Giving Mice A Cold Virus Offers Hope Of New Asthma Treatments

Daily Science Journal (Feb. 8, 2008) — Scientists have been able to recreate rhinovirus infection, which is behind most common colds, in a small animal for the first time. For fifty years since they were discovered, it had been thought that rhinoviruses could only infect humans and chimpanzees. But now a team of scientists led by Professor Sebastian Johnston at the MRC/Asthma UK Centre in Allergic Mechanisms of Asthma at Imperial College London, has been able to infect mice with rhinoviruses.

Scientists have been able to recreate rhinovirus infection, which is behind most common colds, in a small animal for the first time. For fifty years since they were discovered, it had been thought that rhinoviruses could only infect humans and chimpanzees. (Credit: iStockphoto/Jennifer Sheets)

Rhinoviruses are an unwelcome inconvenience for the majority of the population as they cause around three quarters of common colds. However they can also have serious consequences. In susceptible people, they can be fatal. They can lead to the hospitalisation of infants, pneumonia in people with weakened immune systems and they trigger most asthma attacks. They are also the major cause of acute attacks of COPD (chronic bronchitis and emphysema), and are thus the major killer in these diseases.

Professor Johnston said: “Until now it has not been possible to study rhinovirus infection in small animals. This has been a major obstacle to developing new treatments and there is currently no effective treatment for rhinovirus infection.”

It had been thought that mice and other small animals were resistant to rhinoviruses. Of the 100 known strains of rhinovirus, 90 per cent use a binding molecule, called ICAM-1 that is found on the surface of human cells, as their receptor. But the viruses are unable to bind to the mouse version of this receptor.

Professor Johnston explained: "We previously found that once inside the mouse cell a rhinovirus reproduces itself as well as it does in human cells. But the virus couldn’t infect the mouse cell because the receptor (acting like a door key) couldn’t get into the cell.

“Now we’ve modified the mouse receptor so it is more like a human one. This means the virus can infect the cells of these modified mice.”

Professor Johnston added: "We found that mice with the modified receptor were susceptible to infection with a rhinovirus. If combined with an allergen (ovalbumin which is found in egg white) that could cause an allergic reaction in the lungs, the virus could make the response worse and lead to an 'asthma attack'."

The team was able to observe that when the virus was combined with an allergic reaction, the mouse responded similarly to humans. This means it provides a good model for the study of severe asthma attacks.

"These mouse models should provide a major boost to research efforts to develop new treatments for the common cold, as well as for more potentially fatal illnesses such as acute attacks of asthma and of COPD."

The chief executive of the Medical Research Council, Sir Leszek Borysiewicz said: “This important and fundamental discovery will enable us to understand the effects rhinoviruses and common colds have on our health. It will open up new paths to finding treatments which have been delayed for many years and provides us with the opportunities for further breakthroughs in the future.”

Leanne Male, Assistant Director of Research at Asthma UK commented: "Ninety per cent of people with asthma tell us that colds and flu triggers their asthma symptoms but as yet there is no specific treatment for virally induced asthma attacks and steroid treatments are only partially effective against them. We welcome this latest advancement as it will lead to a greater understanding of viral infections and their link with asthma and may help the development of a suitable treatment for virus-induced asthma attacks, thus greatly improving the lives of the 5.2 million people with the condition in the UK."

Journal article: Mouse models of rhinovirus-induced disease and exacerbation of allergic airway inflammation. Published online in Nature Medicine.

The research was funded by the Medical Research Council, Asthma UK and GlaxoSmithKline.

Adapted from materials provided by Imperial College London.

Read the rest of this entry »

Turning Anthrax Toxin Into A Cancer Killer

Daily Science Journal (Jan. 5, 2008) — Most people wouldn't consider anthrax toxin to be beneficial, but this bacterial poison may someday be an effective cancer therapy. Anthrax toxin has actually been shown to be fairly selective in targeting melanoma cells, although the risk of non-cancer toxicity prevents any clinical use.

After binding to cell surface markers, the MMP-activated PA protein (PA-L1) is cleaved by surface associated MMPs, releasing the PA20 fragment. The remaining receptor-bound fragment rapidly oligomerizes to form a heptamer. Up to three molecules of anthrax lethal factor (LF) bind to the heptamer, which is then internalized. Once inside the cell, the complex encounters an acidic environment, which induces a conformational change and allows the LF to enter the cytosol. LF released into the cytosol shuts down multiple signaling pathways, leading to inhibition of tumor angiogenesis and human melanoma cell death. (Credit: Image created by Drs. Shihui Liu, Mahtab Moayeri, and Stephen H. Leppla)

To develop a better and safer treatment, Stephen Leppla and colleagues created a mutated antrax toxin that could only be turned on by matrix metalloproteinases (MMP), proteins that are overproduced only in cancer cells.

When they tested this mutated toxin in mice, the researchers observed that 100% of the animals tolerated a dose that would be lethal for the natural toxin. The MMP-toxin was also better at killing melanoma tumors than natural toxin, due to its higher specificity and longer half-life in the blood.

Even better, Leppla and colleagues saw that MMP-toxin was not limited to melanoma, and could also kill other tumors like colon and lung. This more widespread activity was due to the toxin's ability to inhibit angiogenesis, or the formation of new blood vessels.

These encouraging mouse results suggest that modified anthrax toxin could be clinically viable, and this potent killer might someday be put to good use.

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

Read the rest of this entry »

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.

-------------------------------------------------------------------------------------------

Add On Article :

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.

Read the rest of this entry »