Environmental Epigenetics Has Potential For Preventing And Treating Disease

Daily Science Journal (Feb. 6, 2008) — New research on environmental influences on health and disease has begun to shed light on why genetically identical individuals demonstrate different characteristics, such as susceptibility to disease. Scientists have found that environmental exposure to nutritional, chemical and physical factors can alter the epigenome. Literally meaning “above the genome,” the epigenome refers to differences in gene expression that are inherited without changing the sequence of DNA.

New research* examines some of the epigenetic mechanisms linked to disease, and explores how they occur and their significance in understanding, treating and preventing disease.

Authors Randy L. Jirtle and Dana C. Dolinoy of Duke University Medical Center in Durham, North Carolina, discuss genomic imprinting, a form of gene regulation in which epigenetic modifications in chromosomes result in differences in gene expression. First identified in 1991, there are approximately 80 imprinted genes that have been identified in mice and humans. Because imprinted genes behave as if they have a single set of chromosomes rather than the usual two, the health consequences of mutations in these genes are potentially disastrous, resulting in diseases such as cancer and several severe pediatric developmental disorders.

In addition, mutations that occur in non-imprinted regions can influence the regulation of imprinted genes. The authors previously demonstrated that imprinting evolved anywhere from 230 to 150 million years ago, arising in mammals with the evolution of the placenta. They note that the expression of imprinted genes is species, tissue and developmental stage dependent and may play an important role in the speciation of mammals.

The article cites several studies involving metastable epialleles, which are alternate forms of a gene that are expressed due to epigenetic modifications linked to maternal nutrition and environmental exposure during very early development. The authors note that simple dietary changes were found to protect against the negative effects of environmental toxins on the fetal epigenome. They also cite evidence that embryos are vulnerable to environmentally-induced epigenetic alterations early in their development, highlighting the need to analyze the timing of exposure in order to fully understand environmental epigenomics.

The advent of bioinformatics has allowed researchers to more readily search the entire mouse genome for imprinted genes, but the real power of this approach has been recently demonstrated in its application to the human genome. While 2.5 percent of the mouse genome contains potentially imprinted genes, only 0.75 percent of the human genome is predicted to be imprinted. This means that the mouse genome may not be a suitable model for assessing human disease risk due to epigenetic mutations in imprinted genes. The authors point out the necessity of developing bioinformatic models that can identify metastable epialleles in order to characterize all of the genes susceptible to environmental influences.

With the identification of epigenetically unstable locations in the human genome, it will be possible to screen individuals at an early age for epigenetically susceptible diseases, allowing for closer monitoring and more frequent follow-up. In addition, unlike genetic mutation, epigenetic profiles are potentially reversible. “Therefore, epigenetic approaches for prevention and treatment, such as nutritional supplementation and/or pharmaceutical therapies may be developed to counteract negative epigenomic profiles,” the authors conclude. “The future of epigenomics therapy holds tremendous potential for not only individualized health care but also for population-wide disease diagnostic, screening, and prevention strategies.”

*Article: “Environmental Epigenomics in Human Health and Disease,” Dana C. Dolinoy and Randy L. Jirtle, Environmental and Molecular Mutagenesis, January 2008, 49:1.

Adapted from materials provided by Blackwell Publishing Ltd.

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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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