New Technique Makes Tissues Transparent

Daily Science Journal (Feb. 13, 2008) — If humans had see-through skin like a jellyfish, spotting disease like cancer would be a snap: Just look, and see a tumor form or grow.

Diagram of chicken breast tissue (approximately 250 microns thick) with photo-refractive crystal to counteract the scattering of light and remove the distortion it creates in images. The lower diagram would show the clearest image. (Credit: Caltech Biophotonics Laboratory)

But humans, of course, are not remotely diaphanous. "The reason a person is not transparent is that their tissues are highly scattering," sending light waves careening through the tissue instead of straight through, as they would through the tissue of that jellyfish, explains Changhuei Yang of the California Institute of Technology.

This scattering, in addition to rendering all of us opaque, makes the detection of disease a much trickier issue, requiring a host of diagnostic tests and procedures. But not, perhaps, for much longer, thanks to a new optical trick developed by Yang, an assistant professor of electrical engineering and bioengineering, and his colleagues, that counteracts the scattering of light and removes the distortion it creates in images.

It is well known that light scattering in a material is not exactly the random and unpredictable process one might imagine. In fact, scattering is deterministic, which means that the path that a beam of light takes as it traverses a particular slice of tissue and bounces and rebounds off of individual cells, is entirely predictable; if you again bounce light through that same swath of cells, it will scatter in exactly the same way.

The process is even reversible; if the individual photons of light that scattered through the tissue could be collected and sent back through the tissue, they'd bounce back along the same path and converge at the original spot from which they were sent. "The process is similar to the scattering of billiard balls on a pool table. If you can precisely reverse the paths and velocities of the billiard balls, you can cause the billiard balls to reassemble themselves into a rack," Yang explains.

Yang, along with his colleagues at Caltech, École Polytechnique Fédérale de Lausanne in Switzerland, and MIT, exploited this phenomenon to offset the murky nature of our tissues.

Their technique, called turbidity suppression by optical phase conjugation (TSOPC), is surprisingly simple. The scientists used a holographic crystal to record the scattered light pattern emerging from a 0.46-mm-thick piece of chicken breast. They then holographically played the pattern back through the tissue section to recover the original light beam. "This is similar to grabbing hold of the direction of time flow and turning it around; the time-reversed photons must retrace their trajectories through the tissue," Yang says. "The task is formidable though, as this is comparable to starting with a rack of 10 to the 18th power billiard balls (or photons), scattering them around the table, and attempting to reassemble them into a rack."

"Until we did this study, it wasn't clear that the effect will be observable with biological tissues. We were pleasantly surprised that the effect was readily observable and remarkably robust," Yang says. "This study opens up numerous possibilities in the use of optical time reversal in biomedicine."

One possible use of the technique is in photodynamic therapy, in which a highly focused beam of light is aimed at cancerous cells that have absorbed cell-killing light-sensitive compounds. When the light hits the cells, the compounds are activated and destroy the cells. Photodynamic therapy is most effective in treating cancers on the skin surface. Yang's technique, however, offers a way to concentrate light onto cancer-killing compounds located more deeply within tissue.

Yang's idea is to inject strongly light-scattering particles that are coated with light-activated cancer-killing drugs into diseased tissue. Shine a beam of light into the tissue, and it would be reflected off the scattering compounds as it bounces through the tissue. Some of the scattered light would return to the source, where it could be recorded as a hologram.

This hologram would contain information about the path that the scattered light took through the tissue, and, in effect, describe the optimal path BACK toward the light-scattering molecule--and the cancer-killing compounds. Playing back the signal with a stronger burst of light will then activate the therapeutic drugs, which kill the cancer cells.

In addition, the technique could offer a way to power miniature implants buried deep within tissues. "If you take a quick survey of what is out there at present, you will see that implants are fairly large," Yang says. "For example, a pacemaker is about the size of a cell phone. Why are they so big? A large part of the reason is because they need to carry their own power sources."

The key to making smaller implants, then--say, the size of a pen tip--is to eliminate the power sources. "I think implants that carry photovoltaic receivers are particularly promising," he says. "The effect can be applied to tailor light-delivery mechanisms to efficiently channel light into tissues and onto these implants."

A study describing the process appears in the February issue of the journal Nature Photonics. Zahid Yaqoob, a postdoctoral fellow in electrical engineering at Caltech, performed most of the experiments reported in the paper. The other authors of the paper are Demetri Psaltis, professor of optics and dean of engineering, École Polytechnique Fédérale de Lausanne in Switzerland, and Michael S. Feld, a professor of physics at MIT.

Adapted from materials provided by California Institute of Technology.

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DNA Is Blueprint, Contractor And Construction Worker For New Structures

Daily Science Journal (Feb. 4, 2008) — DNA is the blueprint of all life, giving instruction and function to organisms ranging from simple one-celled bacteria to complex human beings. Now Northwestern University researchers report they have used DNA as the blueprint, contractor and construction worker to build a three-dimensional structure out of gold, a lifeless material.

