Health Research Report
148th Issue Date 08 FEB 2013
Compiled By Ralph Turchiano
In this Issue:
1. Skin, soft tissue infections succumb to blue light
2. Silibinin, found in milk thistle, protects against UV-induced skin cancer
3. 20 hours of TV a week almost halves sperm count
4. Sunlight may help ward off rheumatoid arthritis in women
5. Low vitamin D levels may increase risk of Type 1 diabetes
6. Green tea and red wine extracts interrupt Alzheimer’s disease pathway in cells
7. Olive oil component alleviates intestinal ischemia and reperfusion
8. Some omega-3 oils better than others for protection against liver disease
9. Vitamin D, omega-3 may help clear amyloid plaques found in Alzheimer’s
10. Fish oil may protect dialysis patients from sudden cardiac death
11. Zinc helps against infection by tapping brakes in immune response
Skin, soft tissue infections succumb to blue light
Blue light can selectively eradicate Pseudomonas aeruginosa infections of the skin and soft tissues, while preserving the outermost layer of skin, according to a proof-of-principle study led by Michael R. Hamblin of the Massachusetts General Hospital, and the Harvard Medical School, Boston. The research is published online ahead of print in the journal Antimicrobial Agents and Chemotherapy
“Blue light is a potential non-toxic, non-antibiotic approach for treating skin and soft tissue infections, especially those caused by antibiotic resistant pathogens,” says Hamblin.
In the study, animal models were infected with P. aeruginosa. All of the animals in the group treated with blue light survived, while in the control, 82 percent (9 out of 11) of the animals died.
Skin and soft tissue infections are the second most common bacterial infections encountered in clinical practice, and represent the most common infection presentation—more than 3 percent—in patients visiting emergency departments, says Hamblin. The prevalence of skin and soft tissue infections among hospitalized patients is 10 percent, with approximately 14.2 million ambulatory care visits every year and an annual associated medical cost of almost $24 billion (equivalent to $76 for every American), says Hamblin.
Treatment of skin and soft tissue infections has been significantly complicated by the explosion of antibiotic resistance, which may bring an end to what medical scientists refer to as the antibiotic era, says Hamblin. “Microbes replicate very rapidly, and a mutation that helps a microbe survive in the presence of an antibiotic drug will quickly predominate throughout the microbial population. Recently, a dangerous new enzyme, NDM-1, that makes some bacteria resistant to almost all antibiotics available has been found in the United States. Many physicians are concerned that several infections soon may be untreatable.”
Besides harming public health, antibiotic resistance boosts health care costs. “Treating resistant skin and soft tissue infections often requires the use of more expensive, or more toxic drugs, and can result in longer hospital stays for infected patients,” says Hamblin.
Silibinin, found in milk thistle, protects against UV-induced skin cancer
By Garth Sundem in In the Lab · January 30, 2013 ·
Rajesh Agarwal, PhD, shows that silibinin, found in milk thistle, protects against UVB damage and kills cells damaged by UVA — but is not at all toxic in healthy cells.
A pair of University of Colorado Cancer Center studies published this month show that the milk thistle extract, silibinin, kills skin cells mutated by UVA radiation and protects against damage by UVB radiation – thus protecting against UV-induced skin cancer and photo-aging.
“When you have a cell affected by UV radiation, you either want to repair it or kill it so that it cannot go on to cause cancer. We show that silibinin does both,” says Rajesh Agarwal, PhD, co-program leader of Cancer Prevention and Control at the CU Cancer Center and professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences.
The first study, published in the journal Photochemistry and Photobiology worked with human skin cells subjected to UVA radiation, which makes up about 95 percent of the sun’s radiation that reaches Earth. The Agarwal Lab treated these UVA-affected cells with silibinin. With silibinin, the rate at which these damaged cells died increased dramatically.
“When you take human skin cells – keratinocytes – and treat them with silibinin, nothing happens. It’s not toxic. But when you damage these cells with UVA radiation, treatment with silibinin kills the cells,” Agarwal says, thus removing the mutated cells that can cause skin cancer and photo-aging.
Specifically, the study shows that pretreatment with silibinin resulted in higher release of reactive oxygen species (ROS) within the UVA-exposed cells, leading to higher rates of cell death.
