, March 4, 2009 — A new study provides insight into how a short burst in nitrite can exert lasting beneficial effects on the heart, protecting it from stress and assaults such as heart attacks. In this study, just published in Circulation Research, researchers at Boston University School of Medicine have demonstrated for the first time that short elevations in circulating levels of this simple anion are sufficient to have a lasting impact on the heart by modulating its oxidation status and its protein machinery.

Nitrite, an oxidation product of the ubiquitous short-lived cell signaling molecule, nitric oxide (NO), was until recently thought to be biologically inert at the relatively low levels found in the body. Traces of nitrite are present in our diet and significant amounts are continuously produced from nitrate, another oxidation product of NO and a constituent of green, leafy vegetables. The suspicion that high levels of nitrite and nitrate may cause cancer, as well as concerns about their risk to compromise the ability of red blood cells to deliver oxygen to tissues, have led to strict regulations aimed at limiting our exposure to these substances through drinking water and food products.

In the past few years, however, multiple research groups have shown that low concentrations of nitrite exert numerous beneficial effects, ranging from anti-bacterial activities to increases in local blood flow, and that they can somehow protect tissues from damage when oxygen is suddenly cut off and then rapidly restored, as occurs during heart attacks and strokes.

To study the molecular underpinnings of this protective effect of nitrite, the researchers at Boston University School of Medicine used a rat model in which they administered nitrite only once, causing a short spike in circulating levels, as a way to simulate the types of naturally occurring increases in nitrite that follow exercise or consumption of a meal rich in nitrate.

The researchers used a systems-biology approach in which changes in multiple biological and biochemical systems (e.g., the composition of a large number of proteins, the concentration of several small molecule metabolites, and functional outcomes) are simultaneously monitored and then integrated to produce one final picture in order to provide a broader view of the impact of this treatment on the heart. They tested their theory that following these changes over time and at different doses of nitrite might help to explain the protective effects of nitrite on the heart.

“What we found was that a single brief nitrite treatment elicited persisting changes in the heart’s oxidation status together with lasting alterations to numerous proteins involved in the heart’s energy metabolism, redox regulation, and signaling,” said David H. Perlman, a post-doctoral research associate in the Cardiovascular Proteomics Center at Boston University School of Medicine, and lead author of the study. “These alterations were particularly striking because they persisted at least 24 hours after the actual nitrite levels had returned back to normal, and they were correlated strongly with the improvements in heart function observed at the same time.”

He noted that this type of protection, called ‘cardiac preconditioning’, is a recently discovered phenomenon shown to be caused by numerous pharmacological agents.

“The proteins we have implicated include some key proteins, such as mitochondrial aldehyde dehydrogenase, that have been shown by others to be critical to cardiac protection afforded by other agents and triggers,” added Perlman. “This is exciting because it ties nitrite-triggered cardioprotection into the broader preconditioning field. Our study complements and extends other work, and identifies new players of potential importance for protection of the heart.”

Perlman explained that nitrite levels in our bodies change under a number of circumstances, such as when we run up a flight of stairs or eat a big serving of salad.

“For years, the resulting bursts in nitrite were considered to be of little if any physiological relevance. Now we have good reason to believe that even small spikes in nitrite concentration can alter protein function in the heart in ways that afford protection,” noted Perlman.

“We are intrigued by the breadth and magnitude of the proteomic changes in heart mitochondria elicited by a single, short-lasting elevation in nitrite concentration and believe that our findings will have broad implications for mitochondrial signalling and cardiac energetics,” commented Martin Feelisch, senior author of the study. “It looks as though nitrite is triggering an ancient program aimed at fine-tuning mitochondrial function. Although the present study focussed on the heart, our observations may extend to other tissues and translate into relevant changes in muscle function elsewhere. If true, this may help explain, for example, the training effects of very short periods of exercise, which are known to be associated with elevations in circulating nitrite concentrations.”

Interestingly, only low and high doses of nitrite, but not those in-between, were found to be protective. Although further studies will be needed to fully delineate the mechanisms of nitrite-induced cardioprotection, this study informs ongoing basic and translational studies by highlighting the importance of the dose-effect relationship for nitrite and the broad array of downstream targets possibly involved in its cardioprotective efficacy, the researchers concluded.