Computer rendition of a structure created by using DNA to assemble nanoparticles into well-defined crystal lattices. (Credit: Northwestern University)

Using just one kind of nanoparticle (gold) the researchers built two common but very different crystalline structures by merely changing one thing -- the strands of synthesized DNA attached to the tiny gold spheres. A different DNA sequence in the strand resulted in the formation of a different crystal.

The technique, to be published in the journal Nature, and reflecting more than a decade of work, is a major and fundamental step toward building functional "designer" materials using programmable self-assembly. This "bottom-up" approach will allow scientists to take inorganic materials and build structures with specific properties for a given application, such as therapeutics, biodiagnostics, optics, electronics or catalysis

Most gems, such as diamonds, rubies and sapphires, are crystalline inorganic materials. Within each crystal structure, the atoms have precise locations, which give each material its unique properties. Diamond's renowned hardness and refractive properties are due to its structure -- the precise location of its carbon atoms.

In the Northwestern study, gold nanoparticles take the place of atoms. The novel part of the work is that the researchers use DNA to drive the assembly of the crystal. Changing the DNA strand's sequence of As, Ts, Gs and Cs changes the blueprint, and thus the shape, of the crystalline structure. The two crystals reported in Nature, both made of gold, have different properties because the particles are arranged differently.

"We are now closer to the dream of learning, as nanoscientists, how to break everything down into fundamental building blocks, which for us are nanoparticles, and reassembling them into whatever structure we want that gives us the properties needed for certain applications," said Chad A. Mirkin, one of the paper's senior authors and George B. Rathmann Professor of Chemistry in the Weinberg College of Arts and Sciences, professor of medicine and professor of materials science and engineering. In addition to Mirkin, George C. Schatz, Morrison Professor of Chemistry, directed the work.

By changing the type of DNA on the surface of the particles, the Northwestern team can get the particles to arrange differently in space. The structures that finally form are the ones that maximize DNA hybridization. DNA is the stabilizing force, the glue that holds the structure together. "These structures are a new form of matter," said Mirkin, "that would be difficult, if not impossible, to make any other way."

He likens the process to building a house. Starting with basic materials such as bricks, wood, siding, stone and shingles, a construction team can build many different types of houses out of the same building blocks. In the Northwestern work, the DNA controls where the building blocks (the gold nanoparticles) are positioned in the final crystal structure, arranging the particles in a functional way. The DNA does all the heavy lifting so the researchers don't have to.

Mirkin, Schatz and their team just used one building block, gold spheres, but as the method is further developed, a multitude of building blocks of different sizes can be used -- with different composition (gold, silver and fluorescent particles, for example) and different shapes (spheres, rods, cubes and triangles). Controlling the distance between the nanoparticles is also key to the structure's function.

"Once you get good at this you can build anything you want," said Mirkin, director of Northwestern's International Institute for Nanotechnology.

"The rules that govern self-assembly are not known, however," said Schatz, "and determining how to combine nanoparticles into interesting structures is one of the big challenges of the field."

The Northwestern researchers started with gold nanoparticles (15 nanometers in diameter) and attached double-stranded DNA to each particle with one of the strands significantly longer than the other. The single-stranded portion of this DNA serves as the "linker DNA," which seeks out a complementary single strand of DNA attached to another gold nanoparticle. The binding of the two single strands of linker DNA to each other completes the double helix, tightly binding the particles to each other.

Each gold nanoparticle has multiple strands of DNA attached to its surface so the nanoparticle is binding in many directions, resulting in a three-dimensional structure -- a crystal. One sequence of linker DNA, programmed by the researchers, results in one type of crystal structure while a different sequence of linker DNA results in a different structure.

"We even found a case where the same linker could give different structures, depending on the temperatures at which the particles were mixed," said Schatz.

Using the extremely brilliant X-rays produced by the Advanced Photon Source synchrotron at Argonne National Laboratory in combination with computational simulations, the research team imaged the crystals to determine the exact location of the particles throughout the structure. The final crystals have approximately 1 million nanoparticles.

"It took scientists decades of work to learn how to synthesize DNA," said Mirkin. "Now we've learned how to use the synthesized form outside the body to arrange lifeless matter into things that are useful, which is really quite spectacular."

The Nature paper, entitled "DNA-programmable nanoparticle crystallization" is to be published January 31, 2008. In addition to Mirkin and Schatz, other authors are Sung Yong Park, a former postdoctoral fellow in Schatz's lab and now at the University of Rochester (lead author); graduate student Abigail K. R. Lytton-Jean, Northwestern University; Byeongdu Lee, Advanced Photon Source, Argonne National Laboratory; and Steven Weigand, Northwestern's DND-CAT Synchrotron Research Center at Argonne's Advanced Photon Source.

