heart disease risk.

The Power of Eating Red

Tart cherries, frequently sold as dried, frozen or juice, contain powerful antioxidants known as anthocyanins, which provide the bright, rich red color. Studies suggest these colorful plant compounds may be responsible for cherries’ anti-inflammatory properties and other health benefits.

This new research is the latest linking this red hot “Super Fruit” to protection against heart disease and inflammation. In fact, research suggests the red compounds in cherries that deliver the anti-inflammatory benefits may also help ease the pain of arthritis and gout.

By killing off “angry” immune cells that take up residence in obese fat and muscle tissue, researchers have shown that they can rapidly reverse insulin resistance in obese mice.  The findings reported in the October Cell Metabolism, a publication of Cell Press, suggest that treatments aimed at specific subsets of the so-called macrophage cells might offer a very effective new antidiabetic therapy, according to the researchers.

” We used a genetic ‘trick’ that allowed us to rapidly kill these macrophages,” said Jerrold Olefsky of the University of California, San Diego.  “The treatment killed these cells within hours, and insulin resistance simply reversed itself.  It argues strongly that macrophages are causative for the inflammation that leads to diabetes [in those who are obese].”

” The most interesting thing is that this reversal occurs very rapidly,” added Jaap Neels of INSERM in France, who led the work while in Olefsky’s lab.  “Twenty-four hours later the animals’ insulin response had completely normalized.  They were still obese, but no longer insulin resistant.”

Of course, Neels said, the strategy used in the obese mice wouldn’t translate to the clinic directly.  It’s also unclear whether or not it is the same subtype of macrophage cells that invade fat tissue in people who are obese.  Nevertheless, the findings suggest that you would not necessarily need to target all macrophages to have a beneficial effect on the diseases associated with obesity.  That’s critical because “you don’t want to knock out the whole immune system.”

Over the past decade, it has become quite clear that obesity gives rise to a state of chronic, low-grade inflammation that contributes to insulin resistance and type 2 diabetes, the researchers explained.

Olefsky and Neels’ team along with others recently found that a specific subset of macrophages invades obese fat and muscle tissue.  Although little was known about them, those macrophages are defined by a CD11c marker expressed on their surfaces.  They also produce high levels of proinflammatory chemicals that are linked to the development of obesity-associated insulin resistance.

In the new study, the researchers tested the idea that killing those cells would reverse the inflammatory symptoms that come with obesity using a mouse model developed earlier in which the CD11c-expressing macrophages were artificially made susceptible to diphtheria toxin.

They found that treatment with the toxin not only reversed the animals’ resistance to insulin, but also led to a marked decline in inflammatory signs through the body.  The treated animals showed a decline in the CD11c macrophages in both fat and muscle, they confirmed.

” It shows that high triglycerides in muscle don’t necessarily have to lead to insulin resistance as it has been thought—as long as the high lipid levels aren’t accompanied by inflammation,” Neels said.

The obese mice also had less fat in their livers, an important find given the epidemic of obesity-associated fatty liver disease.

If a unique marker can be identified on the macrophages found in human fat tissue, a drug could be designed to take advantage of those features to bind and kill them, Neels said.  Alternatively, it may be possible to convert the macrophage cells into another, less inflammatory type.

An overload of calories throws critical portions of the brain out of whack, reveals a study in the October 3rd issue of the journal Cell, a Cell Press publication.  That response in the brain’s hypothalamus—the “headquarters” for maintaining energy balance—can happen even in the absence of any weight gain, according to the new studies in mice.

The brain response involves a molecular player, called IKKß/NF-?B, which is known to drive metabolic inflammation in other body tissues.  The discovery suggests that treatments designed to block this pathway in the brain might fight the ever-increasing spread of obesity and related diseases, including diabetes and heart disease.

“This pathway is usually present but inactive in the brain,” said Dongsheng Cai of the University of Wisconsin-Madison.  Cai said he isn’t sure exactly why IKKß/NF-?B is there and ready to spring into action in the brain.  He speculates it may have been an important element for innate immunity, the body’s first line of defense against pathogenic invaders, at some time in the distant past.

” In today’s society, this pathway is mobilized by a different environmental challenge—overnutrition,” he said.  Once activated, “the pathway leads to a number of dysfunctions, including resistance to insulin and leptin,” both important metabolic hormones.

Earlier studies showed that overnutrition can spark inflammatory responses in the peripheral metabolic tissues, including the muscles and liver, and therefore cause various metabolic defects in those tissues that underlie type 2 diabetes.  As a result, scientists identified IKKß as a target for an anti-inflammatory therapy that was effective against obesity-associated diabetes.

Yet whether metabolic inflammation and its mediators played a role in the central nervous system remained uncertain.  Now, the researchers show that a chronic high-fat diet doubles the activity of this inflammatory pathway in the brains of mice.  Its activity is also much higher in the brains of mice who are genetically predisposed to obesity, they found.

