Honokiol, Jack of all trades

The magnolia-derived compound honokiol was discovered by Emory dermatologist Jack Arbiser. UChicago researchers show it has positive effects in a heart disease model.

Leslee Shaw explains coronary artery calcium scoring

And why it's a relatively cost-effective test for predicting heart disease

Brain surgery with a light touch

In epilepsy surgery, how much effect does ablation of the hippocampus and amygdala have on cognitive function -- if the surgeon avoids an open resection?

Honokiol, Jack of all trades

Emory dermatologist Jack Arbiser discovered the anti-angiogenic properties of honokiol, a compound derived from magnolia cones, more than a decade ago. Since then, honokiol has been found to have anti-inflammatory, anti-oxidant and anticancer properties.

A paper published Tuesday in Nature Communications from researchers at the University of Chicago shows that honokiol inhibits the mitochondrial enzyme Sirt3, which has connections to longevity. Manesh Gupta and colleagues demonstrate that honokiol can block cardiac hypertrophy in mice, a finding with possible relevance for the treatment of heart failure.

Sirt3 has been linked both genetically to human life span, and until now, the only way to increase levels of Sirt3 was old-fashioned calorie restriction and/or endurance exercise.

The authors write: It is believed that Sirt3 does not play a role in embryonic development, but rather it fine tunes the activity of mitochondrial substrates by lysine deacetylation to protect cells from stress… To the best of our knowledge, this is the first report describing a pharmacological activator of Sirt3.

 

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Leslee Shaw explains coronary artery calcium scoring

On Thursday, cardiology researcher Leslee Shaw, PhD joined an exclusive club at Emory with her 2015 Dean’s Distinguished Faculty Lecture and Award.* Shaw is the co-director of Emory’s Clinical Cardiovascular Research Institute and research director of Emory Women’s Heart Center. Her lecture focused on the utility of coronary artery calcium (CAC) scoring in predicting cardiovascular disease.

Much cardiovascular risk research has focused on finding imaging or biomarker tests that can provide doctors with cost-effective decision-making power. One prominent question: should the patient take cholesterol-reducing statins? These tests should provide information above and beyond the Framingham Risk Score or its ACC/AHA update, which incorporates information about a patient’s age, sex, cholesterol/HDL, blood pressure and diabetes status.

CAC scoring is a good place to start, Shaw said, since it is a standardized, relatively inexpensive test that measures the buildup of calcium in atherosclerotic plaque, and the radiation dose is low compared with other cardiac imaging techniques. Read more

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Brain surgery with a light touch

As part of reporting on neurosurgeon Robert Gross’s work with patients who have drug-resistant epilepsy, I interviewed a remarkable woman, Barbara Olds. She had laser ablation surgery for temporal lobe epilepsy in 2012, which drastically reduced her seizures and relieved her epilepsy-associated depression.

Emory Medicine’s editor decided to focus on deep brain stimulation, rather than ablative surgery, so Ms. Olds’ experiences were not part of the magazine feature. Still, talking with her highlighted some interesting questions for me.

Emory neuropsychologist Dan Drane, who probes the effects of epilepsy surgery on memory and language abilities, had identified Olds as a good example of how the more precise stereotactic laser ablation procedure pioneered by Gross can preserve those cognitive functions, in contrast to an open resection. Read more

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DBS for drug-resistant epilepsy

Space considerations in print forced us to slim down the feature on deep brain stimulation for drug resistant epilepsy, which appears in the Spring 2015 issue of Emory Medicine. While I encourage you to please read our story profiling playwright Paula Moreland, here are some take-away points:

*Surgery is a viable option for many patients with drug-resistant epilepsy, but not all of them, because the regions of the brain where the seizures start can have important functions. (Look for an upcoming post describing a patient I met for whom the surgical option was helpful.)

*Deep brain stimulation can reduce seizure frequency and improve quality of life for patients with drug-resistant epilepsy.

*In the large clinical trials on deep brain stimulation for epilepsy that have been run so far (SANTE and RNS), most participants do not see their seizures eliminated. Ms. Moreland is an exception.  Read more

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Low doses of imatinib can stimulate innate immunity

Low doses of the anti-cancer drug imatinib can spur the bone marrow to produce more innate immune cells to fight against bacterial infections, Emory and Winship Cancer Institute researchers have found.

The results were published this week in the journal PLOS Pathogens.

The findings suggest imatinib, known commercially as Gleevec, or related drugs could help doctors treat a wide variety of infections, including those that are resistant to antibiotics, or in patients who have weakened immune systems. The research was performed in mice and on human bone marrow cells in vitro, but provides information on how to dose imatinib for new clinical applications.