Adapted from materials provided by Northwestern University, via EurekAlert!, a service of AAAS.

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Virtual Human In HIV Drug Simulation

Daily Science Journal (Feb. 2, 2008) — The combined supercomputing power of the UK and US ‘national grids’ has enabled UCL (University College London) scientists to simulate the efficacy of an HIV drug in blocking a key protein used by the lethal virus. The method – an early example of the Virtual Physiological Human in action – could one day be used to tailor personal drug treatments, for example for HIV patients developing resistance to their drugs.

The study ran a large number of simulations to predict how strongly the drug saquinavir would bind to three resistant mutants of HIV-1 protease, a protein produced by the virus to propagate itself. These protease mutations are associated with the disease’s resistance to saquinavir, an HIV-inhibitor drug.

The study, by Professor Peter Coveney and colleagues at the UCL Department of Chemistry, involved a sequence of simulation steps, performed across several supercomputers on the UK’s National Grid Service and the US TeraGrid, which took two weeks and used computational power roughly equivalent to that needed to perform a long-range weather forecast.

The idea behind the Virtual Physiological Human (VPH) is to link networks of computers across the world to simulate the internal workings of the human body. The VPH – mainly a research initiative at present – allows scientists to simulate the effects of a drug and see what is happening at the organ, tissue, cell and molecular level.

Although nine drugs are currently available to inhibit HIV-1 protease, doctors have no way of matching a drug to the unique profile of the virus as it mutates in each patient. Instead, they prescribe a course of drugs and then test whether these are working by analysing the patient’s immune response. One of the goals of VPH is for such ‘trial and error’ methods to eventually be replaced by patient-specific treatments tailored to a person’s unique genotype.

Professor Peter Coveney says: “This study represents a first step towards the ultimate goal of ‘on-demand’ medical computing, where doctors could one day ‘borrow’ supercomputing time from the national grid to make critical decisions on life-saving treatments.

“For example, for an HIV patient, a doctor could perform an assay to establish the patient’s genotype and then rank the available drugs’ efficacy against that patient’s profile based on a rapid set of large-scale simulations, enabling the doctor to tailor the treatment accordingly.

“We have some difficult questions ahead of us, such as how much of our computing resources could be devoted to helping patients and at what price. At present, such simulations – requiring a substantial amount of computing power – might prove costly for the National Health Service, but technological advances and those in the economics of computing would bring costs down.”

For the moment, Professor Coveney’s group is continuing to look at all the protease inhibitors in a similar way. The VPH initiative, now underway with 72 million euros of initial funding from the EU, will boost collaboration between clinicians and scientists to explore the scope for patient-specific medical treatments based on modern modelling and simulation methods.

Journal reference: ‘Rapid and Accurate Prediction of Binding Free Energies for Saquinavir-Bound HIV-1 Proteases’, by Ileana Stoica, S. Kashif Sadiq, and Peter V. Coveney, is published online in the Journal of the American Chemical Society on Tuesday 29 January 2008.

The study was partially funded by the EPSRC, the EU-supported ViroLab project and the National Science Foundation. The UK National Grid Service also provided access to their resources and support for this project.

Adapted from materials provided by University College London.

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Medicine From Milk: Gene Therapy Transforms Goats Into Pharmaceutical Factories

Daily Science Journal (Feb. 1, 2008) — University of Pennsylvania researchers have used gene therapy to reduce the time it takes to breed large animals capable of producing therapeutic proteins in their milk, such as insulin or those that fight cancer. This represents a significant milestone in drug development, as current methods involve cloning, which takes more time and generally costs more.

Researchers have used gene therapy to reduce the time it takes to breed goats capable of producing therapeutic proteins in their milk, such as insulin or those that fight cancer. (Credit: iStockphoto)

"Having an easier way to harness nature's power to produce large quantities of specific proteins in milk could increase the availability of drugs for people who could otherwise not afford these treatments," said Ina Dobrinski, one of the researchers on the study.

The study also is significant because it may also be a new way to eliminate diseases in future generations of animals, such as those used for livestock. Here's why: To get the goats to produce specific proteins, the researchers used radiation to kill a portion of a male goat's germ cells (the cells that produce sperm). Then they used a modified adeno-associated virus (a well studied and tolerated gene therapy vector) to insert a gene in the remaining cells. Once the new gene took hold in the germ cells, a predictable number of female offspring produced the desired protein in their milk.

The advance is immediately valuable for pharmaceutical development and biology research, but a similar approach could be used to bolster the food supply by eliminating genetic disorders in animals over several generations. It is also possible that once perfected, this technique could eliminate disease genes in humans over several generations, assuming ethical concerns can be resolved adequately.

This study is published in the February 2008 print edition of The FASEB Journal.

