Not all cellular byproducts in the brain need to be cleared out for optimal thinking. Also this week, attacking drug addiction through the immune system and how soy benefits a failing right heart.
Taking Out the Neurotrash
On the face of it, cleaning out cellular waste products in the brain would seem to be a possible strategy for combating dementia, which is often linked to the accumulation of damaged proteins. But researchers led by Thomas Sudhof, MD, of the Stanford University School of Medicine in Stanford, Calif., have found that might not be the case.
Because protein misfolding has been implicated in a range of neurological diseases, it seemed possible that dysfunctional proteasomes -- structures that break down damaged proteins – might play a role. But in mice prone to neurodegeneration, inhibiting the proteasome activity unexpectedly slowed the degeneration and extended the animals' lifespan, Sudhof and colleagues reported in Science Translational Medicine.
In the study animals, proteasomal degradation of the unfolded form of a protein called SNAP-25 leads to the loss of a complex of proteins called SNARE. In turn, that leads to the death of brain cells and synapses -- but inhibiting the proteasomes prevented the deterioration.
In brain tissue samples from patients with Parkinson's or Alzheimer's disease, the SNARE complex was similarly impaired, suggesting that proteasome blockage might have a therapeutic value, the researchers argued.
-- Michael Smith
Immune Mechanism Found for Opioid Addiction
It has been believed that the rewarding effects of opioids came from activation of opioid receptors in the brain. However, Linda Watkins, PhD, of the University of Colorado at Boulder, and colleagues showed in mice and rats that there may be an immune component as well.
They found that when opioids bind to an immune receptor called toll-like receptor 4 (TLR4), the drug's rewarding effects were reinforced. But a non-opioid, unnatural form of naloxone – called (+)-naloxone – blocked that response.
According to findings reported in the Journal of Neuroscience, the drug reduced the self-administration of an opioid in rats and inhibited production of extracellular dopamine in the area of the rat brain involved in opioid reinforcement, without reducing the analgesic effects.
"This work fundamentally changes what we understand about opioids, reward, and addiction. We've suspected for some years that TLR4 may be the key to blocking opioid addiction, but now we have the proof," Watkins said in a statement.
-- Todd Neale
Two Thumbs Up for Molecular Cancer 'Movies'
Computer-simulated moving images of a key cancer protein clamping onto its receptor may point the way to a novel kind of targeted cancer drug, researchers reported.
Expression of the protein, lysine-specific demethylase-1 (LSD1), is elevated in many cancers, where it appears to play a role in binding for epigenetic changes that turn off critical genes to allow uncontrolled cell growth.
The "movie" of LSD1 working with another protein, CoREST, to bind to histone showed that the nano-sized clamp shifted among open and closed configurations, rotating in ways that would fit a wide range of binding partners, the group reported in the Proceedings of the National Academy of Sciences.
Undoing epigenetic changes has been shown to restore expression of affected genes in prior studies without impacting the DNA of healthy cells and thus producing side effects like conventional chemotherapy.
"Epigenetic drug discovery hinges upon identifying the right protein targets and drug molecules, which is challenging because both are highly dynamic," researcher Nadeem A. Vellore, PhD, of the University of Utah in Salt Lake City, said in a statement.
-- Crystal Phend
Prior Flu Exposure No Problem for Universal Vaccine
In the quest to find a universal flu vaccine, researchers have found vaccination may still take in patients with previous flu exposure.
One potential caveat to the creation of a universal flu vaccine is that previous flu exposure may negate the effects of antibodies that neutralize the viral surface protein hemagglutinin, wrote Gary Nabel, PhD, of the NIH, and colleagues in Science Translational Medicine.
Researchers at the NIH tested the effects of a prime-boost vaccine regimen on neutralizing a broad spectrum of influenza strains in mice and ferrets with and without preexisting immunity to the bug.
They found that the strongest hemagglutinin stem-directed immune response "was observed in ferrets previously infected with a divergent 1934 H1N1 virus," which suggested that a broad neutralization of flu bugs could remain effective, even in patients with prior flu exposure.
-- Cole Petrochko
Soy Gets the Right Heart Pumping
A few servings of tofu may be what's best for pulmonary arterial hypertension, an animal study suggested.
It's known that genistein, a soy phytoestrogen, can stop the development of pulmonary hypertension. But what Mansoureh Eghbali, PhD, from UCLA, and colleagues found was that this particular isoflavone can actually reverse the cardiopulmonary functional and structural damage caused by pulmonary hypertension.
Rats given genistein therapy experienced significant improvements in right ventricular (RV) pressure, RV ejection fraction, pulmonary vascular remodeling, and RV hypertrophy, as well as the restoration of the loss of capillaries in the right ventricle, they reported in the journal Hypertension.
Furthermore, in human specimens in vitro, genistein was able to inhibit the excessive proliferation of pulmonary artery smooth muscle cells associated with pulmonary hypertension by greater than 50%.
The therapy, which helps restore RV contractility among other benefits, is promising because most available pharmacological therapies for pulmonary hypertension merely slow down its progressive deterioration, researchers said.
-- Chris Kaiser
Silver Lining for Antimicrobial Wound Dressing
A silver-laced wound dressing demonstrated sustained antimicrobial activity in an in vitro study of simulated wounds containing multidrug-resistant organisms (MDROs).
The dressing had inhibitory and bactericidal effects against free-living and biofilm phenotypes of MDROs. Simulated wound fluid contained strains of 10 MDROs, including Acinetobacter baumanni and methicillin-resistant Staphylococcus aureus, as well as the non-MDRO Clostridium difficile, according to an article in the August issue of the International Wound Journal.
"Demonstrating the in vitro antimicrobial efficacy of the [dressing] against a variety of MDROs may not only indicate potential clinical benefit in preventing or controlling endogenous wound infections where antibiotic options are limited and tolerated by biofilm phenotypes, but it may also act as an antimicrobial barrier to prevent the spread of such pathogens into the wider community," Philip G. Bowler, MPhil, of dressing developer ConvaTec in Flintshire, Wales, and co-authors wrote in conclusion.
The authors acknowledged that several silver-containing wound dressings have been developed, but the silver in the dressings has shown variable antimicrobial activity. The dressing they evaluated consists of sodium carboxymethylcellulose fibers containing ionic silver. On contact with fluid, the fibers in the dressing form a cohesive gel that conforms to the wound's topography.
-- Charles Bankhead