The second study, published this month by the same authors in the journal Molecular Carcinogenesis shows that instead of beneficially killing cells damaged by UVA radiation, treatment with silibinin protects human skill cells from damage by UVB radiation, which makes up about 5 percent of the sun’s radiation reaching Earth.
Again, remember Agarwal’s suggestion that the prevention of UV-induced skin cancer can happen in two ways: by protecting against DNA damage or by killing cells with damaged DNA. With UVA, silibinin kills; with UVB, it protects, in this case by increasing cells’ expression of the protein interleukin-12, which works to quickly repair damaged cells.
“It has been 20 years of work with this compound, silibinin,” Agarwal says. “We first noticed its effectiveness in treating both skin and solid cancers, and we now have a much more complete picture of the mechanisms that allow this compound to work.”
Agarwal and colleagues continue to test the effectiveness of silibinin in cancer prevention and treatment in cell lines and mouse models, and are working toward human trials of silibinin-based therapeutics.
Silibinin and skin cancer chemoprevention studies in the Agarwal Lab are supported by NCI R01 grant CA140368.
20 hours of TV a week almost halves sperm count
But 15 or more hours a week of moderate to vigorous exercise improves it
Healthy young men who watch TV for more than 20 hours a week have almost half the sperm count of men who watch very little TV, indicates a study published online in the British Journal of Sports Medicine.
Conversely, men who do 15 or more hours of moderate to vigorous exercise every week have sperm counts that are 73% higher than those who exercise little, the findings show.
Semen quality seems to have deteriorated over the past few decades, although it’s not clear why, say the authors.
To find out if an increasingly sedentary lifestyle might be a contributory factor, they analysed the semen quality of 189 men between the ages of 18 to 22 in 2009-10, all of whom were from Rochester in New York State, USA.
The men were asked about the quantity and intensity of weekly exercise they had had over the preceding three months, and how much time they spent watching television, DVDs, or videos over the same period.
And they were asked about factors that might affect sperm quality, including medical or reproductive health problems, diet, stress levels, and smoking.
Over half the men were within the normal range for weight for their height, and three out of four were non-smokers. The prevalence of reproductive health problems was low.
The amount of moderate to vigorous physical activity taken every week ranged from 5 to 14 hours, while weekly TV screen time varied from 4 to 20 hours. Men who were more physically active tended to have a healthier diet than those who watched a lot of TV every week.
The analysis showed that those who were the most physically active—15+ hours a week—had a 73% higher sperm count than the least physically active. Exercise did not affect sperm motility, shape, or sample volume.
When analysed by exercise intensity, the results showed that light physical exercise made no difference to the sperm count, no matter how frequent it was.
TV viewing had the opposite effect. Those who watched the most—20 or more hours a week—had a sperm count that was 44% lower than those who watched the least. It had no impact on sperm motility, shape, or sample volume.
And unlike smoking or weight, the amount of TV viewing seemed to counteract the beneficial effects of exercise, although this may be a chance finding, say the authors.
The authors caution that a reduced sperm count does not necessarily curb a man’s fertility or his chances of being able to father a child, but the findings do suggest that a more physically active lifestyle may improve semen quality.
The type of exercise might also be important, say the authors, who conclude: “Future studies should also evaluate the extent to which different exercise types affect semen quality as previous studies suggest that there might be opposing effects of different types of activity on semen characteristics.”
Sunlight may help ward off rheumatoid arthritis in women
Use of sunblock could lessen protective effects, suggest authors
[Exposure to ultraviolet-B and risk of developing rheumatoid arthritis among women in the Nurses’ Health Study Online First doi 10.1136/annrheumdis-2012-202302]
Regular exposure to sunlight—specifically ultraviolet B (UVB)—may reduce the risk of developing rheumatoid arthritis, indicates a large long term study published online in the Annals of the Rheumatic Diseases.
But the effect of UVB exposure was only evident among older women, possibly because younger women are more aware of the hazards of sunlight and so cover up with sun block, suggest the authors.
They base their findings on participants in two phases of the US Nurses’ Health Study (NHS), the first of which has tracked the health of more than 120,000 nurses since 1976, when they were aged between 30 and 55, until 2008.
