20731MAY2015
CNO Report 207
Release Date 29 MAY 2015
Draft Report Compiled by
Ralph Turchiano
In this issue:
1. Penn research points to omega-3 as an intervention for childhood behavioral problems
2. In study, skipping meals is linked to abdominal weight gain
3. Scientists figure out how vitamin E keeps muscles healthy
4. Omega-3 fatty acids enhance cognitive flexibility in at-risk older adults
5. Natural plant chemicals could help fight tooth decay, study shows
6. Caffeine intake associated with reduced levels of erectile dysfunction
7. Drinking chamomile decreases risk of death in older Mexican American women
8. Snacking on protein can improve appetite control and diet quality in teens
9. Thunder god vine used in traditional Chinese medicine is a potential obesity treatment
10. Drug treatment to prevent hip fracture is neither viable nor cost effective
11. Therapy-resistant breast cancer mechanism revealed
12. ASCO: Component in green tea may help reduce prostate cancer in men at high risk
Public Release: 15-May-2015
Penn research points to omega-3 as an intervention for childhood behavioral problems
University of Pennsylvania
At the forefront of a field known as “neurocriminology,” Adrian Raine of the University of Pennsylvania has long studied the interplay between biology and environment when it comes to antisocial and criminal behavior. With strong physiological evidence that disruption to the emotion-regulating parts of the brain can manifest in violent outbursts, impulsive decision-making and other behavioral traits associated with crime, much of Raine’s research involves looking at biological interventions that can potentially ward off these behavioral outcomes.
A new study by Raine now suggests that omega-3, a fatty acid commonly found in fish oil, may have long-term neurodevelopmental effects that ultimately reduce antisocial and aggressive behavior problems in children.
He is a Penn Integrates Knowledge Professor with appointments in the School of Arts & Sciences and the Perelman School of Medicine.
Along with Raine, the study featured Jill Portnoy a graduate student in the Department of Criminology, and Jianghong Liu, an associate professor in the Penn School of Nursing. They collaborated with Tashneem Mahoomed of Mauritius’ Joint Child Health Project and Joseph Hibbeln of the National Institute on Alcohol Abuse and Alcoholism.
It was published in the Journal of Child Psychology and Psychiatry.
When Raine was a graduate student, he, his advisor and colleagues conducted a longitudinal study of children in the small island nation of Mauritius. The researchers tracked the development of children who had participated in an enrichment program as 3-year-olds and also the development of children who had not participated. This enrichment program had additional cognitive stimulation, physical exercise and nutritional enrichment. At 11 years, the participants showed a marked improvement in brain function as measured by EEG, as compared to the non participants. At 23, they showed a 34 percent reduction in criminal behavior.
Raine and his colleagues were interested in teasing apart the mechanisms behind this improvement. Other studies suggested the nutritional component was worth a closer look.
“We saw children who had poor nutritional status at age 3 were more antisocial and aggressive at 8, 11 and 17,” Raine said. “That made us look back at the intervention and see what stood out about the nutritional component. Part of the enrichment was that the children receiving an extra two and a half portions of fish a week.”
Other research at the time was beginning to show that omega-3 is critical to brain development and function.
“Omega-3 regulates neurotransmitters, enhances the life of a neuron and increases dendritic branching, but our bodies do not produce it. We can only get it from the environment,” Raine said.
Research on the neuroanatomy of violent criminals suggested this might be a place to intervene. Other brain-imaging researchers have shown that omega-3 supplementation increases the function of the dorsolateral prefrontal cortex, a region Raine found to have higher rates of damage or dysfunction in criminal offenders.
Raine’s new study featured a randomized controlled trial where children would receive regular omega-3 supplements in the form of a juice drink. One hundred children, aged 8 to 16, would each receive a drink containing a gram of omega-3 once a day for six months, matched with 100 children who received the same drink without the supplement. The children and parents in both groups took a series of personality assessments and questionnaires at the start.
After six months, the researchers administered a simple blood test to see if the children in the experimental group had higher levels of omega-3 than those in the controls. They also had both parents and children take the personality assessments. Six months after that, the researchers had parents and children take the assessment again to see if there were any lasting effects from the supplements.
The assessments had parents rate their children on “externalizing” aggressive and antisocial behavior, such as getting into fights or lying, as well as “internalizing” behavior, such as depression, anxiety and withdrawal. Children were also asked to rate themselves on these traits.
While the children’s self-reports remained flat for both groups, the average rate of antisocial and aggressive behavior as described by the parents dropped in both groups by the six-month point. Critically, however, those rates returned to the baseline for the control group but remained lowered in the experimental group, at the 12-month point.