"For thousands of years, people have domesticated cows and goats to make milk, butter and cheese. And for thousands of years dairy products have been used as folk remedies for practically every human illness. Most have been completely ineffective." said Gerald Weissmann, MD, editor-in-chief of The FASEB Journal. "So it is reassuring that modern science would find a way to use the milk we drink to yield of drugs that actually work."

Adapted from materials provided by Federation of American Societies for Experimental Biology, via EurekAlert!, a service of AAAS.

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How Poxviruses Such As Smallpox Evade The Immune System

Daily Science Journal (Feb. 1, 2008) — Scientists at Saint Louis University and the University of Alabama at Birmingham have uncovered important new information about a key protein that allows viruses such as smallpox to replicate and wreak havoc on the immune system.

The findings further our understanding of how the pox family of viruses work to subvert the immune system, the researchers say. They also believe their work could one day be used to develop new drugs to combat a variety of inflammatory and immunological disorders, including rheumatoid arthritis and some forms of heart disease.

The paper* describes the structure and actions of a powerful substance called interferon-gamma binding protein, which is notorious for the role it plays in helping the poxviruses to replicate. The research explores the interferon-gamma binding protein found in the mousepox virus -- one of the family of viruses that also includes smallpox, monkeypox and cowpox.

"Cracking open and describing the structure and actions of interferon-gamma binding protein is incredibly exciting, given the important role this substance plays in subverting the immune system," said Mark Buller, Ph.D., professor of microbiology and immunology at the Saint Louis University School of Medicine and one of the study's authors. "This breakthrough is something that many others have tried and failed to achieve."

Normally when a virus enters the bloodstream, the immune system responds by producing a substance called interferon-gamma, which assists the development of the immune response that's responsible for ridding the body of the virus.

Poxviruses, however, all come encoded with a potent weapon to evade the immune system: interferon-gamma binding protein. As its name implies, the protein literally binds to interferon-gamma and immobilizes it, preventing it from marshalling the immune system's defenses. The poxvirus is then able to replicate and cause immense damage.

The research describes how interferon-gamma binding protein looks and behaves on the molecular level during this process, something not previously understood.

"The poxviruses are able to evade the immune system very skillfully," Buller said, "so we wanted to identify exactly how these viruses work -- what makes them so effective and efficient."

Buller added that the findings have great potential for use in developing drugs that target immunological and inflammatory disorders, including a type of heart disease called atherosclerosis (sometimes referred to as hardening of the arteries), inflammatory bowel diseases (such as Crohn's disease and ulcerative colitis) and rheumatoid arthritis.

Of all the poxviruses, smallpox in particular has played a gruesome role in human history. The virus is estimated to have caused between 300 million and 500 million deaths in the 20th century alone. Though smallpox was declared officially eradicated in 1979, many experts fear that clandestine samples of the virus may have survived -- thus making it a major bioterrorism concern.

"The damage that the smallpox virus has done to mankind is horrific and enormous, which is why we think it's so important to understand more about the poxviruses and how they operate," Buller said. "The more knowledge we have, the better we should be able to cope with other major viruses and diseases in the future."

Buller pointed to co-author Tony Nuara as being critical to the team's success in understanding more about interferon-gamma binding protein. Nuara, now a fourth-year student at Saint Louis University School of Medicine, was working on his Ph.D. in molecular microbiology when taking part in the research effort.

"Without Tony, this research wouldn't have happened," Buller said. "He solved huge numbers of problems and figured out some answers to puzzling questions that previously had no answer."

Mark R. Walter, Ph.D., associate professor of microbiology at the University of Alabama at Birmingham and the paper's senior author, also noted the efforts of co-authors Sung Il Yoon, Ph.D., Brandi C. Jones, Naomi J. Logsdon and Leigh J. Walter, all of whose work contributed to determining the three-dimensional structure of the binding protein.

"The structure provides a visual blueprint to guide our future studies on interferon-gamma binding protein, which one day may be used to prevent inflammatory disease," Mark Walter said. "This is clearly a notable achievement."

*The research has been published in an early online edition of the Proceedings of the National Academy of Sciences. Jill M. Schriewer of Saint Louis University was also a co-author of the study.

The research was funded by grants from the National Institutes of Health, the UAB Center for Emerging Infections and Emergency Preparedness, and the American Heart Association.

Adapted from materials provided by Saint Louis University, via EurekAlert!, a service of AAAS.

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Green Tea And EGCG May Help Prevent Autoimmune Diseases, Cup Of Green Tea To Keep The Bacteria Away

Daily Science Journal (Jan. 16, 2008) — Green tea may help protect against autoimmune disease, Medical College of Georgia researchers say.

Dr Stephen Hsu and colleagues found that green tea may help protect against autoimmune disease. (Credit: Image courtesy of Medical College of Georgia)

Researchers studied an animal model for type I diabetes and primary Sjogren’s Syndrome, which damages the glands that produce tears and saliva.

