Natural Chemical Found In Broccoli Helps Combat Skin Blistering Disease
Science Daily — Johns Hopkins scientists have found yet another reason why you should listen to your mother when she tells you to eat your vegetables. Sulforaphane, a chemical present at high levels in a precursor form in broccoli and related veggies (cauliflower, Brussels sprouts, etc.), helps prevent the severe blistering and skin breakage brought on by the rare and potentially fatal genetic disease epidermolysis bullosa simplex (EBS).
The researchers treated newborn mice with a severe form of EBS--so bad they all died within three days--with a topical solution containing sulforaphane and found marked improvement; after four days more than 85 percent of the treated mice were alive and blister-free. These findings appear online this week in Proceedings of the National Academy of Sciences.
The basis of EBS, notes study author Pierre Coulombe, Ph.D., professor of biological chemistry, lies in two specific genes that make proteins known as keratins. Normally, the keratins join together and form highly resilient fibers in the lower portion of skin, helping make it durable. If either keratin is defective, they don't mesh and the lower skin tissue becomes unusually fragile and gets damaged from the mildest mechanical stress -- leading to blistering pain, a higher risk of infection, and in the most severe cases, death.
"Humans have around 54 distinct keratins, many of which are similar in structure and function," says Coulombe. "We figured we might be able to exploit this similarity and dial up a replacement by triggering the activation of a suitable signaling pathway in skin." He predicted that sulforaphane might stimulate the formation of a surrogate skin-strengthening keratin to stand in for the defective one.
The desire to learn more about sulforaphane led Coulombe and his co-workers to Paul Talalay, M.D., professor of pharmacology who had previously identified sulforaphane as a cancer-preventive agent. "It turns out that treatment with low doses of sulforaphane triggers the expression of selected keratin genes in skin," says Coulombe. "So we began what evolved into a highly rewarding collaboration and found it does indeed work in a mouse model for EBS."
"This is the first suggestion that we may be able to treat this terrible disease," adds Talalay, a co-author of this study. "And we didn't need to invent a new drug; sulforaphane is naturally found in our diet."
The team will next test whether sulforaphane can stimulate the proper keratin protein in the appropriate subset of human skin cells -- a vital matter for any future medical hopes. Beyond that are issues of how effective a topical application would be on human skin, which is considerably thicker than mouse skin, as well as examining the long term effects of sulforaphane treatment.
"If we can clear these important hurdles, then sulforaphane can potentially be a tremendous therapeutic, with the added benefit of having anticancer properties," Coulombe says. "And when you consider that the only current option for EBS is wrapping gauze around trauma-prone areas to minimize breakage, and otherwise avoiding infection and making sure blisters heal properly, then even a mild success would be a significant benefit for these patients."
The research was funded by the National Institutes of Health, the March of Dimes Birth Defect Research Foundation, the American Institute for Cancer Research, and the Lewis B. and Dorothy Cullman Foundation.
Authors on the paper are Michelle L. Kerns, Daryle DePianto, Albena T. Dinkova-Kostova, Talalay and Coulombe, all of Hopkins.
Note: This story has been adapted from a news release issued by Johns Hopkins Medical Institutions.
http://www.sciencedaily.com/releases/2007/08/070820175429.htm
Johns Hopkins Medical Institutions
Compound in Broccoli Could Boost Immune System, Says Study
Science Daily — A compound found in broccoli and related vegetables may have more health-boosting tricks up its sleeves, according to a new study led by researchers at the University of California, Berkeley.
Veggie fans can already point to some cancer-fighting properties of 3,3'-diindolylmethane (DIM), a chemical produced from the compound indole-3-carbinol when Brassica vegetables such as broccoli, cabbage and kale are chewed and digested. Animal studies have shown that DIM can actually stop the growth of certain cancer cells.
This new study in mice, published online Monday, Aug. 20 in the Journal of Nutritional Biochemistry, shows that DIM may help boost the immune system as well.