The study was carried out as a collaboration between researchers at the Cardiovascular Proteomics Center at Boston University School of Medicine under the direction of Prof. Catherine E. Costello and core lab director Prof. Mark E. McComb, Prof. Martin Feelisch and his lab members of the Whitaker Cardiovascular Institute at Boston University School of Medicine, and Prof. Houman Ashrafian of Oxford University’s Department of Cardiovascular Medicine. It was supported by grants and a contract from the National Institutes of Health, National Heart Lung and Blood Institute and National Center for Research Resources, as well as a Medical Research Council Strategic Appointment Award. It is available in the February 19th online edition of Circulation Research.

Journal reference:

1. Perlman et al. Mechanistic Insights Into Nitrite-Induced Cardioprotection Using an Integrated Metabonomic/Proteomic Approach. Circulation Research, 2009; DOI: 10.1161/CIRCRESAHA.108.187005

Adapted from materials provided by Boston University

Daily Glass Of Beet Juice Can Beat High Blood Pressure, Study Shows


Fresh beets. Researchers have discovered that drinking just 500ml of beetroot juice a day can significantly reduce blood pressure. (Credit: iStockphoto/Yana Petruseva)

Researchers at Barts and The London School of Medicine have discovered that drinking just 500ml of beetroot juice a day can significantly reduce blood pressure. The study could have major implications for the treatment of cardiovascular disease.

Professor Amrita Ahluwalia of the William Harvey Research Institute at Barts and The London School of Medicine, and Professor Ben Benjamin of Peninsula Medical School — Research reveals that it is the ingestion of dietary nitrate contained within beetroot juice – and similarly in green, leafy vegetables – which results ultimately in decreased blood pressure. Previously the protective effects of vegetable-rich diets had been attributed to their antioxidant vitamin content.

Professor Ahluwalia and her team found that in healthy volunteers blood pressure was reduced within just 1 hour of ingesting beetroot juice, with a peak drop occurring 3-4 hours after ingestion. Some degree of reduction continued to be observed until up to 24 hours after ingestion. Researchers showed that the decrease in blood pressure was due to the chemical formation of nitrite from the dietary nitrate in the juice.

The nitrate in the juice is converted in saliva, by bacteria on the tongue, into nitrite. This nitrite-containing saliva is swallowed, and in the acidic environment of the stomach is either converted into nitric oxide or re-enters the circulation as nitrite. The peak time of reduction in blood pressure correlated with the appearance and peak levels of nitrite in the circulation, an effect that was absent in a second group of volunteers who refrained from swallowing their saliva during, and for 3 hours following, beetroot ingestion.

More than 25 per cent of the world’s adult population are hypertensive, and it has been estimated that this figure will increase to 29 per cent by 2025. In addition, hypertension causes around 50 per cent of coronary heart disease, and approximately 75 per cent of strokes. In demonstrating that nitrate is likely to underlie the cardio-protective effect of a vegetable-rich diet, the research of Professor Ahluwalia and her colleagues highlights the potential of a natural, low cost approach for the treatment of cardiovascular disease — a condition that kills over 110,000 people in England every year.

Professor Ahluwalia said: ” Our research suggests that drinking beetroot juice, or consuming other nitrate-rich vegetables, might be a simple way to maintain a healthy cardiovascular system, and might also be an additional approach that one could take in the modern day battle against rising blood pressure’.

The paper, ‘Acute blood pressure lowering, vasoprotective and anti-platelet properties of dietary nitrate via bioconversion to nitrite’, was published online in Hypertension.

Cosmetic Ingredient GML Protects Monkeys From AIDS Virus

Reviewed by Louise Chang, MD, by Daniel J. DeNoon — March 4, 2009 — A new kind of vaginal gel prevents sexual transmission of the AIDS virus in monkey studies.

The anti-HIV ingredient in the gel is glycerol monolaurate or GML. It’s already FDA approved as an ingredient in cosmetics and medicines.

“The results are very encouraging. They point to a novel avenue to prevent sexual transmission of HIV,” study researcher Ashley T. Haase, MD, head of the microbiology department at the University of Minnesota, Minneapolis, said at a telephone news conference.

The surprise finding that GML can block HIV comes from basic research showing that the AIDS virus gains a foothold in the vagina by taking advantage of the body’s immune system. Immune responses to the virus draw T cells — the white blood cells HIV loves to infect — to the site of infection. Without T-cell recruitment, HIV loses its grip.

That’s where GML comes in. The antimicrobial agent affects immune responses and breaks the chain of events that let HIV spread through the body.