The second (NHSII) has tracked the health of a further 115,500 nurses since 1989, when they were aged between 25 and 42, until 2009.
Rather than simply relying on geography to quantify likely levels of UVB exposure, the researchers used a more sensitive assessment, known as UV-B flux, which is a composite measure of UVB radiation, based on latitude, altitude, and cloud cover.
It is measured in R-B units: a count of 440 R-B units over 30 minutes, for example, is sufficient to produce slight redness in untanned white skin.
Exposure was then estimated according to the US state of residence, and ranged from an annual average of 93 in Alaska and Oregon to 196 in Hawaii and Arizona. Likely estimates of UV exposure at birth and by the age of 15 were also included.
Over the study period, 1314 women developed rheumatoid arthritis. Among nurses in the first NHS cohort, higher cumulative exposure to UVB was associated with a reduced risk of developing the disease.
Those with the highest levels of exposure were 21% less likely to develop rheumatoid arthritis than those with the least, the analysis showed.
This backs up the findings of other studies, showing a link between geography and the risk of rheumatoid arthritis as well as other autoimmune conditions, including type 1 diabetes, inflammatory bowel disease, and multiple sclerosis, say the authors.
But no such association for UV-B exposure was found among women in NHSII. These women were younger than those in the first NHS, and so might have been more savvy about the potential hazards of acquiring a tan, suggest the authors.
“Differences in sun protective behaviours (eg greater use of sun block in younger generations) may explain the disparate results,” they explain.
They add that it is unclear at what stage of life the protective effect of UV-B occurs. Many of the study participants didn’t move house between birth and their teens, and there was no difference in the results for these time points.
But they conclude: “Our study adds to the growing evidence that exposure to UV-B light is associated with decreased risk of rheumatoid arthritis. The mechanisms are not yet understood, but could be mediated by the cutaneous production of vitamin D and attenuated by use of sunscreen or sun avoidant behaviour.”
Low vitamin D levels may increase risk of Type 1 diabetes
Boston, MA – Having adequate levels of vitamin D during young adulthood may reduce the risk of adult-onset type 1 diabetes by as much as 50%, according to researchers at Harvard School of Public Health (HSPH). The findings, if confirmed in future studies, could lead to a role for vitamin D supplementation in preventing this serious autoimmune disease in adults. The study was published online February 3, 2013 and will appear in the March 1 print edition of the American Journal of Epidemiology.
“It is surprising that a serious disease such as type 1 diabetes could perhaps be prevented by a simple and safe intervention,” said lead author Kassandra Munger, research associate in the Department of Nutrition at HSPH.
This study provides the strongest findings to date to suggest that vitamin D may be protective against type 1 diabetes.
In type 1 diabetes (once called juvenile-onset or insulin-dependent diabetes), the body’s immune system attacks and permanently disables the insulin-making cells in the pancreas. About 5% of the estimated 25.8 million people in the United States with diabetes have type 1, according to the American Diabetes Association. Although it often starts in childhood, about 60% of type 1 diabetes cases occur after age 20.
Previous studies have suggested that a shortage of vitamin D might boost type 1 diabetes risk, although those studies mostly examined the link between vitamin D levels in pregnancy or childhood and the risk of type 1 diabetes in children. Other research, in young adults, uncovered an association between high vitamin D levels and a lowered risk of multiple sclerosis—an autoimmune disease genetically and epidemiologically related to type 1 diabetes—suggesting that inadequate vitamin D in adulthood may be an important risk factor for autoimmune diseases in general.
Long-term study of military personnel
The researchers conducted a prospective case-control study of U.S. military personnel on active duty, using blood samples from the Department of Defense Serum Repository, which contains more than 40 million samples collected from 8 million military personnel since the mid-1980s. Identifying 310 individuals diagnosed with type 1 diabetes between 1997 and 2009, the team examined blood samples taken before onset of the disease, and compared the samples with those of 613 people in a control group.
The researchers found that white, non-Hispanic, healthy young adults with higher serum levels (>75 nmol/L) of vitamin D had about half the risk of developing type 1 diabetes than those with the lowest levels of vitamin D (<75 nmol/L). Although the researchers found no significant association among Hispanics and blacks, the authors said this may be due to the small number of individuals in these groups.