They found significantly less salivary gland damage in a group treated with green tea extract, suggesting a reduction of the Sjogren’s symptom commonly referred to as dry mouth. Dry mouth can also be caused by certain drugs, radiation and other diseases.

Approximately 30 percent of elderly Americans suffer from degrees of dry mouth, says Dr. Stephen Hsu, a researcher in the MCG School of Dentistry and lead investigator on the study. Only 5 percent of the elderly in China, where green tea is widely consumed, suffer from the problem.

“Since it is an autoimmune disease, Sjogren’s Syndrome causes the body to attack itself and produce extra antibodies that mistakenly target the salivary and lacrimal glands,” he says. There is no cure or prevention for Sjogren’s Syndrome.

Researchers studied the salivary glands of the water-consuming group and a green tea extract-consuming group to look for inflammation and the number of lymphocytes, a type of white blood cells that gather at sites of inflammation to fend off foreign cells.

The group treated with green tea had significantly fewer lymphocytes, Dr. Hsu says. Their blood also showed lower levels of autoantibodies, protein weapons produced when the immune system attacks itself, he says.

Researchers already know that one component of green tea – EGCG – helps suppress inflammation, according to Dr. Hsu. "So, we suspected that green tea would suppress the inflammatory response of this disease. Those treated with the green tea extract beginning at three weeks, showed significantly less damage to those glands over time.”

Researchers also suspect that the EGCG in green tea can turn on the body’s defense system against TNF-alpha – a group of proteins and molecules involved in systemic inflammation. TNF-alpha, which is produced by white blood cells, can reach out to target and kill cells.

“The salivary gland cells treated with EGCG had much fewer signs of cell death caused by TNF-alpha,” Dr. Hsu says. “We don’t yet know exactly how EGCG makes that happen. That will require further study. In some ways, this study gives us more questions than answers.”

These results, published in a recent issue of Autoimmunity, reinforced findings of a 2005 study showing a similar phenomenon in a Petrie dish, Dr. Hsu says. Further study could help determine green tea’s protective role in other autoimmune diseases, including lupus, psoriasis, scleroderma and rheumatoid arthritis, he says.

Adapted from materials provided by Medical College of Georgia.

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Cup Of Green Tea To Keep The Bacteria Away

Beneficial effects of green tea have been known for millenia, particularly in Asian cultures. An ancient Chinese proverb says: "Better to be deprived of food for three days, than tea for one". A cup of green tea contains up to 200 mg of catechins, whose biological activity has been mainly attributed to its antioxidant activity. Efficiency of green tea extract in oral hygiene has been known for centuries and this gave researchers a clue that antibacterial activity might be involved.

Now researchers from the National institute of Chemistry in Ljubljana, Slovenia discovered that the main ingredients of green tea are able to perform other tricks. They found out that green tea catechins inhibit essential bacterial enzyme DNA gyrase, which is the target of several existing clinically used drugs. By the use of NMR spectroscopy, researchers from Slovenia have now pinpointed the ATP-binding site of DNA gyrase as target of EGCG, the most abundant catechin from the green tea extract. Up to now several compounds targeted against the ATP-binding site of bacteria gyrase have been known but couldn't be used as drugs due to their side effects on mammalian cells.

Lead researcher Roman Jerala, the head of the Laboratory of Biotechnology at NIC explains: "We can anticipate to avoid the problem of toxicity using the compounds based on the green tea catechins, which have centuries of established safety record in the human diet."

This finding may be used to develop even more potent antibacterial compounds. Results were recently published in the Journal of Medicinal Chemistry.

Adapted from materials provided by National Institute Of Chemistry, Slovenia.

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Potential New Way Of Treating Inflammatory Diseases Identified

Daily Science Journal (Sep. 19, 2007) — Scientists have shown for the first time that platelets, the cells needed for blood clotting, help white blood cells called neutrophils fight inflammation.

The discovery was made by Ralph Kettritz, Professor of Medicine at the Medical Faculty of the Charite and investigator at the Max Delbrueck Center for Molecular Medicine, Berlin, Germany, and colleagues. The results of the study could lead to new anti-inflammatory compounds for the treatment of inflammatory vascular injury.

"We found an entirely new mechanism by which neutrophils induce inflammation," Kettritz says. "So far, scientists have shown that platelets form clots and neutrophils can cause symptoms of inflammation, such as swelling, redness, and heat. In this study, we show that platelets and neutrophils sometimes work together to heal a wound or fight an infection."

During inflammation -- a protective reaction from the tissues following a wound or infection -- white blood cells attack bacteria and platelets form clots that close any potential wound. White blood cells called neutrophils are the first to launch an attack against the bacteria. They are attracted by substances, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), that are released at the early stages of inflammation. Once activated, neutrophils engulf and destroy bacteria and damaged tissue.