“We thought if we could modulate the immune response at the portal of HIV entry, we could block sexual transmission,” Haase said. “[Colleague] Patrick Schlievert’s work with GML showed that it had many properties that might block HIV expansion and systematic spread.”

Haase, Schlievert, and colleagues gave five rhesus macaque monkeys daily GML treatments before putting 200 infectious doses of deadly SIV — the monkey version of HIV — into their vaginas. Another four animals got a gel without GML.

The four animals not given GML got AIDS. Those treated with GML showed no sign of infection during the short-term study, although one of the five animals showed signs of infection several months later. But just as HIV drugs with different modes of action are more effective when mixed into a drug “cocktail,” Haase says GML could be mixed with different kinds of anti-HIV agents.

“GML could be part of a combined strategy with another vaginal microbicide, such as PRO 2000, with a different mechanism of action,” he suggests.

Ingredients of GML Anti-HIV Gel in Common Use

GML is found in breast milk, Schlievert says, and it is used in many cosmetics and in medicines taken orally or used on the skin. And recent studies show that GML kills many different kinds of germs — including vaginal yeast infections and several different sexually transmitted diseases, said Schlievert, professor of microbiology at the University of Minnesota.

“GML is presently being considered as an additive to tampons because of its ability to interfere with bacterial growth, including the bacteria that cause toxic shock syndrome,” Schlievert said at the news conference.

For vaginal use in the monkey studies — and with an eye toward future human use — GML was mixed with KY Warming Liquid, an over-the-counter product widely used as a personal lubricant.

“What was done was to combine two FDA-approved medical devices to create another approved device,” Schlievert said.

However, Schlievert said GML has not yet been tested for long-term human use.

And there’s a lot more work to do with monkeys before GML gel is ready for human tests. That will have to be done before human studies of GML gel for HIV prevention.

Haase, Schlievert, and colleagues report their findings in the March 4 online edition of the journal Nature.

By Mass High Tech staff, March 4, 2009

Worcester-based biotech Advanced Cell Technology Inc. reports that it has taken in $400,000 in additional funding in a number of recent deals, which the company will use to advance its use of stem cells for treatments of diseases of the eye.

Part of the funding came through the receipt of the final payment from Korean biotech CHA Biotech Co. Ltd., for its recently formed international joint venture with ACT called Stem Cell & Regenerative Medicine International.

In December, ACT (OTC:ACTC) and CHA Biotech formed the stem cell technology development company, which is also based in Worcester. The international joint venture will use ACT’s hemangioblast cell technology to develop human blood cells and was originally called Allied Cell Technology.

Additional funding came in the form of research grants from the National Institutes of Health for amounts that were not disclosed.

ACT is focusing its efforts and the new funding on its retinal pigment epithelium cells (RPE) program, which chairman and CEO William M. Caldwell says has “potential therapeutic impact on some 200 different retinal disease conditions.” The company says it plans to file an Investigational New Drug application with the U.S. Food and Drug Administration during the second half of this year.

59859FCC-A62D-417B-8BC8-0143B1ABBC47.jpg — Industrial hygienists designed a flexible undergarment to take accurate readings of vital signs such as heart rate, breathing rate, and body temperature. They monitor these indicators to protect firefighters from overexertion and putting themselves in danger. The information can be sent wirelessly to a monitoring station for real-time monitoring.

Firefighting is a dangerous job, but the biggest risk doesn’t come from the fire, smoke, or chemicals. Half of all firefighters who die in the line of duty suffer fatal heart attacks. Now, researchers are testing special gear that someday may alert others if a fellow firefighter is in trouble. They risk their lives ý to save lives. But there’s an invisible threat that puts them most at risk.

“Contrary to popular belief, firemen don’t get burned, blown up or fall into holes. They die of heart attacks,” Dave Hostler, Director of the Emergency Responder Human Performance Lab at the University of Pittsburgh, told Ivanhoe.

Firefighting is a physically demanding job. A firefighter may force his body to work at ninety-percent of its maximum heart rate for up to twenty minutes — that’s anywhere from 160 to 180 beats a minute. “To somebody who is not in good shape, 160, 170 is a terrible stress,” Hostler told Ivanhoe.

This specially designed vest has five built-in sensors that track vital signs. Inside the National Personal Protective Laboratory, researchers who study human performance want to know if this flexible undergarment called a lifeshirt takes accurate readings. How well does it track a firefighters body temperature, heart rate, and breathing?