“Compared to the baseline at zero months,” Raine said, “both groups show improvement in both the externalizing and internalizing behavior problems after six months. That’s the placebo effect.
“But what was particularly interesting was what was happening at 12 months. The control group returned to the baseline while the omega-3 group continued to go down. In the end, we saw a 42 percent reduction in scores on externalizing behavior and 62 percent reduction in internalizing behavior.”
At both the six- and 12-month check-ins, parents also answered questionnaires about their own behavioral traits. Surprisingly, parents also showed an improvement in their antisocial and aggressive behavior. This could be explained by the parents taking some of their child’s supplement, or simply because of a positive response to their child’s own behavioral improvement.
The researchers caution that this is still preliminary work in uncovering the role nutrition plays in the link between brain development and antisocial behavior. The changes seen in the one-year period of the experiment may not last, and the results may not be generalizable outside the unique context of Mauritius.
Beyond these caveats, however, there is reason to further examine omega-3’s role as a potential early intervention for antisocial behavior.
“As a protective factor for reducing behavior problems in children,” Liu said, “nutrition is a promising option; it is relatively inexpensive and can be easy to manage.”
Follow-up studies will include longer-term surveillance of children’s behavioral traits and will investigate why their self-reports did not match the parental reports.
Public Release: 19-May-2015
In study, skipping meals is linked to abdominal weight gain
Research in animals shows spikes, drops in insulin affect liver
Ohio State University
COLUMBUS, Ohio – A new study in animals suggests that skipping meals sets off a series of metabolic miscues that can result in abdominal weight gain.
In the study, mice that ate all of their food as a single meal and fasted the rest of the day developed insulin resistance in their livers – which scientists consider a telltale sign of prediabetes. When the liver doesn’t respond to insulin signals telling it to stop producing glucose, that extra sugar in the blood is stored as fat.
These mice initially were put on a restricted diet and lost weight compared to controls that had unlimited access to food. The restricted-diet mice regained weight as calories were added back into their diets and nearly caught up to controls by the study’s end.
But fat around their middles – the equivalent to human belly fat – weighed more in the restricted-diet mice than in mice that were free to nibble all day long. An excess of that kind of fat is associated with insulin resistance and risk for type 2 diabetes and heart disease.
“This does support the notion that small meals throughout the day can be helpful for weight loss, though that may not be practical for many people,” said Martha Belury, professor of human nutrition at The Ohio State University and senior author of the study. “But you definitely don’t want to skip meals to save calories because it sets your body up for larger fluctuations in insulin and glucose and could be setting you up for more fat gain instead of fat loss.”
The research is published online in the Journal of Nutritional Biochemistry.
Belury and colleagues were able to tie these findings to the human tendency to skip meals because of the behavior they expected to see – based on previous work – in the mice on restricted diets. For three days, these mice received half of the calories that were consumed daily by control mice. Food was gradually added so that by day six, all mice received the same amount of food each day.
But the mice that had been on restricted diets developed gorging behavior that persisted throughout the study, meaning they finished their day’s worth of food in about four hours and then ended up fasting for the next 20 hours.
“With the mice, this is basically bingeing and then fasting,” Belury said. “People don’t necessarily do that over a 24-hour period, but some people do eat just one large meal a day.”
The gorging and fasting in these mice affected a host of metabolic measures that the researchers attributed to a spike and then severe drop in insulin production. In mice that gorged and then fasted, the researchers saw elevations in inflammation, higher activation of genes that promote storage of fatty molecules and plumper fat cells – especially in the abdominal area – compared to the mice that nibbled all day.
To check for insulin resistance, the scientists used a sophisticated technique to assess glucose production. The liver pumps out glucose when it receives signals that insulin levels are low – for example, while people sleep, the liver supplies glucose to the brain. But that production stops after a meal, when insulin is released by the pancreas and performs its main task of removing sugar from the blood and shepherding the glucose to multiple types of cells that absorb it for energy.
With this research technique, Belury and colleagues found that glucose lingered in the blood of mice that gorged and fasted – meaning the liver wasn’t getting the insulin message.
“Under conditions when the liver is not stimulated by insulin, increased glucose output from the liver means the liver isn’t responding to signals telling it to shut down glucose production,” Belury said. “These mice don’t have type 2 diabetes yet, but they’re not responding to insulin anymore and that state of insulin resistance is referred to as prediabetes.”
Insulin resistance is also a risk for gaining abdominal fat known as white adipose tissue, which stores energy.
