Reviving drugs with anti-stroke potential, minus side effects

pH-dependent NMDA receptor antagonists -- more active in the injured areas of the brain

A structure for SorLA/LR11

First identified by Alzheimer's researchers at Emory, the structure of the SorLA protein, aka LR11, was recently determined. SorLA appears to scavenge toxic beta-amyloid in the brain.

Explainer: oncolytic viruses

Viruses are masters of stealth and manipulation. So cancer researchers can learn a lot from them.

Reviving drugs with anti-stroke potential, minus side effects

Neuroprotective drugs might seem impractical or improbable right now, after two big clinical trials testing progesterone in traumatic brain injury didn’t work out. But one close observer of drug discovery is predicting a “coming boom in brain medicines.” Maybe this research, which Emory scientists have been pursuing for a long time, will be part of it.

In the 1990s, neuroscientists identified a class of drugs that showed promise in the area of stroke. NMDA receptor antagonists could limit damage to the brain in animal models of stroke. But one problem complicated testing the drugs in a clinical setting: the side effects included disorientation and hallucinations.

Now researchers have found a potential path around this obstacle. The results were published in Neuron.

“We have found neuroprotective compounds that can limit damage to the brain during ischemia associated with stroke and other brain injuries, but have minimal side effects,” says senior author Stephen Traynelis, PhD, professor of pharmacology at Emory University School of Medicine.

“These compounds are most active when the pH is lowered by biochemical processes associated with injury of the surrounding tissue. This is a proof of concept study that shows this mechanism of action could potentially be exploited clinically in several conditions, such as stroke, traumatic brain injury and subarachnoid hemorrhage.” Read more

Posted on by Quinn Eastman in Neuro Leave a comment

A structure for SorLA/LR11

The importance of the SorLA or LR11 receptor in braking Alzheimer’s was originally defined here at Emory by Jim Lah and Allan Levey’s labs. Japanese researchers recently determined the structure of SorLA and published the results in Nature Structural and Molecular Biology. Their findings point toward a direct role for SorLA in binding toxic circulating beta-amyloid and transporting it to the lysosome for degradation. Hat tip to Alzforum.

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Explainer: oncolytic viruses

A recent publication from Bill Kaiser’s and Ed Mocarski’s labs in Cell Host & Microbe touches on a concept that needs explaining: oncolytic viruses.

Viruses have been subverting the machinery of healthy cells for millions of years, and many viruses tend to infect particular tissues or cell types. So they are a natural starting point for researchers to engineer oncolytic viruses, which preferentially infect and kill cancer cells.

Several oncolytic viruses have progressed to advanced clinical trials. Amgen’s “T-Vec”, a modified herpes simplex virus, could be the first to be approved by the FDA this year based on its efficacy against metastatic melanoma.  Read more

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Immune ‘traffic jam’ from viral infection

Several drugs now used to treat cancer and autoimmune diseases are actually repurposed tools derived from the immune system. One of the ways these “therapeutic antibodies” work is to grab onto malignant or inflammatory cells and escort them to their doom.

Emory researchers have found that in a mouse model of chronic viral infection, a kind of traffic pileup inside the body limits how effective therapeutic antibodies can be.

The results, published this week in Immunity, have implications for biotechnology researchers who continue to refine antibodies for therapeutic purposes, as well as bolster our understanding of how chronic viral infections impair the immune system.

Researchers led by Rafi Ahmed, PhD, director of the Emory Vaccine Center, were studying mice infected by LCMV (lymphocytic choriomeningitis virus). They injected several antibodies with the goal of removing various types of immune cells from the mice.  One end of the antibody molecule is supposed to bind the target cell, while another acts as a flag for other cells to get rid of the target cell.

However, during a chronic LCMV infection, the mouse’s immune system is producing its own antibodies against the virus, which form complexes with viral proteins. These immune complexes prevented the injected antibodies from having the effect the scientists wanted, which was to deplete their target cells.

Excessive amounts of immune complexes appear to be “clogging” the Fc gamma receptors that immune cells would use to grab the antibodies bound to the target cell, says postdoctoral fellow Andreas Wieland, PhD, first author of the Immunity paper. That these immune complexes form was not news; but how much they interfere with other antibodies was, Wieland says. Fc gamma receptors were already known to be important for antibodies to be effective against influenza and HIV. Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Nox4 inhibitor expands its reach to A-T

Emory dermatologist Jack Arbiser has been investigating (and recently patented) inhibitors of the enzyme Nox4 as potential anti-cancer drugs.

Nox4 has emerged as a potential therapeutic target in ataxia-telangiectasia, a rare multifaceted genetic disorder that leads to neurological problems, a weakened immune system and an increased risk of cancer. Ataxia-telangiectasia (or A-T) is caused by a defect in ATM, a sensor responsible for managing cells’ responses to DNA damage and other kinds of stress.

In a February PNAS paper, researchers at the National Cancer Institute led by William Bonner report that a Nox4 inhibitor can dial back oxidative stress and DNA damage in ataxia-telangiectasia cells, and can reduce cancer rates in a mouse model of the disease. Nox4 was activated in cells and tissue samples obtained from A-T patients.