"We provide clear evidence that DIM is effective in augmenting the immune response for the mice in the study, and we know that the immune system is important in defending the body against infections of many kinds and cancer," said Leonard Bjeldanes, UC Berkeley professor of toxicology and principal investigator of the study. "This finding bodes well for DIM as a protective agent against major human maladies."
Previous studies led by Bjeldanes and Gary Firestone, UC Berkeley professor of molecular and cell biology, have shown that DIM halts the division of breast cancer cells and inhibits testosterone, the male hormone needed for growth of prostate cancer cells.
In the new study, the researchers found increased blood levels of cytokines, proteins which help regulate the cells of the immune system, in mice that had been fed solutions containing doses of DIM at a concentration of 30 milligrams per kilogram. Specifically, DIM led to a jump in levels of four types of cytokines: interleukin 6, granulocyte colony-stimulating factor, interleukin 12 and interferon-gamma.
"As far as we know, this is the first report to show an immune stimulating effect for DIM," said study lead author Ling Xue, who was a Ph.D. student in Bjeldanes' lab at the time of the study and is now a post-doctoral researcher in molecular and cell biology at UC Berkeley.
In cell cultures, the researchers also found that, compared with a control sample, a 10 micromolar dose of DIM doubled the number of white blood cells, or lymphocytes, which help the body fight infections by killing or engulfing pathogens. (A large plateful of broccoli can yield a 5-10 micromolar dose of DIM.)
When DIM was combined with other agents known to induce the proliferation of lymphocytes, the effects were even greater than any one agent acting alone, with a three- to sixfold increase in the number of white blood cells in the culture.
"It is well-known that the immune system can seek out and destroy tumor cells, and even prevent tumor growth," said Xue. "An important type of T cell, called a T killer cell, can directly kill certain tumor cells, virally infected cells and sometimes parasites. This study provides strong evidence that could help explain how DIM blocks tumor growth in animals."
DIM was also able to induce higher levels of reactive oxygen species (ROS), substances which must be released by macrophages in order to kill some types of bacteria as well as tumor cells. The induction of ROS - three times that of a control culture - after DIM was added to the cell culture signaled the activation of macrophages, the researchers said.
"The effects of DIM were transient, with cytokine and lymphocyte levels going up and then down, which is what you'd expect with an immune response," said Bjeldanes. "Interestingly, to obtain the effects on the immune response, DIM must be given orally, not injected. It could be that the metabolism of the compound changes when it is injected instead of eaten."
To examine the anti-viral properties of DIM, the researchers infected mice with reoviruses, which live in the intestines but are not life-threatening. Mice that had been given oral doses of DIM were significantly more efficient in clearing the virus from their gut - as measured by the level of viruses excreted in their feces - than mice that had not been fed DIM.
"This means that DIM is augmenting the body's ability to defend itself by inhibiting the proliferation of the virus," said Bjeldanes. "Future studies will determine whether DIM has similar effects on pathogenic viruses and bacteria, including those that cause diarrhea."
The discovery of DIM's effects on the immune system helps bolster its reputation as a formidable cancer-fighter, the researchers said. "This study shows that there is a whole new universe of cancer regulation related to DIM," said Firestone, who also co-authored the new study. "There are virtually no other agents known that can both directly shut down the growth of cancer cells and enhance the function of the immune system at the same time."
Two co-authors of the study are from Michigan State University's Department of Food Science and Human Nutrition - James Pestka, professor of food science, and Maoxiang Li, a visiting research associate.
DIM is currently under investigation in government-funded clinical trials as a treatment for prostate and cervical cancer.
The University of California has filed patent applications on the use of DIM and its derivatives for immune modulation. Berkeley BioSciences, Inc., a company co-founded by Bjeldanes and Firestone, has licensed the related patent applications from the University of California and is researching and developing immune-enhancing nutritional supplements and therapeutics based on this discovery.
This study was supported by the Department of Defense's Army Breast Cancer Research Program, the National Institutes of Health and a Strategic Partnership Research Grant from the Michigan State University Foundation.