“Even though the gorging and fasting mice had about the same body weights as control mice, their adipose depots were heavier. If you’re pumping out more sugar into the blood, adipose is happy to pick up glucose and store it. That makes for a happy fat cell – but it’s not the one you want to have. We want to shrink these cells to reduce fat tissue,” Belury said.
Public Release: 19-May-2015
Scientists figure out how vitamin E keeps muscles healthy
Medical College of Georgia at Georgia Regents University
AUGUSTA, Ga. — Body builders have it right: vitamin E does help build strong muscles, and scientists appear to have figured out one important way it does it.
Vitamin E has long known as a powerful antioxidant, and now scientists have shown that without it, the plasma membrane, which essentially keeps a cell from spilling its contents and controls what moves in and out, cannot properly heal.
That’s a big problem for many cells, such as muscle cells, which get membrane tears just from being used.
“Every cell in your body has a plasma membrane, and every membrane can be torn,” said Dr. Paul L. McNeil, cell biologist at the Medical College of Georgia at Georgia Regents University and corresponding author of the study in the journal Free Radical Biology and Medicine.
The scientist suspects knowing the cell membrane repair action of vitamin E has implications for muscular dystrophy, and common diabetes-related muscle weakness, as well as traumatic brain injury, resulting from collisions on a football field, battlefield, or roadway. With a traumatic brain injury, for example, one of the first events that happens is that the plasma membrane of the neurons, key cells in the central nervous system, tear.
“Part of how we build muscle is a more natural tearing and repair process — that is the no pain, no gain portion — but if that repair doesn’t occur, what you get is muscle cell death. If that occurs over a long period of time, what you get is muscle-wasting disease,” said McNeil.
The association between vitamin E and healthy muscles is well-established; for example, mammals and birds deprived of the vitamin experience muscle-wasting disease, in some cases lethal disease. A poor diet resulting in low vitamin E levels in the elderly contributes to frailty syndrome, a condition where muscles are weak and people are unsteady on their feet. The ubiquitous vitamin’s well-established role as a powerful antioxidant has led to its use in antiaging products and in helping delay the onset of Alzheimer’s by protecting neurons from free radicals.
Exactly how vitamin E protects muscle, as well as other cell types, has been unknown.
“This means, for the first time, 83 years after its initial discovery, we know what the cellular function of vitamin E is, and knowing that cellular function, we can now ask whether we can apply that knowledge to medically relevant areas,” McNeil said.
For the new study, rats were fed either normal rodent chow, chow where vitamin E had been removed, or vitamin E-deficient chow where the vitamin was supplemented. First, there was a period of training to ascertain the rats’ innate ability to run downhill on a treadmill — a challenging move for muscles, called an eccentric contraction. The exercise helps lengthen muscles and can produce the most soreness in athletes because of the high mechanical stress as the muscle contracts and lengthens simultaneously. Gravity is an additional force.
They found vitamin E-deficient rats were generally deficient in their running ability compared with controls and made significantly more visits to a grid, despite the fact that they received a mild electric shock when they stood there. The scientists also administered a dye that could not permeate an intact plasma membrane and found it easily penetrated the muscle cells of vitamin E-deficient rats. McNeil notes that a healthy cell makes a patch within a minute and has completely restored the cell membrane within a few minutes. Later examination of the quadriceps muscle fibers under a microscope showed rats fed normal chow or chow where vitamin E had been restored were essentially the same. The large thigh muscle fibers in rats fed vitamin E-deficient chow were smaller and inflamed.
While exactly how free radicals, or reactive oxygen species, interfere with important cell membrane repair remains a mostly unanswered question, McNeil suspects they basically get in the way. Free radicals are essentially waste products produced by normal body functions, such as using oxygen, as well as exposures to cigarette smoke and other air pollutants and chemicals. Because it’s lipid-soluble, vitamin E can actually insert itself into the membrane to prevent free radicals from attacking. It also can help keep phospholipids, a major membrane component, compliant so they can better repair after a tear. For example, exercise causes the muscle cell powerhouse, the mitochondria, to burn a lot more oxygen than normal and so produce more free radicals while the physical force tears the membrane. Vitamin E enables adequate plasma membrane repair despite the oxidant challenge, helping keep the situation in check. McNeil’s finding that vitamin E is essential to rapid cell membrane repair, and ultimately cell survival, likely holds up across different cell types because, in culture at least, when the scientists have treated a number of different cells types with vitamin E, they documented similar enhanced cell membrane repair.