The researchers report that that increased activity of the IKKß/NF-?B pathway can be divorced from obesity itself -infusions of either glucose or fat into the brains of mice alone led to this inflammatory brain reaction.

Further studies revealed that this activity in the brain leads to insulin and leptin resistance.  Insulin lowers blood sugar by causing cells of the body to take it up from the bloodstream.  Leptin is a fat hormone important for appetite control.

Moreover, the researchers found that treatments preventing the activity of IKKß/NF-?B in the animals’ brains protected them from obesity.

While chronic inflammation is generally considered a consequence of obesity, the new results suggest the inflammatory reaction might also be a cause of the imbalance that leads to obesity and associated diseases, including diabetes.  As Cai says, it appears that inflammation and obesity are “quite intertwined.”  An abundance of calories itself promotes inflammation, while obesity also feeds back to the neurons to further promote inflammation in a kind of vicious cycle.

The findings could lead to treatments that might stop this cycle before it gets started.

“Our work marks an initial attempt to study whether inhibiting an innate immune pathway in the hypothalamus could help to calibrate the set point of nutritional balance and therefore aid in counteracting energy imbalance and diseases induced by overnutrition,” the researchers said.  “We recognize that the significance of this strategy has yet to be realized in clinical practice; currently, most anti-inflammatory therapies have limited direct effects on IKKß/NF-?B and limited capacity to be concentrated in the central nervous system.  Nonetheless, our discoveries offer potential for treating these serious diseases.”

If realized, such a strategy would likely offer a safe approach given that the critical pathway appears to be unnecessary in the hypothalamus under normal circumstances, they noted.

Antibodies are proteins that are a crucial component of the immune system.  They are produced in large amounts by immune cells known as plasma cells, which live in just a few parts of the body, including the bone marrow and special areas of the various parts of the body that are exposed to the outside (e.g., the gut, nose, and airways).  These areas are known as mucosa-associated lymphoid tissue (MALT) and include tissues such as the tonsils, but what regulates plasma cell survival in MALT has not been determined.  Now, however, Bertrand Huard and colleagues, at Geneva University Medical Center, Switzerland, have provided new insight into the molecular mechanisms controlling plasma cell survival in MALT.

In the study, analysis of tonsils and MALT from the lower gut indicated that a protein known as APRIL is important for promoting the survival of plasma cells in human MALT.  APRIL was found to work by increasing plasma cell expression of proteins that protect cells from a form of death known as apoptosis.  Expression of APRIL was shown to be greater in tonsils infected with a microbe than in noninfected tonsils and the cells producing the increased APRIL were identified as immune cells known as neutrophils that had been recruited to the site of infection.  APRIL from the neutrophils was retained in the tonsils bound to molecules known as heparan sulfate proteoglycans, creating an APRIL-rich niche for the plasma cells to survive in.  The authors therefore suggest that the longevity of plasma cells in MALT is controlled, in part, by APRIL-secreting neutrophils recruited to sites of infection.

Among the first cells of the immune system to respond to microorganisms that invade our body are neutrophils.  Although neutrophils are considered the “good guys” in such circumstances, they also contribute to the noninfectious chronic inflammation that underlies various diseases, including autoimmune diseases such as rheumatoid arthritis.  One mechanism by which neutrophils protect us is to internalize microorganisms and destroy them using proteins known as neutrophil serine proteases (NSPs), but whether NSPs have a role in noninfectious chronic inflammation has not been clearly determined.  However, using mice lacking two very similar NSPs, PR3 and NE, a team of researchers at the Max-Planck-Institute of Neurobiology, Germany, have now shown that these two NSPs have a crucial role in one form of noninfectious chronic inflammation.  Detailed analysis revealed that PR3 and NE destroy an anti-inflammatory molecule known as PGRN and in this way help to promote inflammation in the absence of invading microorganisms.  The authors therefore suggest that these data provide rationale for considering inhibitors of NSPs as anti-inflammatory drugs.

Researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the National Institutes of Health (NIH), have identified a promising new target for autoimmune disease treatment – a cell-surface receptor called DR3. Their research in mice, published on line in the journal Immunity, suggests that blocking this receptor could slow or stop the damaging inflammation characteristic of autoimmune diseases, potentially without leaving the body vulnerable to serious infections, as many current therapies do.

DR3 is a protein on the surface of cells. It is a member of the tumor necrosis factor (TNF) family of receptors, which bind to molecules related to TNF, a cell-signaling protein that promotes inflammation. Many of today’s most potent treatments for inflammatory diseases, such as rheumatoid arthritis and psoriasis, interfere with the action of TNF, thereby blocking inflammation. Since current anti-TNF therapies don’t work in all autoimmune diseases, however, the researchers turned to the study of DR3, which is a close relative of TNFR1, the main receptor for TNF.