“The risk of type 1 diabetes appears to be increased even at vitamin D levels that are commonly regarded as normal, suggesting that a substantial proportion of the population could benefit from increased vitamin D intake,” said Alberto Ascherio, professor of epidemiology and nutrition at HSPH, the study’s senior author.
About vitamin D
Worldwide, an estimated 1 billion people have inadequate levels of vitamin D in their blood, and deficiencies can be found in all ethnicities and age groups. While sun exposure is an excellent source of vitamin D, sunscreen, clothing, skin pigmentation, and winter months reduce vitamin D production. Food tends to be a poor source of vitamin D, with “good” sources, such as salmon and fortified milk, containing 400IU or less per serving. “Whereas it is premature to recommend universal use of vitamin D supplements for prevention of type 1 diabetes, the possibility that many cases could be prevented by supplementation with 1,000-4,000 IU/day, which is largely considered safe, is enticing,” the authors said.
Green tea and red wine extracts interrupt Alzheimer’s disease pathway in cells
Natural chemicals found in green tea and red wine may disrupt a key step of the Alzheimer’s disease pathway, according to new research from the University of Leeds.
In early-stage laboratory experiments, the researchers identified the process which allows harmful clumps of protein to latch on to brain cells, causing them to die. They were able to interrupt this pathway using the purified extracts of EGCG from green tea and resveratrol from red wine.
The findings, published in the Journal of Biological Chemistry, offer potential new targets for developing drugs to treat Alzheimer’s disease, which affects some 800,000 people in the UK alone, and for which there is currently no cure.
“This is an important step in increasing our understanding of the cause and progression of Alzheimer’s disease,” says lead researcher Professor Nigel Hooper of the University’s Faculty of Biological Sciences. “It’s a misconception that Alzheimer’s is a natural part of ageing; it’s a disease that we believe can ultimately be cured through finding new opportunities for drug targets like this.”
Alzheimer’s disease is characterised by a distinct build-up of amyloid protein in the brain, which clumps together to form toxic, sticky balls of varying shapes. These amyloid balls latch on to the surface of nerve cells in the brain by attaching to proteins on the cell surface called prions, causing the nerve cells to malfunction and eventually die.
“We wanted to investigate whether the precise shape of the amyloid balls is essential for them to attach to the prion receptors, like the way a baseball fits snugly into its glove,” says co-author Dr Jo Rushworth. “And if so, we wanted to see if we could prevent the amyloid balls binding to prion by altering their shape, as this would stop the cells from dying.”
The team formed amyloid balls in a test tube and added them to human and animal brain cells. Professor Hooper said: “When we added the extracts from red wine and green tea, which recent research has shown to re-shape amyloid proteins, the amyloid balls no longer harmed the nerve cells. We saw that this was because their shape was distorted, so they could no longer bind to prion and disrupt cell function.
“We also showed, for the first time, that when amyloid balls stick to prion, it triggers the production of even more amyloid, in a deadly vicious cycle,” he added.
Professor Hooper says that the team’s next steps are to understand exactly how the amyloid-prion interaction kills off neurons.
“I’m certain that this will increase our understanding of Alzheimer’s disease even further, with the potential to reveal yet more drug targets,” he said.
Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, the UK’s leading dementia research charity, which part-funded the study, said: “Understanding the causes of Alzheimer’s is vital if we are to find a way of stopping the disease in its tracks. While these early-stage results should not be a signal for people to stock up on green tea and red wine, they could provide an important new lead in the search for new and effective treatments. With half a million people affected by Alzheimer’s in the UK, we urgently need treatments that can halt the disease – that means it’s crucial to invest in research to take results like these from the lab bench to the clinic.”
Olive oil component alleviates intestinal ischemia and reperfusion
New research published in the Journal of Leukocyte Biology shows that oleuropein aglycone, a polyphenol present in olive oil, reduces inflammation associated with intestinal ischemia and reperfusion injury in mice
Here’s another reason why you should include olive oil in your diet: A new research report published in the Journal of Leukocyte Biology suggests that at least one compound in olive oil significantly reduces intestinal ischemia (restricted blood supply) and the resulting reperfusion injury (tissue damage caused when blood supply returns). The compound, called “oleuropein aglycone,” is the most prominent polyphenol found in olive oil and could become a novel therapeutic target aimed at treating intestinal ischemia and reperfusion injury in humans. Ultimately, this research could lead to therapeutic benefits for patients with spinal cord injuries, arthritis and pleurisy, as well as those suffering from intestinal ischemia/reperfusion.