“The major medical significance here is yet to be uncovered,” McNeil said, but could one day mean not just supplements to aid sluggish membrane repair in diseases such as muscular dystrophy, but preventive therapy for high-risk individuals such as astronauts or soldiers.
McNeil’s 2011 study in Nature Communications indicated that, at least in cell culture, one way vitamin E keeps muscles healthy is by enabling cell membrane repair. Those studies linked the antioxidant and membrane repair benefits of vitamin E. Muscle cells in culture repaired better when vitamin E was added; when cells were exposed to free radicals, repair failed. Those findings led McNeil to see if the findings held up in research rats. Still earlier work showed that muscle cells were more fragile and membrane tears more common in muscular dystrophy. Good sources of vitamin E include vegetable oils; nuts; seeds such as sunflower seeds; green leafy vegetables; and fortified breakfast cereals, fruit juices, and margarine, according to the National Institutes of Health.
Public Release: 19-May-2015
Omega-3 fatty acids enhance cognitive flexibility in at-risk older adults
University of Illinois at Urbana-Champaign
CHAMPAIGN, Ill. — A study of older adults at risk of late-onset Alzheimer’s disease found that those who consumed more omega-3 fatty acids did better than their peers on tests of cognitive flexibility — the ability to efficiently switch between tasks — and had a bigger anterior cingulate cortex, a brain region known to contribute to cognitive flexibility.
The analysis suggests, but does not prove, that consuming DHA and EPA, two omega-3 fatty acids found in fish, enhanced cognitive flexibility in these adults in part by beefing up the anterior cingulate cortex, the researchers report in the journal Frontiers in Aging Neuroscience.
“Recent research suggests that there is a critical link between nutritional deficiencies and the incidence of both cognitive impairment and degenerative neurological disorders, such as Alzheimer’s disease,” said University of Illinois neuroscience, psychology, and speech and hearing science professor Aron Barbey, who led the study with M.D./Ph.D. student Marta Zamroziewicz. “Our findings add to the evidence that optimal nutrition helps preserve cognitive function, slow the progression of aging and reduce the incidence of debilitating diseases in healthy aging populations.”
The researchers focused on aspects of brain function that are sometimes overlooked in research on aging, Zamroziewicz said. “A lot of work in cognitive aging focuses on memory, but in fact cognitive flexibility and other executive functions have been shown to better predict daily functioning than memory does,” she said.
“Executive function” describes processes like planning, reasoning, paying attention, problem solving, impulse control and task switching.
“These functions tend to decline earlier than other cognitive functions in aging,” Zamroziewicz said.
The new research built on previous studies that found associations between omega-3 fatty acid consumption, cognitive flexibility and the size of the anterior cingulate cortex.
“There’s been some work to show that omega-3 fatty acids benefit cognitive flexibility, and there’s also been work showing that cognitive flexibility is linked to this specific brain region, the anterior cingulate. But there’s been very little work actually connecting these pieces,” Zamroziewicz said.
The new study focused on 40 cognitively healthy older adults between the ages of 65 and 75 who are carriers of a gene variant (APOE e4) that is known to contribute to the risk of developing late-onset Alzheimer’s disease.
The researchers tested participants’ cognitive flexibility, measured levels of the fatty acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) in their blood, and imaged their brains using MRI. Statistical analyses teased out the relationships between these factors.
“We wanted to confirm that higher omega-3 fatty acids related to better cognitive flexibility, and we did in fact see that,” Zamroziewicz said. “We also wanted to confirm that higher omega-3 fatty acids related to higher volume in the anterior cingulate cortex, and we saw that. Finally, we were able to show that higher volume in the anterior cingulate cortex was an intermediary in the relationship between omega-3 fatty acids and cognitive flexibility.”
Public Release: 20-May-2015
Natural plant chemicals could help fight tooth decay, study shows
University of Edinburgh
Oral care products containing a natural chemical that stops bacteria harming teeth could help prevent decay, a study suggests.
The plant natural product acts against harmful mouth bacteria and could improve oral health by helping to prevent the build-up of plaque, researchers say.
The compound – known as trans-chalcone – is related to chemicals found in liquorice root. The study shows that it blocks the action of a key enzyme that allows the bacteria to thrive in oral cavities.
The bacteria – Streptococcus mutans – metabolise sugars from food and drink, which produces a mild acid and leads to the formation of plaque. Without good dental hygiene, the combination of plaque and mouth acid can lead to tooth decay.