In addition to neutrophils, two other types of white blood cells, called macrophages and lymphocytes, also engage in the fight against bacteria. These cells are activated by a chemical compound called tumor necrosis factor (TNF) released by the neutrophils. Although there are several ways by which neutrophils release TNF, Kettritz and colleagues found that neutrophils can be stimulated to produce TNF in a totally new and different way.

"Usually, TNF is produced when specific chemicals bind to proteins called receptors on the surface of a neutrophil, which tells the cell that it should make TNF," Kettritz says. "This time, we found that a neutrophil can acquire receptors that are not already present on its surface and use them to stimulate the production of TNF."

The receptors, called GPIIb/IIIa, are sent to neutrophils by platelets. Like a letter sent in an envelope, these receptors are packaged in vesicles called microparticles that, when they reach a neutrophil, bind to its surface and release the receptors. Once released, the receptors are incorporated into the neutrophil's cell membrane.

Kettritz and his team also found that these newly-acquired receptors did not work alone. To stimulate neutrophils to produce TNF, the GPIIb/IIIa receptor works in tandem with the receptor for GM-CSF (the substance produced during the early stages of inflammation). The scientists found that the neutrophil produces TNF both when GPIIb/IIIa binds to a protein outside the cell called fibronectin and when the GM-CSF receptor binds to GM-CSF.

"We have shown for the first time that platelets can, by using microparticles, help other cells -- in this case, neutrophils -- respond to inflammation," Kettritz says. "We also found for the first time that receptors involved in blood clotting also trigger an inflammatory response."

These results may help devise new drugs against several types of inflammation by targeting the GPIIb/IIIa receptors acquired by neutrophils. In particular, drugs currently used to prevent blood clotting by inhibiting GPIIb/IIIa receptors on platelets may be used against inflammation.

Kettritz and colleagues tested three of these drugs -- abciximab, epifibatide, and tirofiban -- on cell cultures in which neutrophils had received the GPIIb/IIIa receptors from platelets and confirmed the drugs' effects on inflammation. The scientists showed that all three drugs inhibited the production of TNF, which reduced inflammation in these cells. These results also led the researchers to speculate that some of the beneficial effects of the three drugs on patients with acute coronary syndrome result from their anti-inflammatory properties.

If the drugs' effects are confirmed in clinical trials, they could be used against several types of inflammation that include acute vasculitis, an inflammation of blood vessels that can affect any organ in the body. Also, the drugs have been used successfully to treat acute coronary syndrome, which refers to certain types of heart attack and unstable angina. The new results show that these beneficial effects may be due not only to their anti-clotting properties, but also to their anti-inflammatory qualities.

"The results of this study are very encouraging," Kettritz says. "Although specific drugs that target GPIIb/IIIa receptor actions on neutrophils may need to be developed in the future, these three drugs can now be tested in clinical trials, which could make them -- or modified versions of them -- new anti-inflammatory drugs."

The new study, to be published in the September 21 issue of the Journal of Biological Chemistry, was selected as a "Paper of the Week" by the journal's editors, meaning that it belongs to the top one percent of papers reviewed in significance and overall importance.

Article: "Beta 2-integrins and acquired GPIIb/IIIa receptors cooperate in NF-KB activation of human neutrophils," by Birgit Salanova, Mira Choi, Susanne Rolle, Maren Wellner, Friedrich C. Luft, and Ralph Kettritz

Adapted from materials provided by American Society for Biochemistry and Molecular Biology, via EurekAlert!, a service of AAAS.

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Green Tea Holds Promise As New Treatment For Inflammatory Skin Diseases, Tea Extracts Help Treat Damaged Skin In Cancer Patients

Daily Science Journal (Aug. 7, 2007) — Green tea could hold promise as a new treatment for skin disorders such as psoriasis and dandruff, Medical College of Georgia researchers say.

Dr Hsu says, "There are no cures for autoimmune diseases. But it is possible that this is a non-toxic way to regulate them. We need further study -- on humans -- to determine the full effects." (Credit: Medical College of Georgia)

Researchers studied an animal model for inflammatory skin diseases, which are often characterized by patches of dry, red, flaky skin caused by the inflammation and overproduction of skin cells. Those treated with green tea showed slower growth of skin cells and the presence of a gene that regulates the cells' life cycles.

"Psoriasis, an autoimmune disease, causes the skin to become thicker because the growth of skin cells is out of control," says Dr. Stephen Hsu, an oral biologist in the MCG School of Dentistry and lead investigator on the study published in the Aug. 18 edition of Experimental Dermatology. "In psoriasis, immune cells, which usually protect against infection, instead trigger the release of cytokines, which causes inflammation and the overproduction of skin cells."

Other autoimmune diseases with similar side effects include lupus, which can lead to skin lesions, and dandruff.