Note: This story has been adapted from a news release issued by University of California - Berkeley.
http://www.sciencedaily.com/releases/2007/08/070820175422.htm
University of California - Berkeley
Weight Loss: Early Sign of Dementia?
Researchers Say Weight Loss Could Be Warning Sign in Middle-Aged Women
By Jennifer Warner
WebMD Medical News
Reviewed by Louise Chang, MD
Aug. 20, 2007 -- Weight loss among middle-aged and older women may be an early warning sign of dementia.
Researchers found that middle-aged women who went on to develop dementia started losing weight up to 20 years before the disease was diagnosed and weighed about 12 pounds less than those without the disease by the time of diagnosis.
"One explanation for the weight loss is that, in the very early stages of dementia, people develop apathy, a loss of initiative, and also losses in the sense of smell," says researcher David Knopman, MD, of the Mayo Clinic in Rochester, Minn., in a news release. "When you can't smell your food, it won't have much taste, and you might be less inclined to eat it. And, apathy and loss of initiative may make women less likely to prepare nutritious meals and more likely to skip meals altogether."
Researchers say the results contradict previous studies that have suggested that obesity in middle age may raise the risk of dementia. Obesity is also associated with diabetes, hypertension, and heart disease, which are known risk factors for dementia.
Weight Loss May Signal Dementia
In the study, researchers reviewed the medical records for 30 or more years of people diagnosed with dementia in Rochester, Minn., from 1990 to 1994 and a group of healthy people matched for sex and age.
The results, published in Neurology, showed that there were no differences in weight between those diagnosed with dementia and the others 20 to 30 years before the memory-robbing disease was detected. But women with dementia weighed less than the healthy people 11 to 20 years before the disease emerged -- and those weight differences grew over time.
In fact, researchers found an increasing risk of dementia with decreasing weight in women for up to 10 years before dementia was diagnosed.
However, men who later developed dementia did not lose weight in the years prior to diagnosis, which researchers attribute to hormonal or social reasons.
"Middle-aged and elderly men are less likely to be preparing their own meals," Knopman says. "Their spouses or adult children were more likely making meals for them, which would lessen the effect of the apathy, loss of initiative, and loss of sense of smell."
SOURCES: Knopman, D. Neurology, August 21, 2007; vol 69: 739-746. News release, American Academy of Neurology.
Estrogen Tells Brain Where Fat Goes
Future 'Designer Estrogen' Might Prevent Menopause Weight Gain
By Daniel J. DeNoon
WebMD Medical News
Reviewed by Louise Chang, MD
Aug. 20, 2007 -- A woman's brain uses estrogen to balance food intake with energy output -- and to tell fat where to go.
That's why women not only gain weight after menopause, but also why the weight they gain goes to the wrong places, suggest Deborah J. Clegg, PhD, and colleagues at the University of Cincinnati.
Clegg and colleagues used recently developed "gene silencing" techniques to inactivate a set of switches in the brains of female rats. The switches are estrogen receptors, which normally respond to estrogen. Clegg and colleagues removed these receptors from a specific part of the brain that controls food intake, energy expenditure, and fat distribution.
What happened? The rats' bodies slowed down. They had less energy. And they began to gain weight, even though they weren't given any extra food.
Moreover, the rats put on belly fat -- fatty tissue around the abdominal organs -- the most dangerous kind of fat. It's linked to heart disease and diabetes.
"Women are protected from these negative consequences as long as they carry their weight in their hips and saddlebags," Clegg says in a news release. "But when they go through menopause and the body fat shifts to the abdomen, they have to start battling all of these medical complications."
Clegg's hope is that her studies will lead to the development of "designer estrogen therapies" that would target these brain regions and reduce a menopausal woman's tendency to gain weight.
Clegg reported the findings at the 234th national meeting of the American Chemical Society.
SOURCES: 234th national meeting of the American Chemical Society, Boston, Aug. 19-23, 2007. News release, American Chemical Society.
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