Researchers found that blocking the activity of the enzyme prevents bacteria forming a protective biological layer – known as a biofilm – around themselves. Plaque is formed when bacteria attach themselves to teeth and construct biofilms. Preventing the assembly of these protective layers would help stop bacteria forming plaque, the teams says.
Oral care products that contain similar natural compounds could help people improve their dental hygiene, researchers say.
The study, led by scientists at the University of Edinburgh, is the first to show how trans-chalcone prevents bacteria forming biofilms.
The team worked out the 3D structure of the enzyme – called Sortase A – which allows the bacteria to make biofilms. By doing this, researchers were able to identify how trans-chalcone prevents the enzyme from functioning.
The study, published in the journal Chemical Communications, was supported by Wm. Wrigley Jr. Company and the University of Edinburgh.
Dr Dominic Campopiano, of the University of Edinburgh’s School of Chemistry, who led the study, said: “We were delighted to observe that trans-chalcone inhibited Sortase A in a test tube and stopped Streptococcus mutans biofilm formation. We are expanding our study to include similar natural products and investigate if they can be incorporated into consumer products. This exciting discovery highlights the potential of this class of natural products in food and healthcare technologies.”
Public Release: 20-May-2015
Caffeine intake associated with reduced levels of erectile dysfunction
University of Texas Health Science Center at Houston
HOUSTON – (May 20, 2015) – Men who drink the equivalent caffeine level of two to three cups of coffee a day are less likely to have erectile dysfunction (ED), according to researchers from The University of Texas Health Science Center at Houston (UTHealth).
The results of a study published recently in PLOS ONE found that men who consumed between 85 and 170 milligrams of caffeine a day were 42 percent less likely to report ED, while those who drank between 171 and 303 milligrams of caffeine a day were 39 percent less likely to report ED compared to those who drank zero to seven milligrams a day. This trend was also true among overweight, obese and hypertensive men.
“Even though we saw a reduction in the prevalence of ED with men who were obese, overweight and hypertensive, that was not true of men with diabetes. Diabetes is one of the strongest risk factors for ED, so this was not surprising,” said David S. Lopez, Dr.P.H., M.P.H., lead author and assistant professor at UTHealth School of Public Health.
According to the journal article, the suggested biological mechanism is that caffeine triggers a series of pharmacological effects that lead to the relaxation of the penile helicine arteries and the cavernous smooth muscle that lines cavernosal spaces, thus increasing penile blood flow.
In the United States, 18.4 percent of men 20 years and older have ED, suggesting that more than 18 million men are affected. Caffeine is consumed by more than 85 percent of adults, according to previous research.
Data for the study came from the National Health and Nutrition Examination Survey and ED was assessed by a single question during a computer-assisted interview. Caffeine sources in the study included coffee, tea, soda and sports drinks.
Public Release: 20-May-2015
Drinking chamomile decreases risk of death in older Mexican American women
University of Texas Medical Branch at Galveston
Researchers from The University of Texas Medical Branch at Galveston have found that drinking chamomile tea was associated with a decreased risk of death from all causes in Mexican-American American women over 65. The findings were recently published online in The Gerontologist.
Chamomile is one of the oldest, most-widely used and well-documented medicinal plants in the world and has been recommended for a variety of healing applications. It is currently widely used as an herbal remedy in Mexico and among Mexican-Americans.
The study examined a seven-year period during which researchers tracked the effects of chamomile and the cause of death in older Mexican- Americans. The researchers analyzed data from 1,677 women and men from the Hispanic Established Populations for Epidemiologic Study of the Elderly, a population-based study of Mexican-Americans aged 65 and older from five Southwestern states, including Texas. Fourteen percent of the people in the study drank chamomile tea.
The data showed that consuming chamomile was associated with a 29 percent decreased risk of death from all causes among women compared with nonusers, even after adjusting for demographics, health conditions and health behaviors. This effect was not present in men.
“The reason for a difference in our reported findings between Hispanic women and men is not clear, although women were shown to be more frequent users of chamomile than men,” said Bret Howrey, assistant professor in the UTMB department of family medicine. “This difference may be due to traditional gender roles whereby women manage the day-to-day activities of the household, including family health, and may also reflect greater reliance on folk remedies such as herbs.”
It is unclear how chamomile use is associated with decreased mortality. Recent studies of chamomile have shown potential benefits in treating hyperglycemia, upset stomach, diabetic complications and anxiety disorder. Chamomile has also been touted for its cholesterol-lowering, antioxidant, antimicrobial, anti-inflammatory and anti-platelet effects. The exact pathway for the reduction in mortality represents an important area for future research.
