Resveratrol Slows Metabolism in Double-Blind Study

Scientists at the Dutch Maastricht University have reported results from a double-blind, placebo-controlled trial of resveratrol, the sirtuin activator and red wine compound so far much-touted, but not rigorously tested, as an anti-aging compound. The scientists gave 11 obese but otherwise healthy men either 150 mg of resveratrol or placebo for 30 days, and found that this regimen had many of the same beneficial effects on metabolism as caloric restriction. Among the benefits they observed were reduced systolic blood pressure, changes to lipid metabolism, and changes to resting and sleeping metabolic rate. The authors concluded that their study "[extended] findings, which so far have been observed only in cell and rodent models, to the human situation, showing that resveratrol has promising beneficial metabolic effects, and suggest that resveratrol has the potential to improve metabolic health in subjects at risk for developing the metabolic syndrome." They also noted that even though the levels of resveratrol the patients received were much lower than those used in animals, the plasma levels of resveratrol were higher, suggesting the compound is metabolized differently in mice and men. The work appeared in the Nov. 1, 2011, issue of Cell Metabolism.

Meanwhile, Back at the Lab . . .

. . . Scientists from the Salk Institute for Biological Studies and the University of California at Los Angeles have identified an additional effect that explains why caloric restriction extends lifespan. In their studies, the authors overexpressed the transcription factor PCG-1 in fruit flies, either systemwide or specifically in intestinal stem cells. In both cases, the animals had more active mitochondria – the energy powerhouses of cells. Animals overexpressing PCG-1 specifically in intestinal stem cells also aged more slowly than their wild-type cousins, and lived, on the average, a third longer. Their paper was also published in the Nov. 1, 2011, issue of Cell Metabolism.

Microtubules Influence Cell Survival after Stroke

Scientists at Rutgers University have identified two possible new targets to prevent the neuronal damage that follows stroke. The two proteins, cypin and PSD-95, interact with microtubules in synapses, the points of connection between neurons. Microtubules are the cell's equivalent of a transportation highway, stabilizing cells and organizing the transport of proteins from one part of the cell to another. The scientists mimicked some of the features of stroke – in particular, very high levels of excitatory neurotransmitters, which can be toxic to cells – in cell culture and found that under such circumstances, high levels of cypin stabilized microtubules and helped cells survive. High levels of PSD-95 had the opposite effect. The authors hope that targeting the pathway therapeutically could help improve the survival of brain cells after a stroke. The paper was published in the Oct. 26, 2011, issue of The Journal of Neuroscience.

Obesity Gene Isn't Destiny

Environmental factors determine whether risk genes will lead to disease, but much remains to be learned about how genes and environmental factors interact. An international team led by the British Medical Research Council Epidemiology Unit has found that at least in one case, that interaction is direct: Adults with the risky variant of fat mass and obesity associated or FTO gene were more likely to actually be overweight if they were physically inactive than if they were physically active. The authors did a meta-analysis of 45 studies, and found that adults with the risk gene who were physically active were almost 30 percent less likely to be obese than those with the risk gene who were physically inactive. No hint of such a relationship was found in children and adolescents, which may be due to the generally higher activity levels of children. The work appeared in the Nov. 1, 2011, issue of PLoS Medicine.

Breast Cancer Moves from Protein to Factor

Scientists from the Whitehead Institute for Biomedical Research, the University of Miami, and Harvard University have shown that in ER-positive breast cancer, high levels of the protein heat shock factor 1 or HSF-1 are associated with poorer survival. The team had shown in earlier work that HSF-1, which is a transcription factor and allows cells to survive under stressful conditions, is expressed in cancer cells. The new work shows that such expression correlates with decreased survival. Because they saw decreased survival even in patients that had been treated with tamoxifen, the authors believe that high levels of heat shock factor may contribute to tamoxifen resistance. The authors said their work validates HSF-1 as prognostic factor, and validates efforts to use both heat shock factor and its downstream targets, including hsp90, as therapeutic targets. Their work appeared in the Oct. 31, 2011, online issue of the Proceedings of the National Academy of Sciences.