Working with mouse models of asthma and multiple sclerosis, both immune system diseases, the researchers found that mice engineered to lack DR3 were resistant to those diseases. “The implication is that blocking DR3 in mice, and possibly in humans, is a potential therapy for these diseases and perhaps others in which the immune system goes awry,” said Richard Siegel, M.D., Ph.D., a scientist in the NIAMS’ Immunoregulation Group, who led the research effort.

While closely related to TNFR1, DR3 is expressed in T cells, a different kind of immune cell (a white blood cell that identifies and fights infection) than those that express TNFR1, Dr. Siegel said. The NIAMS group collaborated with a laboratory in Cardiff, Wales, which had generated genetically engineered mice deficient in DR3, as well as with a research group at the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), which has developed mouse models of disease with strong T cell components, such as asthma and multiple sclerosis. “These findings open up new avenues for therapy of these two diseases as well as to other autoimmune diseases in which T cells play a role in causing or perpetuating the disease,” said Siegel.

The researchers hope that DR3-blocking agents will be effective anti-inflammatory treatments someday. Siegel noted that if they were to be used in rheumatic diseases, they would be a complement to strategies that block TNF because they hit a different arm of the immune system. “It could be potentially synergistic or complementary,” he said.

Of critical importance, the NIAMS scientists found that removing DR3 did not appear to suppress the immune response or the ability to fight infection within the mice – a problem with many other treatments for autoimmune disease. “We could see the effect of DR3 deficiency in the diseased organ, but when we looked systemically at the immune response at other places in the mouse, it was barely affected,” said Dr. Siegel. The group’s findings suggest that DR3-blocking agents might be more effective at specifically treating autoimmune disease without breaking down the body’s defenses against infections, a long-sought goal of researchers in the field.

Oral ingestion of pomegranate extract reduces the production of chemicals that cause inflammation suggests a study published in BioMed Central’s open access Journal of Inflammation. The findings indicate that pomegranate extract may provide humans with relief of chronic inflammatory conditions.

The group from the Department of Medicine of Case Western Reserve University, Cleveland Ohio, led by Tariq Haqqi, showed that blood samples collected from rabbits fed pomegranate extract inhibited inflammation.

Pomegranate extract is already used as a treatment in alternative medicine for inflammatory conditions, such as arthritis. Although pomegranate extract has antioxidant and anti-inflammatory actions in experiments on isolated tissues, it is not known whether ingestion of it can produce the same anti-inflammatory effects in living systems, either because the active compounds are not absorbed from the gut or because the levels of these compounds in the blood are not high enough.

Pomegranate extract, the equivalent of 175mls of pomegranate juice, was given to rabbits orally. The levels of antioxidants were measured in blood samples obtained after drinking the pomegranate extract and compared to blood samples collected before ingestion of pomegranate extract.

Plasma collected from rabbits following ingestion of pomegranate extract contained significantly higher levels of antioxidants than samples collected before ingestion of pomegranate extract; the extract also significantly reduced the activity of proteins that cause inflammation, specifically cyclooxygenase-2. It also reduced the production of pro-inflammatory compounds produced by cells isolated from cartilage.

The results of this study indicate the beneficial effects of pomegranate extract when ingested. According to Haqqi “the use of dietary nutrients or drugs based on them as an adjunct in the treatment of chronic inflammatory conditions may benefit patients”. He adds that, “Current treatment with anti-inflammatory drugs can have serious side effects following long-term use. Further research is needed, however, especially on the absorption of orally ingested substances into the blood.”

Individuals who have health conditions associated with chronic inflammation are often at increased risk of developing cancer at the site of the chronic inflammation.  For example, individuals with inflammatory bowel disease and those who are chronically infected with the bacterium Helicobacter pylori are at increased risk of colon cancer and stomach cancer, respectively.  New insight into the mechanisms by which chronic inflammation can contribute to the development cancer has been generated in mice by Leona Samson and colleagues, at Massachusetts Institute of Technology, Boston.

Using mice lacking the protein Aag, which is involved in the repair of DNA damaged by inflammation-associated molecules known as reactive oxygen and nitrogen species (RONS), it was shown that Aag-mediated DNA repair limits cell damage in a mouse model of episodic inflammatory bowel disease and reduces the severity of the colon cancer that develops in the mice experiencing episodic bowel inflammation.  In addition, in a mouse model of Helicobacter pylori infection, Aag-deficient mice were found to exhibit more severe cell damage and the damaged area of the stomach resembled that observed prior to the development of stomach cancer.  The authors therefore conclude that repair of DNA damage caused by RONS seems to be important for protection against chronic inflammation–induced cancer.