“The phenolic compounds of olive oil can reduce the secondary injury associated with intestinal damage,” said Salvatore Cuzzocrea, Ph.D., a senior researcher involved in the work from the Department of Biology and Environmental Sciences at the University of Messina in Messina, Italy. “Oleuropein aglycone may be useful in the therapy of inflammation-associated disease.”
To make this discovery, scientists used four groups of mice. The first group was subjected to intestinal ischemia by splanchnic arterial occlusion (SAO) followed by reperfusion. The second group was the same as the first but was also administered oleuropein aglycone. The third group of mice underwent identical surgical procedures except for SAO shock and was kept under anesthesia for the duration of the experiment. The last group was the same as the third, but was also given oleuropein aglycone. The histological structure of the gastrointestinal tract from the third group was typical of a normal architecture, but did not present any early inflammation. The ileum from animals subjected to intestinal ischemia/reperfusion injury (IRI) showed severe histological alteration with edema of the distal portion of the villi and the expression of pro-inflammatory cytokines, apoptosis and neutrophil infiltration were significantly increased. Oleuropein aglycone treated-mice showed reduced IRI-induced organ injury including a considerable reduction of inflammatory and apoptotic levels.
“Olive oil’s healing properties have been known for millennia,” said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology, “but until relatively recently, we have had few direct scientific insights into exactly how it works in the body. Not only does this report shed light on the molecular details of how olive oil may provide health benefits, but it may open new doors to enhancing treatments based on this discovery.”
Some omega-3 oils better than others for protection against liver disease
CORVALLIS, Ore. – Research at Oregon State University has found that one particular omega-3 fatty acid has a powerful effect in preventing liver inflammation and fibrosis – common problems that are steadily rising along with the number of Americans who are overweight.
The American Liver Foundation has estimated that about 25 percent of the nation’s population, and 75 percent of those who are obese, have nonalcoholic fatty liver disease. This early-stage health condition can sometimes progress to more serious, even fatal diseases, including nonalcoholic steatohepatitis, or NASH, as well as cirrhosis and liver cancer.
The study, published online in the Journal of Nutrition, was one of the first to directly compare the effects of two of the omega-3 fatty acids often cited for their nutritional value, DHA and EPA.
In research with laboratory animals, it found that EPA had comparatively little effect on preventing the fibrosis, or scarring, that’s associated with NASH. However, DHA supplementation reduced the proteins involved in liver fibrosis by more than 65 percent.
“A reduction of that magnitude in the actual scarring and damage to the liver is very important,” said Donald Jump, a principal investigator with the Linus Pauling Institute at OSU and a professor in the College of Public Health and Human Sciences.
“Many clinical trials are being done with omega-3 fatty acids related to liver disease,” Jump said. “Our studies may represent the first to specifically compare the capacity of EPA versus DHA to prevent NASH. It appears that DHA, which can also be converted to EPA in the human body, is one of the most valuable for this purpose.”
The issues have taken center stage as the weight of Americans continues to rise, with a related increase in the incidence of fatty liver disease and liver damage.
NASH is a progressive form of liver disease that is associated with chronic inflammation and oxidative stress, resulting from excess fat storage in the liver. Chronic inflammation can eventually lead to fibrosis, cirrhosis, or even liver cancer. While management of lifestyle, including weight loss and exercise, is one approach to control the onset and progression of fatty liver disease, other approaches are needed to prevent and treat it.
About 30-40 percent of people with nonalcoholic fatty liver disease progress to NASH, which in turn can result in cirrhosis, a major risk factor for liver cancer. While this research studied the prevention of fatty liver disease, Jump said, ongoing studies are examining the capacity of DHA to be used in NASH therapy.
The levels of omega-3 oils needed vary with the health concern, officials say.
