Worming out clues to motor disorder
Environmental exposure to manganese (Mn) – from pesticides, industrial fumes and gasoline additives – is an established risk factor for Parkinson’s disease. Parkinson’s disease and Mn-intoxicated patients both display a characteristic movement disorder (tremors, rigidity, slowed movements) that involves degeneration of dopamine neurons.
To better understand the molecular mechanisms that contribute specifically to this neurodegeneration, Alexander Benedetto, Ph.D., Michael Aschner, Ph.D., and colleagues studied Mn toxicity in vivo, in the nematode worm C. elegans. They established that extracellular, and not intracellular, dopamine is responsible for Mn-induced dopaminergic neurodegeneration. They demonstrated that this process requires functional dopamine reuptake transporters and is associated with oxidative stress and lifespan reduction. They found that the dopamine-dependency of Mn toxicity required an enzyme called dual-oxidase BLI-3 and that overexpression of an anti-oxidant protein (SKN-1) protected against Mn toxicity.
The findings, reported Aug. 26 in PLoS Genetics, establish novel evidence of the molecular links between Mn exposure, Parkinson’s disease, aging and oxidative stress.
— Leigh MacMillan
Spicing up radiation therapy
Natural compounds derived from spices such as cinnamon and turmeric may sensitize tumors to radiation therapy, according to a report in the Oct. 15 issue of Bioorganic & Medicinal Chemistry Letters.
Heat shock, one of the most effective radiosensitizers, induces a “proteotoxic stress” that initiates a series of events leading to cell death. Because of the technical difficulties of inducing hyperthermia clinically, Sekhar Konjeti, Ph.D., Michael Freeman, Ph.D., and colleagues have been searching for and synthesizing compounds that mimic this effect and enhance radiosensitivity at physiological temperatures.
The investigators identified two natural compounds (hydroxychalcones called D-501 and D-601) and found that both induce “heat shock” and enhance radiation-induced death in cultured colon and pancreatic cancer cells. An inhibitor of cytochrome P450 (an enzyme involved in drug metabolism) blocked the radiosensitizing effect of D-601, suggesting that a metabolite mediates the radiosensitization.
Although future studies are needed to identify this metabolite, these findings offer new leads for developing novel radiosensitizing agents from natural products.
— Melissa Marino
Infection connection in lung disease
Premature babies are at risk of bronchopulmonary dysplasia (BPD), a chronic lung disorder resulting from arrested lung development. The condition is most common in infants exposed to inflammatory stimuli, for example, an infection in the womb. In animal models of the disease, inflammation inhibits fibroblast growth factor-10 (FGF-10), a key growth factor for airway development. However, the mechanisms connecting inflammation and FGF-10 expression are unclear.
To identify mediators of this process, Lawrence Prince, M.D., Ph.D., and colleagues collected fluid from the lungs of preterm infants (some exposed to maternal infection), and examined the effect of this fluid on cultured fetal mouse lung cells. They found that substances in the fluid of infection-exposed infants caused an activation of NF-kappaB (an inflammatory signaling molecule), which in turn disrupted the function of a transcription factor (Sp1), resulting in reduced FGF-10 and abnormal airway development.
The findings, in the Oct. 15 Journal of Immunology, suggest potential new targets for developing therapies to prevent or treat BPD in preterm infants.
— Melissa Marino
Extracting drug info from EMRs
Patient medication information is often stored as free-text in clinical notes of electronic medical records (EMRs). Being able to extract this information is important for clinical research on drug toxicity and efficacy – as well as for clinical operations. Commercial “natural language processing” (NLP) systems can reliably extract information about drug names from EMRs but are limited in their ability to extract information about dose, route and frequency.
Hua Xu, Ph.D., and colleagues have developed a medication extraction system called MedEx, which is able to extract dose, route and frequency information from Vanderbilt EMRs with better efficacy than the commercial systems. In the Sept/Oct Journal of the American Medical Informatics Association, they report that, together with other NLP tools, MedEx was able to reliably extract this medication information from EMRs from an institution other than the one at which the system was developed.
For this advance, the team’s system placed 2nd in the 2009 Informatics for Integrating Biology and the Bedside NLP Challenge.
— Melissa Marino
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