Researchers put a volunteer through the paces wearing full firefighter gear. They monitor the signals from the sensors in his vest and compare them with measurements taken by the lab equipment.

“The signals would be sent back to a central command stations,” Ron Shaffer, Director of the Research Branch of the National Personal Protective Laboratory, told Ivanhoe. A firefighter with a dangerously high heart rate could be pulled out of a fire. It’s technology that could someday save the life of someone who works to save lives.

How does the heart use pressure to pump blood?

The heart is a muscle, and when it contracts or beats, it pumps blood out. The heart contracts in two stages. First, the right and left atria contract at the same time to pump blood to the right and left ventricles. The ventricles then contract together to pump blood out of the heart.
The heart muscle relaxes before the next heartbeat to allow blood to fill up the heart again, since it must be filled with blood to pump. An average heart can pump 2.4 ounces of blood per heartbeat, or 1.3 gallons per minute. Your blood vessels act like pipes to carry the blood to and from the heart, distributing it through the body.

In order for blood to flow, it has to have a pressure difference, since blood — like any other fluid — flows from the high pressure to low pressure, just like a waterfall. That’s why the pressure in the left ventricle is the highest, followed a slightly lower pressure in the left atrium. The pressure in the right ventricle is lower than the left atrium, but still higher than that of the right ventricle. So the left ventricle, with its high pressure, is able to push blood with sufficient force to send it through the body all the way down to the toes, with enough pressure left to bring it back to the right atrium and repeat the cycle.


Stem Cell: Paul Leonard/Photo Researchers

March 4, 2009, by Christine Cyr — Over the past decade, no topic has been more controversial in the worlds of science, politics, and religion than stem cell research. Of course, the debate has centered over the ethics of harvesting embryonic stem cells to cure degenerative diseases. But researchers at the universities of Edinburgh and Toronto may have solved the problem by devising a method to turn human skin cells into stem cells so that can be safely transplanted into humans.

We know you readers know your stuff, and you’re probably thinking, “Wait a minute…didn’t someone already figure out how to make stem cells from skin cells?” Yes. Back in 2007, Japanese professor Shinya Yamanaka discovered a way to turn skin cells into induced pluripotent stem (iPS) cells—which act similarly to embryonic stem cells. Yamanaka’s method was a huge step toward solving the fiercely controversial debate over stem cell research (because scientists wouldn’t have to use embryos). And because Yamanaka used the donor’s own skin cells, the iPS cells were a genetic match—meaning they’d be much less likely to be rejected by the donor’s immune system than embryonic stem cells might.

But Yamanaka’s method came with a complication. To turn skin cells into iPS cells, four specific genes—c-Myc, Klf4, Oct4 and Sox—must be injected into the DNA. Yamanaka injected these genes by using a number of viruses. The problem is that the viruses might mutate, and eventually cause cancer to develop in the tissue grown from iPS cells.

So, for the past few years, the puzzle for stem cell researchers has been based on how to reprogram skin cells into iPS cells without using viruses.

The breakthrough came when two scientists on opposite sides of the Atlantic discovered they’d solved different halves of the same puzzle. In Edinburgh, a team of scientists led by Dr. Keisuke Kaji from the Medical Research Council (MRC) Centre for Regenerative Medicine, successfully injected the four crucial genes in one single fragment of DNA. But Kaji’s team also needed to remove the genes after reprogramming the cells—to avoid abnormalities in the cells’ development—and they hadn’t yet figured out how to do this. Meanwhile, a team led by Dr. Andras Nagy from the University of Toronto developed a reprogramming system that allowed for removing the genes; yet because his team delivered the genes into four different parts of the genome, they hadn’t yet figured out how to remove all of them.
By chance, Kaji and Nagy ended up meeting and combined their efforts, using Kaji’s system of inserting the genes into one fragment of DNA and Nagy’s “footprint-less” removal system. Before this study, non-viral methods for reprogramming skin cells had only worked on mice. This is the first time they’ve worked on human skin cells.

“It will still take time before these iPS cells can be given to patients,” said Sir Ian Wilmut, director of the MRC Centre for Regenerative Medicine, and who also led the team that cloned Dolly the sheep. “But I believe the team has made great progress, and combining this work with that of other scientists working on stem cell differentiation, there is hope that the promise of regenerative medicine could soon be met.”