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Other authors include UTMB’s M. Kristen Peek, Juliet McKee, Mukaila Raji, Kenneth Ottenbacher and Kyriakos Markides.
This research was supported by the National Institutes of Health.
Public Release: 21-May-2015
Snacking on protein can improve appetite control and diet quality in teens
Soy-protein snacks promote feelings of fullness and reduce unhealthy eating habits in young people
University of Missouri-Columbia
COLUMBIA, Mo. — Although eating high-protein, afternoon snacks can aid appetite control in adults, little information exists to guide parents on what types of snacks might benefit their adolescent children. Now, MU researchers have found that afternoon snacking, particularly on high-protein-soy foods, reduces afternoon appetite, delays subsequent eating and reduces unhealthy evening snacking in teenagers.
“Our research showed that eating high-protein snacks in the afternoon helps teens improve the quality of their diets as well as control appetite,” said Heather Leidy, an assistant professor of nutrition and exercise physiology at MU. “Standard meals tend to go to the wayside for kids this age — particularly from mid-afternoon to late evening — and many of the convenient ‘grab-and-go’ snacks are high in fat and sugar. When kids eat high-protein snacks in the afternoon, they are less likely to eat unhealthy snacks later in the day, which is particularly important for kids who want to prevent unhealthy weight gain.”
Male and female adolescents between the ages of 13 and 19 who were classified as either normal weight or overweight participated in the study, which was led by Leidy in collaboration with colleagues at DuPont Nutrition & Health. The researchers assessed how snacking in the afternoon affected teens’ appetite, drive to eat and food choices later in the day and whether these were different when teens skipped eating snacks altogether. The researchers also measured how afternoon snacking affected teens’ cognitive performance and mood.
“In addition to the appetite and satiety benefits, we found that when the teens ate the high-protein snacks, they incorporated more protein throughout the day and consumed less dietary fat,” Leidy said. “Thus, adding protein snacks in the afternoon could be a good strategy for individuals who are trying to eat more protein throughout the day. In addition, we also found that the high-protein snacks improved certain aspects of mood and cognitive function.”
The afternoon protein snacks were soy-protein pudding. Leidy said that although high-protein puddings with soy are not available to the public, similar high-quality protein sources should elicit similar benefits.
“Health professionals increasingly are recommending that people eat more high-protein, plant-based foods like soy, which are high quality and tend to be inexpensive and environmentally friendly,” Leidy said. “Our study demonstrated that the positive effects on appetite and satiety can be extended to consuming soy-protein products.”
Public Release: 21-May-2015
Thunder god vine used in traditional Chinese medicine is a potential obesity treatment
Cell Press
An extract from the thunder god vine, which has a long history of use in traditional Chinese medicine, reduces food intake and causes up to a 45% decrease in body weight in obese mice. The weight-loss compound, called Celastrol, produces its potent effects by enhancing the action of an appetite-suppressing hormone called leptin. The findings, published May 21 in Cell, are an early indicator that Celastrol could be developed into a drug for the treatment of obesity.
“During the last two decades, there has been an enormous amount of effort to treat obesity by breaking down leptin resistance, but these efforts have failed,” says senior study author Umut Ozcan, an endocrinologist atBoston Children’s Hospital and Harvard Medical School. “The message from this study is that there is still hope for making leptin work, and there is still hope for treating obesity. If Celastrol works in humans as it does in mice, it could be a powerful way to treat obesity and improve the health of many patients suffering from obesity and associated complications, such as heart disease, fatty liver, and type 2 diabetes.”
Leptin is a fat-cell-derived hormone that signals to the brain when the body has enough fuel and energy. Humans and mice that lack leptin signaling eat voraciously and become morbidly obese, suggesting that leptin-enhancing drugs may be effective for treating obesity. But leptin does not reduce hunger or food intake in obese individuals despite high levels of the hormone in the bloodstream, leading many researchers to speculate that leptin insensitivity is the root cause of obesity. Despite longstanding research efforts, drugs that can effectively alleviate leptin resistance have not yet been found. However, one potential clue to this problem came several years ago when Ozcan and his team discovered that leptin resistance is associated with a stress response in a cell structure called the endoplasmic reticulum (ER).
In the new study, Ozcan and his team screened an existing database containing whole-genome gene expression profiles from human cells that were treated with more than one thousand small molecules. They found that Celastrol was the most effective at producing an expression profile that could be associated with improved ER function and leptin sensitivity in human cells. Within only one week of Celastrol treatment, obese mice reduced their food intake by about 80% compared to untreated obese mice. By the end of the third week, treated mice lost 45% of their initial body weight almost entirely by burning fat stores.
