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Extramural Papers of the Month

By Jerry Phelps
July 2007

S-nitrosothiols: Possibilities in Fighting Asthma and Heart Disease

Jonathan Stamler and colleagues at Duke University and the Howard Hughes Medical Institute report in the May 4th issue of Cell new findings suggesting the endogenous compound S-nitrosothiol may have clinical implications for a variety of diseases including asthma and heart failure. They found that S-nitrosothiol, a specialized form of nitric oxide, inhibits a key regulatory system that ordinarily shuts off receptors once they have been stimulated.

The G-protein coupled receptors represent the largest known family of cell-surface receptors and are involved in many aspects of mammalian physiology including processes as diverse as responses to odorants, light, and pain. About half of all drugs on the market today target the G-protein coupled receptors. Many of these drugs lose their effectiveness over time because the receptors they target are recycled into the cell and are turned off.

In a series of experiments in laboratory animals and cell culture systems, the researchers found that a lack of nitric oxide led to a decrease in the number of beta adrenergic receptors on the surface of cells. Administration of S-nitrosothiols to mice prevented the receptors from being turned off. If these findings are confirmed in humans, they may lead to the development of new non-sensitizing therapeutic agents for many conditions such as heart disease, asthma, high blood pressure, chronic pain, diabetes and others.

Citation: Whalen EJ, Foster MW, Matsumoto A, Ozawa K, Violin JD, Que LG, Nelson CD, Benhar M, Keys JR, Rockman HA, Koch WJ, Daaka Y, Lefkowitz RJ, Stamler JS. 2007. Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2. Cell 129(3):511-522.

Mutant Astrocytes Play a Role in the Degeneration of Motor Neurons in Amyotrophic Lateral Sclerosis

Astrocytes carrying a version of the mutant protein that causes amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, are responsible for the death of motor neurons, reported NIEHS grantee Serge Przedborski in the May 2007 issue of Nature Neuroscience.

Mutations in the gene for superoxide dismutase (SOD1) are known to cause ALS, in which progressive degeneration of motor neurons leads to paralysis and certain death. In the NIEHS-funded study and an accompanying study published simultaneously, the authors expressed this mutant protein in a variety of single cell types in culture. Motor neurons degenerated and died when they were co-cultured with astrocytes expressing mutant SOD1, while mutant SOD1 in neurons, fibroblasts or microglia did not cause neuronal death.

The researchers also reported that the astrocytes expressing mutant SOD1 killed only spinal motor neurons that degenerate in ALS and not other types of neurons. They show that cell death was due to a soluble toxic factor released by the astrocytes. These findings suggest that stem cell therapy focused on replacing damaged neurons may not be feasible in ALS because mutant astrocytes would most likely kill the replacement neurons. If the toxic factor can be identified in future studies, this finding may offer novel strategies for therapy.

Citation: Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S. 2007. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10(5):615-622.

Green Tea and Skin Cancer

A study funded by NIEHS and the National Cancer Institute reported that drinking green tea can reverse the effects of sun damage to the skin and prevent skin cancer. The study found that green tea prevents UV radiation-induced suppression of the immune system, which has been considered a risk factor for skin cancer.

Green tea has been shown to be rich in antioxidant and anti-inflammatory compounds known as polyphenols and epigallocatechins, which are known to have anti-carcinogenic qualities. In this study, the researchers found that drinking green tea may also help doctors treat internal cancers and heal the pre-cancerous rough, scaly keratosis that some people get from prolonged, chronic exposure to the sun.

The study found that in a mice model, green tea polyphenols administered in drinking water or the application of epigallocatechin-3-gallate to the skin prevented skin tumors through a variety of mechanisms including the induction of interleukin 12, interleukin 12-dependent DNA repair following nucleotide excision repair, inhibition of ultraviolet radiation-induced immunosuppression and angiogenic factors, and stimulation of cytotoxic T-cells in the tumor microenvironment.

The study still needs independent confirmation, but it offers hope for a new and significant therapy for the prevention of skin cancer and a new treatment option for patients suffering from skin cancer.

Citation: Katiyar S, Elmets CA, Katiyar SK. 2007. Green tea and skin cancer: photoimmunology, angiogenesis and DNA repair. J Nutr Biochem 18(5):287-296.

Mercury Content Reduced in Daphnia Fed High Quality Algae

New research by NIEHS-funded scientists at Dartmouth College finds that organisms fed nutritious, high-quality food end up with much lower concentrations of toxic methylmercury in their tissues. The result suggests ways in which methylmercury, a neurotoxin that can accumulate to hazardous levels, can be slowed in its passage up the food chain in fish and ultimately to humans.

The investigators studied the water flea Daphnia pulex, a species of plankton that is one of the chief food sources for freshwater fish. The team measured, over five days, the growth of two groups of juvenile Daphnia. Both groups were fed the same amount of algae contaminated with trace amounts of methylmercury; however, one group's algae was of greater nutritional value.

The Daphnia that received the nutritious, phosphorous-rich algae grew 3.5 times faster than the other group. They also ended up with one-third the concentration of the toxin in their tissues because the toxin was diluted.

Daphnia and other plankton are a major source of methylmercury for lake fish. The research suggests that when water fleas and other organisms grow rapidly by feeding on high quality food, the rate at which methylmercury is accumulated and transferred through the food chain may decrease.

Citation: Karimi R, Chen CY, Pickhardt PC, Fisher NS, Folt CL. 2007. Stoichiometric controls of mercury dilution by growth. Proc Natl Acad Sci U S A. 104(18):7477-7482.



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