Green tea, already shown to suppress inflammation, helps by regulating the expression of Caspase-14, a protein in genes that regulates the life cycle of a skin cell.

"That marker guides cells by telling them when to differentiate, die off and form a skin barrier," Dr. Hsu says. "In people with psoriasis, that process is interrupted and the skin cells don't die before more are created and the resulting lesions form."

Animal models treated with green tea also showed reduced levels of proliferating cell nuclear antigen, a gene expressed when skin cells multiply. In psoriasis, the gene is over-expressed and speeds production of skin cells.

"Before treatment, the antigen, PCNA, was present in all layers of the skin," Dr. Hsu says. "Typically, PCNA is only found in the basal layer, the innermost layer where skin cells continually divide and new cells push the older ones to the skin surface, where they eventually slough off. After being treated with green tea, the animal models showed near-normal levels of PCNA in only the basal layers."

This research is important because some treatments for psoriasis and dandruff can have dangerous side effects, he says.

"The traditional treatment of ultraviolet light and medication, while it can control the lesions and be used long term, may cause squamous cell carcinoma – the second most common form of skin cancer," Dr. Hsu says. "Some of the most effective anti-dandruff shampoos also have carcinogens in them. While the U.S. Food and Drug Administration allows that in small amounts, the bottom line is that we don't know the long-term effects of using those products continuously."

Green tea, which is plant-derived, may be an alternative, he says. But scientists must work to overcome some barriers with the treatment.

The chemicals in green tea are so active that they are oxidized too quickly when mixed with other ingredients. They also dissolve in water, which cannot penetrate the skin's barrier.

Researchers are looking for a balanced formula that can dissolve in fats, which can permeate the skin, Dr. Hsu says.

Adapted from materials provided by Medical College of Georgia.

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Tea Extracts Help Treat Damaged Skin In Cancer Patients

Tea extracts work as an effective treatment for patients who suffer from damaged skin following radiation treatment for cancer. Researchers show that this might partly be due to the anti-inflammatory properties of tea.

In a study published in the open access journal BMC Medicine, researchers show that tea acts at the cellular level, by inhibiting inflammatory pathways, to reduce inflammation. They also show that tea extracts reduce the duration of radiation-induced skin damage by up to 10 days in patients who received radiation treatment.

Frank Pajonk, from the University of California in Los Angeles, USA, and colleagues from the University of Freiburg, Germany, studied the effects of green tea and black tea extracts on patients who had been treated with radiotherapy, which can damage the skin. The authors then analysed the effects of the same tea extracts on human and mouse white blood cells in culture.

Pajonk et al. find that tea extracts reduce the duration of skin toxicity following radiotherapy by 5 to 10 days. Green tea extracts are more effective than black tea extracts in some patients. Pajonk et al. also show that tea extracts reduce the release of pro-inflammatory cytokines, such as IL-1beta, IL-6, IL-8, TNFalpha and PGE2, in human white blood cells in culture, with green tea having higher anti-inflammatory properties than black tea. Both black tea and green tea inhibit one major inflammatory pathway in mouse white blood cells.

Pajonk et al. add that tea's high content of polyphenols is likely to be responsible for its high anti-inflammatory activity, but that other pathways are probably involved in its clinical effectiveness.

Adapted from materials provided by BioMed Central, via EurekAlert!, a service of AAAS.

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Researchers Explain Carbon Monoxide's Anti-inflammatory Effects

Daily Science Journal (Jul. 1, 2007) — In a study appearing in the April 2007 issue of The FASEB Journal, scientists from Harvard University and the University of Pittsburgh have shown for the first time that the anti-inflammatory effects of carbon monoxide originate within cells' own molecular engines, mitochondria.

Specifically, mitochondria react to low levels of carbon monoxide by releasing chemical signals that reduce or shut down the body's inflammatory response, raising the possibility for the development of new anti-inflammatory therapies, one of which may be low levels of inhaled carbon monoxide.

According to the study's first author, Brian S. Zuckerbraun, M.D. of the University of Pittsburgh, "this study may contribute to our understanding and development of controlled carbon monoxide as a therapeutic agent."

Inflammation is a normal defense mechanism used by the body to ward off infection, but over time, severe or chronic inflammation can damage tissues. In some cases, such as in organ transplantation, the body's inflammatory response over the short-term also can cause more harm than good. Current approaches to controlling inflammation are not always successful, making the need for new approaches urgent. In particular, inhaled medical grade carbon monoxide has been shown to be useful in animal models for organ transplantation, vascular injury, inflammatory bowel disease, organ injury resulting from severe blood loss, as well as experimental hepatitis and experimental pulmonary hypertension.

"The findings described in this study are particularly relevant, given that April is National Donate Life Month," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "Transplants are rejected because of inflammation gone awry. If we block inflammation, as with carbon monoxide or agents that release it in a controlled fashion, we can not only make transplantation safer, but extend its benefits to many more who need it."