“Omega-3 fatty acids are typically recommended for the prevention of cardiovascular disease,” Jump said. “Recommended intake levels of omega-3 fatty acids in humans for disease prevention are around 200-500 milligrams of combined DHA and EPA per day.”
Levels used in therapy to lower blood triglycerides, also a risk factor for cardiovascular disease, are higher, about 2-4 grams of combined EPA and DHA per day. The OSU studies with mice used DHA at levels comparable to the triglyceride therapies.
“DHA was more effective than EPA at attenuating inflammation, oxidative stress, fibrosis and hepatic damage,” the researchers wrote in their conclusion. “Based on these results, DHA may be a more attractive dietary supplement than EPA for the prevention and potential treatment of NASH in obese humans.”
This work was the result of a four-year study supported by the USDA National Institute of Food and Agriculture, as well as the National Institutes of Health. Co-authors on the paper included Christopher M. Depner and Kenneth A. Philbrick, both graduate students in the Nutrition Graduate Program at OSU.
About the OSU College of Public Health and Human Sciences: The College creates connections in teaching, research and community outreach while advancing knowledge, policies and practices that improve population health in communities across Oregon and beyond.
Vitamin D, omega-3 may help clear amyloid plaques found in Alzheimer’s
A team of academic researchers has pinpointed how vitamin D3 and omega-3 fatty acids may enhance the immune system’s ability to clear the brain of amyloid plaques, one of the hallmarks of Alzheimer’s disease.
In a small pilot study published in the Feb. 5 issue of the Journal of Alzheimer’s Disease, the scientists identified key genes and signaling networks regulated by vitamin D3 and the omega-3 fatty acid DHA (docosahexaenoic acid) that may help control inflammation and improve plaque clearance.
Previous laboratory work by the team helped clarify key mechanisms involved in helping vitamin D3 clear amyloid-beta, the abnormal protein found in the plaque. The new study extends the previous findings with vitamin D3 and highlights the role of omega-3 DHA.
“Our new study sheds further light on a possible role for nutritional substances such as vitamin D3 and omega-3 in boosting immunity to help fight Alzheimer’s,” said study author Dr. Milan Fiala, a researcher at the David Geffen School of Medicine at UCLA.
For the study, scientists drew blood samples from both Alzheimer’s patients and healthy controls, then isolated critical immune cells called macrophages from the blood. Macrophages are responsible for gobbling up amyloid-beta and other waste products in the brain and body.
The team incubated the immune cells overnight with amyloid-beta. They added either an active form of vitamin D3 called 1alpha,25–dihydroxyvitamin D3 or an active form of the omega-3 fatty acid DHA called resolvin D1 to some of the cells to gauge the effect they had on inflammation and amyloid-beta absorption.
Both 1alpha, 25-dihydroxyvitamin D3 and resolvin D1 improved the ability of the Alzheimer’s disease patients’ macrophages to gobble-up amyloid-beta, and they inhibited the cell death that is induced by amyloid-beta. Researchers observed that each nutrition molecule utilized different receptors and common signaling pathways to do this.
Previous work by the team, based on the function of Alzheimer’s patients’ macrophages, showed that there are two groups of patients and macrophages. In the current study, researchers found that the macrophages of the Alzheimer’s patients differentially expressed inflammatory genes, compared with the healthy controls, and that two distinct transcription patterns were found that further define the two groups: Group 1 had an increased transcription of inflammatory genes, while Group 2 had decreased transcription. Transcription is the first step leading to gene expression.
“Further study may help us identify if these two distinct transcription patterns of inflammatory genes could possibly distinguish either two stages or two types of Alzheimer’s disease,” said study author Mathew Mizwicki, an assistant researcher at the David Geffen School of Medicine at UCLA.
While researchers found that 1alpha,25-dihydroxyvitamin D3 and resolvin D1 greatly improved the clearance of amyloid-beta by macrophages in patients in both groups, they discovered subtleties in the effects the two substances had on the expression of inflammatory genes in the two groups. In Group 1, the increased-inflammation group, macrophages showed a decrease of inflammatory activation; in Group 2, macrophages showed an increase of the inflammatory genes IL1 and TLRs when either 1alpha,25-Dihydroxyvitamin D3 or resolvin D1 were added.