The Nox4 inhibitor the NCI team used, fulvene-5, was originally identified by Arbiser in a 2009 Journal of Clinical Investigation paper as a possible treatment for hemangiomas, a common tumor in infants that emerges from blood vessels.

David Lambeth, an expert on the NADPH oxidase family of enzymes, and his team recently described Nox4 as an “hydrogen peroxide-generating oxygen sensor.”

 

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Insecticide-ADHD link, with caveats

Gary Miller’s lab at Emory was the launching pad for this study from Rutgers, published last week in the FASEB Journal, showing a potential connection between a common type of insecticide used at home and in agriculture, pyrethroids, and attention deficit hyperactivity disorder (ADHD).  Read more

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Threshold for long-term marijuana effects on lung function

Intuition may suggest that smoke is bad for the lungs, whether it comes from a campfire or from tobacco or marijuana. A practical question is: how bad is an occasional joint, compared with some background level of air pollution and the lungs’ ability to cope?

Since a few states have been loosening restrictions on marijuana, a group of Emory pulmonologists – Jordan Kempker, Eric Honig, and Greg Martin — decided to look at the long-term effects of marijuana smoking on lung function. Their findings, published in the Annals of the American Thoracic Society (PDF), have already attracted some attention. Read more

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Extend that New Year’s energy – to what benefit?

Surveys indicate that many of us make New Year’s resolutions to eat more healthily or exercise more frequently, yet do not sustain the enthusiasm of January throughout the year.

What if the burst of energy and good intentions could be maintained over a longer period, perhaps with the help of a coach? What kinds of health benefits would appear?

Researchers from Emory and Georgia Tech recently published an analysis of the changes in the health profiles in 382 Center for Health Discovery & Well Being participants who completed a one-year evaluation.

The senior author is Greg Gibson, PhD, professor of biology and director of the Center for Integrative Genomics at Georgia Tech. Georgia Tech postdoctoral fellow Rubina Tabassum, now at the University of Helsinki, is the first author.

“What do most people in developed countries need to do? Eat better, exercise more regularly and stress less,” Gibson says. “It’s unclear whether most of the impact comes from the interaction with partners, or simply from participation and goal-setting, but the overall effect is quite good.”

The main points:

*These are “essentially healthy” people — healthier than the general population in the United States – but almost half started out with high blood pressure and cholesterol levels. There was no control group, and not everyone pursued the same exact program. The average age was 48 years and 28 percent of the group was considered obese. That’s less than the United States population as a whole.

*On average, the 382 participants lost a moderate amount of weight (it works out to about three pounds) and saw their blood pressure and LDL-cholesterol go down significantly over that first year (121 to 116 mmHG for systolic BP, 112 to 105 mg/dL for LDL-C). They also reported lower scores for depression and anxiety.

Read more

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General-heavy army disastrous in immune battle

Immunologists have identified two big groups of T cells: “helper” CD4+ cells and “killer” CD8+ cells.* The helper cells can produce immune regulatory molecules and promote antibody responses, while the killer cells recognize and destroy virally-infected cells.

A vaccine against a virus that stimulates only helper CD4+ cells leads to uncontrolled lethal inflammation in mice once the animals are challenged with the virus, a recent paper in Science shows. Emory Vaccine Center director Rafi Ahmed is a co-author.

Senior author Dan Barouch, from Harvard/Beth Israel Deaconess Medical Center, tells The Scientist that CD4+ cells are like generals directing the battle of the immune system and “if you just have strategic generals and no soldiers, it turns out to be worse than having no army at all.” Rebalancing the system with antiviral CD8+ T cells or antibodies helps limit the problems.

The findings mesh with work by Yerkes investigators [Guido Silvestri and colleagues] suggesting that HIV vaccines that boost CD4+ cells in gateway mucosal tissues lead to higher rates of infection. In both cases, the lesson is: having more helper CD4+ T cells around actually does not help. Read more

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Carbohydrates not silent to immune system

Donor antibodies, administered intravenously or subcutaneously, make up a commercial product used to treat both immunodeficiencies and inflammatory or auto-immune diseases.

These preparations contain a complex mix of antibodies against glycans, the carbohydrate molecules on the outsides of cells, a Jan. 7 paper in Science Translational Medicine reveals.

At first glance, the findings are remarkable because:

A. Immunologists have long thought that carbohydrates, by themselves, are not good at provoking the immune system. (The assumption was: you need some protein for antigen presentation and getting T cells interested.) The data shows exceptions to the rule.

B. Some of the antibodies react against human carbohydrate structures. Instead of attacking them in an auto-immune fashion, they may actually be blocking viruses or bacteria from using those structures as gateways to infection.

The lab of Stephan von Gunten at the University of Bern collaborated with the National Center for Functional Glycomics led by biochemists Rick Cummings and David Smith at Emory to analyze the spectrum of carbohydrate structures bound by donor antibodies. Read more

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