CELL DEATH PROTEINS KEY TO FIGHTINING DISEASE

Melbourne researchers have uncovered key steps involved in programmed cell death, offering new targets for the treatment of diseases including lupus, cancers and neurodegenerative diseases

The research teams from the Walter and Eliza Hall Institute worked together to discover the three-dimensional structure of a key cell death protein called Bak and reveal the first steps in how it causes cell death. Their studies were published in Molecular Celland Proceedings of the National Academy of Sciences.

Programmed cell death, known as apoptosis, occurs naturally when the body has to remove unwanted cells. Chemical signals tell the cell to die by activating the apoptosis proteins Bak and Bax, which break down the 'energy factory' of the cell, known as the mitochondria. When this process goes awry, defective cells such as cancer cells can continue to live, or healthy cells can die unnecessarily, such as occurs in Alzheimer's disease.

Visualizing death proteins

Using the Australian Synchrotron, Mr Jason Brouwer, Dr Peter Czabotar, Dr Ruth Kluck and colleagues from the institute's Structural Biology division investigated how the structure of Bak changes in order to initiate cell death. The research was published in Molecular Cell.

"Understanding the way cell death proteins work and what they look like is crucial to finding new ways to treat disease," Dr Czabotar said. "Our research showed how Bak morphs from one shape to another to trigger apoptosis. Once Bak becomes 'activated' within the cell, it couples with another Bak molecule to form a 'dimer', which then goes on to initiate apoptosis."

Dr Czabotar said understanding apoptosis would allow researchers to develop new ways to treat disease. "Knowing the structure of these proteins and how they work in the cell is essential in designing new treatments to fight disease."

Seeking the hole story

Dr Dana Westphal, Dr Kluck, Dr Grant Dewson, Professor Jerry Adams and colleagues from the Molecular Genetics of Cancer and Cell Signalling and Cell Death divisions examined how the Bak and Bax dimers attach to mitochondria and perforate them. The research was published in Proceedings of the National Academy of Sciences.

Dr Kluck said dimers of Bak and Bax break open the mitochondrial surface, but the mechanism remains poorly understood. "A crucial stage of apoptosis is the release of key proteins from within the mitochondria," she said. "Scientists thought this happened by Bak and Bax poking through the mitochondrial membrane to form a hole, but our work has shown this doesn't happen. Instead, these proteins collapse onto the oily surface of the mitochondria and crowd the surface until holes form."

"We and others are now working to discover exactly how these proteins come together to destroy the mitochondria and trigger apoptosis. A deeper understanding of this pivotal event is likely to suggest new ways to regulate apoptosis to combat disease."

 

LIVING NEAR MAJOR ROADS MAY INCREASE SUDDEN CARDIAC DEATH IN WOMEN

Living close to a major road may increase women's risk of dying from sudden cardiac death, according to new research in the American Heart Association journal Circulation.

 

"It's important for healthcare providers to recognize that environmental exposures may be under-appreciated risk factors for diseases such as sudden cardiac death and fatal coronary heart disease," said Jaime E. Hart, Sc.D., study lead author and an instructor in medicine at Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts. "On a population level, living near a major roadway was as important a risk factor as smoking, diet or obesity."

While researchers previously found a modest increase in coronary heart disease risk among people who live near major roadways, the new study may be the first to examine the impact of roadway proximity to the risk of sudden cardiac death. Researchers note that roadway proximity could be a marker for exposure to air pollution.

The researchers studied data from 107,130 women (predominately white, average age 60) who were part of the Nurses' Health Study from 1986-2012. Calculating residential distance to roadways and after adjusting for a large number of other factors including age, race, calendar time, cigarette smoking, physical activity, and diet, researchers found:

In 523 cases of sudden cardiac death, living within 50 meters (164 feet) of a major road increased the risk of sudden cardiac death by 38 percent, compared to living at least 500 meters (.3 miles) away.

Each 100 meters (328 feet) closer to roadways was associated with a 6 percent increased risk for sudden cardiac death.

In the 1,159 cases of fatal coronary heart disease, risk increased 24 percent.

The public's exposure to major roadways is comparable to major sudden cardiac death risk factors, researchers said.

Researchers weren't able to measure all possible risk factors associated with living near a major road. They also said more research is needed among men and among women of different ages, races and income levels because nearly all participants were middle-age to elderly, white and of middle- to upper-socioeconomic class.

The Environmental Protection Agency estimated that 35 million people in the United States lived within 300 meters (984 feet) of a major road in 2009, and a growing number lived in close proximity to major roads worldwide.

"Regardless of where you live, adopting heart-healthy habits, such as maintaining a healthy weight, being physically active, eating nutritious foods, quitting smoking, and managing stress, can help decrease your risk of heart and blood vessel disease," said Hart, who is also an instructor at the Harvard School of Public Health.

"Our next step is to try to determine what specific exposures, such as air pollution, are driving the association between heart disease and major roadway proximity."

POTASSIUM RICH FOODS CUT STROKE DEATH RISKS AMONG OLDER WOMEN

Postmenopausal women who eat foods higher in potassium are less likely to have strokes and die than women who eat less potassium-rich foods, according to new research in the American Heart Association's journal Stroke.