More study is needed, Fiala said, but these differences could be associated with the severity of patients’ nutritional and/or metabolic deficiencies of vitamin D3 and DHA, as well as the omega-3 fatty acid EPA (eicosapentaenoic acid).
“We may find that we need to carefully balance the supplementation with vitamin D3 and omega-3 fatty acids, depending on each patient in order to help promote efficient clearing of amyloid-beta,” Fiala said. “This is a first step in understanding what form and in which patients these nutrition substances might work best.”
According to Fiala, an active (not oxidized) form of omega-3 DHA, which is the precursor of the resolvin D1 used in this study, may work better than more commercially available forms of DHA, which generally are not protected against the oxidation that can render a molecule inactive.
The next step is a larger study to help confirm the findings, as well as a clinical trial with omega-3 DHA, the researchers said.
Fish oil may protect dialysis patients from sudden cardiac death
INDIANAPOLIS — Medical literature long has touted the benefits of omega-3 fatty acids for the heart. But until now, researchers have not studied the potential benefit for people on hemodialysis, who are among the highest-risk patients for sudden cardiac death.
A study published Feb. 6 online in the journal Kidney International, which included 100 patients who died of sudden cardiac death during their first year of hemodialysis and 300 patients who survived, is the first to examine this question.
Allon N. Friedman, M.D., associate professor of medicine in the Division of Nephrology at the Indiana University School of Medicine and first author of the study, said the findings are impressive enough that he believes a placebo-controlled clinical study is warranted to confirm the results.
“We found that higher levels of omega-3 fatty acids in the blood of patients who were just starting hemodialysis were very strongly associated with a lower risk of sudden cardiac death over the first year of their treatment,” Friedman said.
The five-year survival rate for patients on hemodialysis is 35 percent, with the risk of death highest in the first few months of starting treatment. The most common cause of death in these patients is sudden cardiac death, which accounts for about one out of every four deaths.
“The risk of sudden cardiac death in hemodialysis patients is highest during the first year of treatment. The annual rate of sudden cardiac death is about 6 to 7 percent, which may even exceed the rate in patients with heart failure,” Friedman said. “This study is a first step toward identifying a possible treatment for sudden cardiac death in dialysis patients.
“Because omega-3 fatty acids can be obtained from certain foods, such as fish oil, our findings also have important implications for the type of diet we recommend to patients on dialysis,” Friedman said.
Others involved in the research are Zhangsheng Yu, Rebeka Tabbey and Cheryl Denski from the Indiana University Department of Biostatistics; Hector Tamez, Julia Wenger and Ravi Thadhani from the Division of Nephrology at Massachusetts General Hospital; and Yong Li and Bruce A. Watkins with the Department of Nutritional Sciences, Lipid Chemistry and Molecular Biology Laboratory at the University of Connecticut.
Zinc helps against infection by tapping brakes in immune response
COLUMBUS, Ohio – New research suggests that zinc helps control infections by gently tapping the brakes on the immune response in a way that prevents out-of-control inflammation that can be damaging and even deadly.
Scientists determined in human cell culture and animal studies that a protein lures zinc into key cells that are first-responders against infection. The zinc then interacts with a process that is vital to the fight against infection and by doing so helps balance the immune response.
This study revealed for the first time that zinc homes in on this pathway and helps shut it down, effectively ensuring that the immune response does not spiral out of control. The team led by Ohio State University researchers also found that if there is not enough zinc available at the time of infection, the consequences include excessive inflammation.
In this research, zinc’s activity was studied in the context of sepsis, a devastating systemic response to infection that is a common cause of death in intensive-care unit patients. But scientists say these findings might also help explain why taking zinc tablets at the start of a common cold appears to help stem the effects of the illness.
“We do believe that to some extent, these findings are going to be applicable to other important areas of disease beyond sepsis,” said Daren Knoell, senior author of the study and a professor of pharmacy and internal medicine at Ohio State. “Without zinc on board to begin with, it could increase vulnerability to infection. But our work is focused on what happens once you get an infection – if you are deficient in zinc you are at a disadvantage because your defense system is amplified, and inappropriately so.