This dramatic weight loss is greater than that produced by bariatric surgery — an operation on the stomach and/or intestines that helps patients with extreme obesity to lose weight. Moreover, Celastrol decreased cholesterol levels and improved liver function and glucose metabolism, which collectively may translate into a lower risk of heart disease, fatty liver, and type 2 diabetes.
Even though Celastrol did not produce toxic effects in mice, Ozcan strongly urges caution for now because in-depth toxicology studies and controlled clinical trials are needed to demonstrate the compound’s safety in humans. “Celastrol is found in the roots of the thunder god vine in small amounts, but the plant’s roots and flowers have many other compounds,” he says. “As a result, it could be dangerous for humans to consume thunder god vine extracts to lose weight.”
In future studies, Ozcan and his team will investigate the molecular mechanisms by which Celastrol improves leptin sensitivity and produces weight loss. “We have been heavily focusing on this line of research in my laboratory and hope that this approach will help us to understand the mechanisms in nature that are leading to the development of obesity,” Ozcan says. “In the end, my main goal is to see this research leading to a novel and powerful treatment for obesity in humans.”
Public Release: 26-May-2015
Drug treatment to prevent hip fracture is neither viable nor cost effective
Current strategy is inefficient and associated with considerable harms, say experts
BMJ
Professor Teppo Järvinen and colleagues say drug treatment “can achieve at best a marginal reduction in hip fractures at the cost of unnecessary harms and considerable waste of monetary resources.” The article is part of The BMJ‘s Too Much Medicine campaign — to highlight the threat to human health and the waste of resources caused by unnecessary care.
Worldwide, about 1.5 million hip fractures occur each year. They impose an enormous burden on healthcare resources and, with a growing elderly population, their incidence is predicted to rise.
Before the late 1980’s, osteoporosis was diagnosed after a bone fracture. But in 1994, a new definition – based on low bone mineral density – was introduced to identify people at increased fracture risk who were likely to benefit from bone building drugs.
Fracture risk calculators now classify 72% of US white women aged over 65 years and 93% of those aged over 75 years as candidates for long term drug treatment. Yet rates of hip fracture have fallen steadily in most Western countries, regardless of access to drugs, say the authors.
Most hip fractures, they say, have little to do with osteoporosis, but rather are caused by falls in frail older adults.
Evidence on cost effectiveness of drug treatment is completely lacking, they add, while the focus on drug treatment means that feasible alternative strategies, such as physical activity, are overlooked.
They also point to the harms from overdiagnosis and treatment, including the psychological burden associated with a disease label, and adverse effects of drug treatment such as nausea, vomiting, and serious bone complications (osteonecrosis of the jaw and drug-induced pathological fractures of the thigh bone).
Recent evidence also challenges the justification for the general use of calcium and vitamin D supplements to prevent fractures, they write.
The dominant approach to hip fracture prevention “is neither viable as a public health strategy nor cost effective,” conclude the authors.
“Pharmacotherapy can achieve at best a marginal reduction in hip fractures at the cost of unnecessary psychological harms, serious medical adverse events, and forgone opportunities to have greater impacts on the health of older people,” they add. “As such, it is an intellectual fallacy we will live to regret.”
Therapy-resistant breast cancer mechanism revealed
Kumamoto University
Mitsuyoshi Nakao, Director of the Institute of Molecular Embryology and Genetics in Kumamoto University and Associate Professor Noriko Saitoh revealed that a cluster of defined, non-coding RNAs are mechanistically involved in endocrine therapy resistance in human breast cancer cells. Furthermore, resveratrol, a kind of polyphenol, was found to repress these RNAs and inhibit the proliferative activity of breast cancer cells which had acquired resistance. The work was published in Nature Communications on April 29th, 2015.
Breast cancer is one of the most common types of cancer in women. In recent years, both early diagnosis and emerging therapies have been improved by the progress of medical technology. However, the fact that many patients suffer from metastasis and later recurrence of this disease is an important issue.
The keys to help understand the nature of breast cancer cells are estrogens and estrogen receptors. These molecules together present a “lock-and-key” theory for breast cancer therapy. About 60~70% of breast cancers are estrogen receptor-ƒ¿ (ER)-positive and highly depend on estrogen for cellular growth and survival. Thus, endocrine therapies, such as those using an aromatase inhibitor, block estrogen action and are clinically the most effective for ER-positive breast cancers. Unfortunately, these treatments are often followed by disease recurrence because most breast tumors are initially responsive to these therapies but then develop resistances through unknown mechanisms. Cancer recurrence is further associated with metastasis and invasion. For this reason, identification of the mechanism of therapy resistance has been strongly anticipated.