"Previous studies have shown that potassium consumption may lower blood pressure. But whether potassium intake could prevent stroke or death wasn't clear," said Sylvia Wassertheil-Smoller, Ph.D., study senior author and distinguished university professor emerita, department of epidemiology and population health at Albert Einstein College of Medicine, Bronx, NY.

"Our findings give women another reason to eat their fruits and vegetables. Fruits and vegetables are good sources of potassium, and potassium not only lowers postmenopausal women's risk of stroke, but also death."

Researchers studied 90,137 postmenopausal women, ages 50 to 79, for an average 11 years. They looked at how much potassium the women consumed, as well as if they had strokes, including ischemic and hemorrhagic strokes, or died during the study period. Women in the study were stroke-free at the start and their average dietary potassium intake was 2,611 mg/day. Results of this study are based on potassium from food, not supplements.

The researchers found:

Women who ate the most potassium were 12 percent less likely to suffer stroke in general and 16 percent less likely to suffer an ischemic stroke than women who ate the least.

Women who ate the most potassium were 10 percent less likely to die than those who ate the least.

Among women who did not have hypertension (whose blood pressure was normal and they were not on any medications for high blood pressure), those who ate the most potassium had a 27 percent lower ischemic stroke risk and 21 percent reduced risk for all stroke types, compared to women who ate the least potassium in their daily diets.

Among women with hypertension (whose blood pressure was high or they were taking drugs for high blood pressure), those who ate the most potassium had a lower risk of death, but potassium intake did not lower their stroke risk.

Researchers suggested that higher dietary potassium intake may be more beneficial before high blood pressure develops. They also said there was no evidence of any association between potassium intake and hemorrhagic stroke, which could be related to the low number of hemorrhagic strokes in the study.

The U.S. Department of Agriculture recommends that women eat at least 4,700 mg of potassium daily. "Only 2.8 percent of women in our study met or exceeded this level. The World Health Organization's daily potassium recommendation for women is lower, at 3,510 mg or more. Still, only 16.6 percent of women we studied met or exceeded that," said Wassertheil-Smoller.

"Our findings suggest that women need to eat more potassium-rich foods. You won't find high potassium in junk food. Some foods high in potassium include white and sweet potatoes, bananas and white beans."

While increasing potassium intake is probably a good idea for most older women, there are some people who have too much potassium in their blood, which can be dangerous to the heart. "People should check with their doctor about how much potassium they should eat," she said.

The study was observational and included only postmenopausal women. Researchers also did not take sodium intake into consideration, so the potential importance of a balance between sodium and potassium is not among the findings. Researchers said more studies are needed to determine whether potassium has the same effects on men and younger people.

COMMON ANTIBIOTICS LINKED WITH HEART DEATH

The antibiotic clarithromycin -- widely used for treating common bacterial infections -- is associated with an increased risk of heart deaths, finds a study published on thebmj.com today.

The authors say their findings require urgent confirmation, given that many millions of people are prescribed the drug each year. But they stress that the absolute risk is small and that prescribing practice should not be changed until results have been confirmed in an independent study.

Clarithromycin belongs to a group of antibiotics known as macrolides. Macrolide antibiotics prolong the duration of electrical activity of the heart muscle (known as the QT interval) and are therefore thought to increase the risk of potentially fatal heart rhythm problems.

Given this background, the cardiac safety profiles of individual macrolides need to be studied in greater detail to help guide clinical treatment decisions.

So a team of Danish researchers decided to assess the risk of cardiac death associated with clarithromycin and another macrolide called roxithromycin, compared with penicillin V, an antibiotic with no known cardiac risk.

Using national databases, they identified over 5 million treatment courses among Danish adults aged 40-74 years from 1997 to 2011 (160,297 with clarithromycin, 588,988 with roxithromycin and 4,355,309 with penicillin V).

Individuals with serious disease, who may be at high baseline risk of death, were excluded from the analysis.

A total of 285 cardiac deaths were observed during ongoing use with the study drugs, 18 of which occurred during use of clarithromycin and 32 during use of roxithromycin.

After adjusting for factors such as age, sex, baseline cardiac risk and use of other medication, ongoing use of clarithromycin was associated with a 76% higher risk of cardiac death compared with use of penicillin V. There was no increased risk of cardiac death with clarithromycin after treatment had ended.

The absolute risk difference was 37 cardiac deaths per 1 million courses with clarithromycin. No increased risk of cardiac death was found with ongoing or past use of roxithromycin.

"Our study expands on the available knowledge of the cardiac safety of macrolides, being the first large scale population based observational study to show significantly increased cardiac risk with clarithromycin and the relative cardiac safety of roxithromycin," write the authors.

The authors emphasise that the absolute increase in risk is small and should have limited, if any, effect on the prescribing practice in individual patients. However, they note, "clarithromycin is one of the more commonly used antibiotics in many countries and many millions of people are prescribed this drug each year; thus, the total number of excess (potentially avoidable) cardiac deaths may not be negligible."

Before these results are used to guide clinical decision making, "confirmation in independent populations is an urgent priority given the widespread use of macrolide antibiotics," they conclude.