Gene Therapy Increases Neurogenesis

Researchers from Boston University have used gene therapy to reduce amyloid-beta deposits and improve memory in a mouse model of Alzheimer's disease. The scientists showed that when they used a viral vector to deliver the gene for fibroblast growth factor 2 (FGF) into the hippocampus of mice prone to developing Alzheimer's disease, the animals grew increased numbers of new neurons in their brains, which improved their scores on a memory test. The animals also cleared amyloid plaques through phagocytosis better than controls who received a scrambled version of the gene. The authors concluded that their data "indicate that virus-mediated FGF2 gene delivery has potential as an alternative therapy of Alzheimer's disease and possibly other neurocognitive disorders." The work appeared in the Oct. 31, 2011, issue of the Proceedings of the National Academy of Sciences.

Measles' Return Ticket to Lungs Identified

Scientists from the Mayo Clinic have identified the receptor that the measles virus uses to get into the airway of its hosts, both explaining why measles is an extremely contagious viral disease and suggesting a way to predict which cancer patients will benefit most from measles-based oncolytic treatment. Recent studies have traced the virus' travels after infection and shown that it first infects immune system cells and hitches a ride to the lymph nodes, where it replicates. Measles is spread when it is coughed out, but how it gets back from the lymph nodes into the upper respiratory tract has remained unclear. In their paper, the authors identified nectin-4 as the receptor the measles virus uses to infect cells of the upper respiratory tract. The findings explain why the measles virus is extremely contagious. Because nectin-4 is overexpressed on several types of tumors, they also suggest that it might be a biomarker to identify cancer patients most likely to benefit from oncolytic tumor therapy based on the measles virus. The work appeared in the Nov. 3, 2011, issue of Nature.

Blood from Grains

The title of their paper says it all: Scientists from the Chinese Wuhan University have achieved the "large-scale production of functional human serum albumin from transgenic rice seeds." Serum albumin is a carrier protein for hormones and fatty acids, and a part of human blood. It is used in the treatment of a number of disorders, ranging from burns to cirrhosis. Currently it is isolated from donated blood, which makes it vulnerable to both shortages and contamination. In their work, the authors reported being able to efficiently produce recombinant human serum albumin in rice. The recombinant protein made up more than 10 percent of the rice's soluble proteins. In animal studies, both its effectiveness at treating cirrhosis and its immunogenicity were similar to that of plasma-derived human serum albumin. The work appeared in the Oct. 31, 2011, issue of the Proceedings of the National Academy of Sciences.

Nitroglycerin May Harm in Heart Attacks

Scientists at Stanford University have discovered that nitroglycerin – which has been used for more than a century to treat heart cardiac problems – may be adding to the damage if a treated person has a heart attack during or shortly after treatment. Tolerance to nitroglycerin develops because treatment leads to the inactivation of aldehyde dehydrogenase, a cardioprotective enzyme. In their work, the researchers found that in rats, "16 hours of prior, sustained nitroglycerin treatment resulted in infarcts that were twice as large as those in untreated control animals and in diminished cardiac function at three days and two weeks after the myocardial infarction." The damage could be mitigated by also treating the animals with Alda-1, an aldehyde dehydrogenase activator that the team described in 2008. (See BioWorld Today, Sept. 12, 2008.) The new work appeared in the Nov. 3, 2011, issue of Science Translational Medicine.

Kalydeco Trial Results Published

A team led by researchers from the University of Washington's Seattle Children's Hospital has published the full results of the pivotal trial for Kalydeco (ivacaftor, VX-770) that was the basis of Vertex Pharmaceuticals Inc.'s new drug application for the compound. Kalydeco increases the activity of one version of the CFTR protein, the protein that is mutated in patients with cystic fibrosis; it is the first treatment that directly affects the cause of cystic fibrosis rather than treating its symptoms. The authors said that twice-daily oral treatment with Kalydeco led to improvements in lung function that lasted for the duration of the trial, and to "substantial improvements" the risk of respiratory problems, and sweat chloride concentrations (which are used to measure how well the chloride transporter that is mutated in cystic fibrosis is working.) Vertex filed for approval of Kalydeco in October. (See BioWorld Today, Oct. 20, 2011.) The trial results were reported in the Nov. 3, 2011, issue of The New England Journal of Medicine.

– Anette Breindl, Science Editor