To analyze the cancer cell adaptation process, the research group used the human breast cancer cell line MCF7. These cells are ER-positive and can continue growth even after long term estrogen deprivation (LTED), similar to cancer cells that are resistant to endocrine therapy. It was determined that the expression of the ER gene (ESR1) was up-regulated during this adaptation in the LTED cells, and that novel ncRNAs, important in LTED cell adaptation, are produced from the ESR1 gene locus and the up-regulated ESR1 gene. Fluorescence in situ hybridization (FISH) analyses showed that these ncRNAs, termed Eleanors (ESR1 locus enhancing and activating non-coding RNAs), were localized at the site of actively transcribed ESR1 locus, resulting in the formation of distinct RNA foci in the nucleus. It was further revealed that resveratrol, a kind of polyphenol, exerted a repressive effect on the Eleanors via the ER and down-regulated the ESR1 gene which inhibited the proliferative activity of the LTED cells.
These findings uncovered the molecular basis for endocrine therapy-resistant breast cancer, showing the essential role of a new type of ncRNA-mediated regulation of the ESR1 gene locus.
In summary, Eleanors ncRNAs are actively involved in the epigenetic adaptation of ER-positive breast cancer cells via high expression of the ESR1 gene. These findings highlight the ncRNA-mediated mechanisms in cancer cell adaptation, which may be diagnostic and therapeutic targets for endocrine therapy-resistant breast cancer.
Public Release: 28-May-2015
ASCO: Component in green tea may help reduce prostate cancer in men at high risk
Polyphenon E reduced combined rates of prostate cancer and atypical small acinar proliferation rates, as well as decreased levels of prostate-specific antigen in men who have premalignant prostate lesions or high-grade intraepithelial neoplasia
H. Lee Moffitt Cancer Center & Research Institute
TAMPA, Fla. – Prostate cancer is the second most common type of cancer in men and is predicted to result in an estimated 220,00 cases in the United States in 2015. In recent years, an emphasis has been placed on chemoprevention – the use of agents to prevent the development or progression of prostate cancer. A team of researchers led by Nagi B. Kumar, Ph.D., R.D., F.A.D.A. at Moffitt Cancer Center recently published results of a randomized trial that assessed the safety and effectiveness of the active components in green tea to prevent prostate cancer development in men who have premalignant lesions. The results will be presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.
Twenty percent of green tea is consumed in Asian countries where prostate cancer death rates are among the lowest in the world and the risk of prostate cancer appears to be increased among Asian men who abandon their original dietary habits upon migrating to the U.S.
Laboratory studies have shown that substances in green tea called, “catechins” inhibit cancer cell growth, motility and invasion, and stimulate cancer cell death. Green tea catechins also prevent and reduce tumor growth in animal models. Epigallocatechin-3-gallate (EGCG) is the most abundant and potent catechin found in green tea responsible for these cancer prevention effects.
The goal of this trial was to evaluate if a one-year intervention with green tea catechins could suppress prostate cancer development in men who had high-grade intraepithelial neoplasia (HGPIN) or atypical small acinar proliferation (ASAP). The researchers used decaffeinated green tea capsules called Polyphenon E that contained a mixture of catechins that predominantly contained EGCG at a dose of 200 mgs twice a day.
The researchers compared Polyphenon E in 49 men to placebo tablets in 48 men over a 1 year treatment period. Overall, the difference in the number of prostate cancer cases at the end of 1 year between the two treatment groups was not statistically significant. However, in men who only had HGPIN at the beginning of the trial, they observed a lower combined rate of ASAP and prostate cancer development with Polyophenon E. ASAP is an entity that reflects a broad group of lesions in the prostate with insufficient changes in the cells to be definitively diagnosed as prostate cancer. Additionally, men on Polyphenon E had a significant decrease in prostate-specific antigen (PSA) levels. PSA is a biomarker that in combination with other risk factors is used to screen patients for prostate cancer, and high levels signify a higher risk of prostate cancer.
The Moffitt researchers observed a significant increase in the levels of EGCG in the blood plasma of men on Polyphenon E, and the capsules at this dose were tolerated in this group of men.
The ASCO poster session will take place Monday, June 1, 1:15-4:45 p.m. in S Hall A. The study was published in the April 14 issue of the journal Cancer Prevention Research. Funding support was received from the National Institutes of Health/National Cancer Institute (R01 CA12060-01A1).
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