“We think that low doses of imatinib are mimicking ‘emergency hematopoiesis,’ a normal early response to infection,” says senior author Daniel Kalman, PhD, associate professor of pathology and laboratory medicine at Emory University School of Medicine.

Imatinib, is an example of a “targeted therapy” against certain types of cancer. It blocks tyrosine kinase enzymes, which are dysregulated in cancers such as chronic myelogenous leukemia and gastrointestinal stromal tumors.

Imatinib also inhibits normal forms of these enzymes that are found in healthy cells. Several pathogens – both bacteria and viruses – exploit these enzymes as they transit into, through, or out of human cells. Researchers have previously found that imatinib or related drugs can inhibit infection of cells by pathogens that are very different from each other, including tuberculosis bacteria and Ebola virus. Read more

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Recording seizures from within the brain

To go along with the (new) Spring 2015 Emory Medicine magazine set of features on deep brain stimulation for depression, movement disorders and epilepsy, here is a fascinating 2013 case report from Emory neurosurgeon Robert Gross and colleagues. The first author is electrical engineer Otis Smart.

It’s an example of the kinds of insights that can be obtained from implantable electrical stimulation devices, which can record signals from seizures inside the brain over long periods of time (more than a year).

As the authors write, “the technology can record brain activity while the patient is in a more naturalistic environment than a hospital, becoming an invasive ambulatory EEG.” Read more

Posted on by Quinn Eastman in Neuro 1 Comment

Regrouping on fragile X drug strategies

Fragile X syndrome has many fascinating aspects:

* the complex inheritance pattern

* its status as the most common inherited form of intellectual disability and a major single-gene cause of autism spectrum disorder (ASD)

*the importance of the RNA-binding protein FMRP as a regulator of synaptic plasticity in neurons

*the potential applicability of drugs developed for fragile X for other forms of ASD

Readers interested in neurodevelopment disorders may want to check out this Nature Reviews Drug Discovery piece, which chews over some setbacks in clinical research on fragile X. Emory researchers have a strong connection with the drug strategies used in the recent clinical trials, but have also been working on alternative approaches. Read more

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Potential HIV drugs hit three targets at once

Drug discovery veteran Dennis Liotta and his team continue to look for ways to fight against HIV. Working with pharmaceutical industry colleagues, he and graduate student Anthony Prosser have discovered compounds that are active against three different targets: immune cells’ entry gates for the virus (CCR5 and CXCR4), and the replication enzyme reverse transcriptase. That’s like one arrow hitting three bulls eyes. An advantage for these compounds: it could be less likely for viral resistance to develop.

For more, please go to the American Chemical Society — there will be a press conference from the ACS meeting in Denver on Monday, and live YouTube.

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ACC 2015: Newer heart risk calculator may better accounts for racial differences

A risk calculator for cardiovascular disease, developed as a companion for the 2013 American College of Cardiology/American Heart Association cholesterol guidelines, may account for racial differences in sub-clinical vascular function better than the Framingham Risk Score, Emory cardiology researchers say.

Their findings are scheduled for presentation Monday at the American College of Cardiology meeting in San Diego.

African Americans, especially men, tend to have a higher prevalence of cardiovascular disease, but this differences are not reflected in the Framingham Risk score. Arterial stiffness is a sign of heart disease risk that tends to appear more prominently among African Americans than whites. Cardiovascular research fellow Jia Shen, MD, MPH, and Emory colleagues analyzed data on arterial stiffness and structure from 1235 people – 777 whites and 458 African-Americans — enrolled in two large studies (Center for Health Discovery and Well Being and META-Health). Read more

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Who regulates the regulators? Drosha

MicroRNAs have emerged as important master regulators in cells, since each one can shut down several target genes. Riding on top of the master regulators is Drosha, the RNA-cutting enzyme that initiates microRNA processing in the nucleus. Drosha and its relative Dicer have been attracting attention in cancer biology, because they are thought to be behind a phenomenon where cancerous cells can “infect” their healthy neighbors via tiny membrane-clothed packets called exosomes.

At Emory, pharmacologist Zixu Mao and colleagues recently published in Molecular Cell their findings that Drosha is regulated by stress (experimentally: heat or peroxide) through p38 MAP kinase.

Although we mention relevance to cancer above, this is one of those basic cell biology findings that may have applicability to several areas of medicine. Alterations in miRNA processing have been linked to neurodegenerative disease (Fragile X-associated tremor/ataxia syndrome, for one example). MicroRNA-packed exosomes are also being studied by biomedical engineers as potential therapeutic tools in regenerative medicine, so knowing what cellular stress does to miRNA production could be useful. Read more

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