“The benefit to health is explicit: Zinc is beneficial because it stops the action of a protein, ultimately preventing excess inflammation.”
While this study and previous work linking zinc deficiency to inflammation might suggest that supplementation could help very sick ICU patients, it’s still too early to make that leap.
“I think the question is whom to give zinc to, if anybody at all. We predict that not everybody in the ICU with sepsis needs zinc, but I anticipate that a proportion of them would,” Knoell said. “Zinc is a critical element that we get from our diet, but we do not think we can give zinc and fix everything. Usually, if there is zinc deficiency, we would expect to see other nutrient deficiencies, too.”
Zinc deficiency affects about 2 billion people worldwide, including an estimated 40 percent of the elderly in the United States – who are also among the most likely Americans to end up in an ICU.
The research is published in the journal Cell Reports.
Knoell’s lab previously showed that zinc-deficient mice developed overwhelming inflammation in response to sepsis compared to mice on a normal diet. Zinc supplementation improved outcomes in the zinc-deficient mice.
Until now, the beneficial effects of zinc in combating infection have not been fully understood at the molecular level. This is because zinc has numerous complex jobs in the body and interacts with thousands of proteins to sustain human life. Of all the zinc contained in our bodies, only about 10 percent of it is readily accessible to help fight off an infection, said Knoell, also an investigator in Ohio State’s Davis Heart and Lung Research Institute.
“We believe that our findings help to narrow an important gap that has existed in our understanding of how this relatively simple metal helps us defend ourselves from infection,” he said.
In this work, Knoell and colleagues sought to zero in on zinc’s role in preventing the inflammation that had led to such poor outcomes in the zinc-deficient mice.
In experiments using human monocytes – cells involved in the first line of defense against an invading pathogen – the researchers examined what happens when the immune response is launched.
When a pathogen is recognized, a series of molecules wake up from dormancy to create a process that activates the innate immune response. A major part of this process involves the NF-κB pathway, named for a highly active protein that is known to play an important role in the immune response to infection. Once NF-κB is activated and enters the nucleus, a gene is expressed that produces a zinc transporter called ZIP8. The transporter then rapidly mobilizes to the cell’s wall, where it can then shuttle zinc from the bloodstream into the cell.
After cell entry, zinc is then directed to and binds to a different protein in the NF-kB pathway. When this happens, it halts any further activity in that process. The cumulative impact of this feedback loop is that it prevents excessive inflammation, which can be damaging to cells and the body.
“The immune system has to work under very strict balance, and this is a classic example of where more is not always better,” Knoell said. “We want a robust inflammatory response, which is part of our natural programming to defend us against a bug. But if that is unchecked, and there is too much inflammation, then it not only attacks the pathogen but can also cause much more collateral damage.”
The researchers knew from previously published experiments that if ZIP8 activation was prevented, zinc couldn’t come into the cell and the cells died. In the current study, collaborators who specialize in computational modeling of protein interactions helped identify the likely target of zinc once it enters the cell: specific binding sites on a protein called IKKB. When researchers allowed this protein to function unchecked in mice with zinc deficiency, the animals developed excessive inflammation in response to sepsis – confirmation that IKKB was zinc’s target to turn off the inflammatory pathway.
“There are certainly other zinc targets in the cell, but we found evidence that zinc is brought in by ZIP8 to turn the pathway off by interacting with this protein at a specific region,” Knoell said.
The recommended daily allowance for zinc ranges from 8 to 11 milligrams for most adults. Red meat and poultry provide the majority of zinc in the American diet, according to the National Institutes of Health. Other food sources include beans, nuts, some shellfish, whole grains, fortified cereals and dairy products. The nutrient is also available in supplement form. Knoell said it is possible but relatively uncommon to take in too much zinc to reach toxic levels.
His lab is continuing to study the NF-κB pathway, inflammation and zinc deficiency in other disease processes. And though zinc would be inexpensive and easy to take as a supplement, Knoell said many questions remain about whether zinc should be considered as an intervention for specific disorders.
“There might be therapeutic implications about giving supplemental zinc in a strategic manner to help improve some people with certain conditions. But also, could we learn from this so someday we can be more diagnostic about who it is that needs zinc? And if so, what dose and for how long?” he said.
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