Adapted from materials provided by Federation of American Societies for Experimental Biology, via EurekAlert!, a service of AAAS.

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New Process Boosts Levels Of Heart-healthy Compounds In Cocoa Powder, (Add On- Cocoa, But Not Tea, May Lower Blood Pressure)

Daily Science Journal (Jun 10, 2007) — Scientists in Spain are reporting development of a new process to make cocoa powder with higher amounts of the healthful chemical compounds linked to chocolate's beneficial effects. The study is scheduled for publication in the May 30 issue of ACS' Journal of Agricultural and Food Chemistry.

Cocoa beans -- the source of chocolate -- in a cacao pod. (Credit: Photo by Keith Weller; courtesy of USDA/Agricultural Research Service)

Juan Carlos Espin de Gea and colleagues report that the new cocoa powder contains levels of some flavonoids 8 times higher than conventional cocoa. They achieved the higher flavonoid content by omitting the traditional fermentation and roasting steps used in the processing of cocoa beans. Those steps destroy some flavonoids, which are natural antioxidants.

Researchers used the flavonoid-enriched cocoa powder in a clinical trial to determine whether the compounds were bioavailable — in a form that humans can absorb. In the trial, six healthy volunteers consumed a milk drink made with flavonoid-enriched cocoa. The same volunteers later drank chocolate milk made from traditional cocoa. Blood and urine tests established the bioavailability of flavonoids in the enriched-milk drink, showing that people do absorb higher levels of the compounds.

Based on the results, researchers suggest further clinical trials on the health benefits of flavonoid-enriched cocoa powder.

Adapted from materials provided by American Chemical Society, via EurekAlert!, a service of AAAS.

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Cocoa, But Not Tea, May Lower Blood Pressure

Foods rich in cocoa appear to reduce blood pressure but drinking tea may not, according to an analysis of previously published research in the April 9 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.

Current guidelines advise individuals with hypertension (high blood pressure) to eat more fruits and vegetables, according to background information in the article. Compounds known as polyphenols or flavonoids in fruits and vegetables are thought to contribute to their beneficial effects on blood pressure and cardiovascular risk. "Tea and cocoa products account for the major proportion of total polyphenol intake in Western countries," the authors write. "However, cocoa and tea are currently not implemented in cardioprotective or anti-hypertensive dietary advice, although both have been associated with lower incidences of cardiovascular events."

Dirk Taubert, M.D., Ph.D., and colleagues at the University Hospital of Cologne, Germany, conducted a meta-analysis of 10 previously published trials, five of cocoa's effects on blood pressure and five involving tea. All results were published between 1966 and 2006, involved at least 10 adults and lasted a minimum of seven days. The studies were either randomized trials, in which some participants were randomly assigned to cocoa or tea groups and some to control groups, or used a crossover design, in which participants' blood pressure was assessed before and after consuming cocoa products or tea.

The five cocoa studies involved 173 participants, including 87 assigned to consume cocoa and 86 controls, 34 percent of whom had hypertension (high blood pressure). They were followed for a median (middle) duration of two weeks. Four of the five trials reported a reduction in both systolic (the top number, when the heart contracts) and diastolic (the bottom number, when the heart relaxes) blood pressure. Compared with those who were not consuming cocoa, systolic blood pressure was an average of 4.7 millimeters of mercury lower and diastolic blood pressure was an average of 2.8 millimeters of mercury lower.

The effects are comparable to those achieved with blood pressure-lowering medications, the authors note. "At the population level, a reduction of 4 to 5 millimeters of mercury in systolic blood pressure and 2 to 3 millimeters of mercury in diastolic blood pressure would be expected to substantially reduce the risk of stroke (by about 20 percent), coronary heart disease (by 10 percent) and all-cause mortality (by 8 percent)," they write.

Of the 343 individuals in the five tea studies, 171 drank tea and 172 served as controls, for a median duration of four weeks. Drinking tea was not associated with a reduction in blood pressure in any of the trials.

Tea and cocoa are both rich in polyphenols, but while black and green tea contain more compounds known as flavan-3-ols, cocoa contains more of another type of polyphenol, procyanids. "This suggests that the different plant phenols must be differentiated with respect to their blood pressure-lowering potential and thus cardiovascular disease prevention, supposing that the tea phenols are less active than cocoa phenols," the authors write.

The findings do not indicate a widespread recommendation for higher cocoa intake to decrease blood pressure, but it appears reasonable to substitute phenol-rich cocoa products such as dark chocolate for other high-calorie or high-fat desserts or dairy products, they continue. "We believe that any dietary advice must account for the high sugar, fat and calorie intake with most cocoa products," the authors conclude. "Rationally applied, cocoa products might be considered part of dietary approaches to lower hypertension risk."

Adapted from materials provided by JAMA and Archives Journals.

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