Publications

Tryptophan 2,3-dioxygenase (TDO), a liver-specific cytosolic hemoprotein, is the rate-limiting enzyme in L-tryptophan catabolism and thus a key serotonergic determinant. Glucocorticoids transcriptionally activate the TDO gene with marked enzyme induction. TDO is also regulated by heme, its prosthetic moiety, as its expression and function are significantly reduced after acute hepatic heme depletion. Here we show in primary rat hepatocytes that this impairment is not due to faulty transcriptional activation of the TDO gene but rather due to its posttranscriptional regulation by heme. Accordingly, in acutely heme-depleted hepatocytes, the de novo synthesis of TDO protein is markedly decreased (>90%) along with that of other hepatic proteins. This global suppression of de novo hepatic protein syntheses in these heme-depleted cells is associated with a significantly enhanced phosphorylation of the alpha-subunit of the eukaryotic initiation factor eIF2 (eIF2alpha), as monitored by the phosphorylated eIF2alpha/total eIF2alpha ratio. Heme supplementation reversed these effects, indicating that heme regulates TDO induction by functional control of an eIF2alpha kinase. A cDNA was cloned from heme-depleted rat hepatocytes, and DNA sequencing verified its identity to the previously cloned rat brain heme-regulated inhibitor (HRI). Proteomic, biochemical, and/or immunoblotting analyses of the purified recombinant protein and the immunoaffinity-captured hepatic protein confirmed its identity as a rat heme-sensitive eIF2alpha kinase. These findings not only document that a hepatic HRI exists and is physiologically relevant but also implicate its translational shut-off of key proteins in the pathogenesis and symptomatology of the acute hepatic heme-deficient conditions clinically known as the hepatic porphyrias.

Huntington's disease (HD) is a fatal inherited neurodegenerative disorder. HD is caused by polyglutamine expansions in the huntingtin (htt) protein that result in neuronal loss and contribute to HD pathology. The mechanisms of neuronal loss in HD are elusive, and there is no therapy to alleviate HD. To find small molecules that slow neuronal loss in HD, we screened 1,040 biologically active molecules to identify suppressors of cell death in a neuronal cell culture model of HD. We found that inhibitors of mitochondrial function or glycolysis rescued cell death in this cell culture and in in vivo HD models. These inhibitors prevented cell death by activating prosurvival ERK and AKT signaling but without altering cellular ATP levels. ERK and AKT inhibition through the use of specific chemical inhibitors abrogated the rescue, whereas their activation through the use of growth factors rescued cell death, suggesting that this activation could explain the protective effect of metabolic inhibitors. Both ERK and AKT signaling are disrupted in HD, and activating these pathways is protective in several HD models. Our results reveal a mechanism for activating prosurvival signaling that could be exploited for treating HD and possibly other neurodegenerative disorders.

OBJECTIVES

To investigate whether underweight, normal-weight, overweight, and obese older adults differ in aspects of their oral health-related quality of life (OHRQoL).

DESIGN

Cross-sectional study using a 54-item OHRQoL questionnaire.

SETTING

Five counties in central Alabama: Jefferson and Tuscaloosa (urban), and Hale, Bibb, and Pickens (rural).

PARTICIPANTS

The 291 subjects were recruited from participants in the University of Alabama at Birmingham Study of Aging, a longitudinal study of mobility. Participants ranged in age from 65 to 90 (60.5% women, 50.5% non-Hispanic white, and 50.5% rural).

MEASUREMENTS

Participants completed an in-home interview about their OHRQoL using a 54-item questionnaire and were classified into four categories of body mass index (BMI) (<20.0 (underweight), 20.0-24.9 (normal), 25.0-29.9 (overweight), and >/=30.0 (obese)). Multivariate analyses were used to examine associations between BMI and OHRQoL, adjusting for age, race, sex, depression, education, perceived income, comorbidity score, life-space mobility, and physical activity level.

RESULTS

The results suggested that a parabolic effect existed, with strongest associations occurring in the underweight and obese categories. With the normal BMI group as the reference group, obese participants were more likely to avoid eating foods they would like to eat, overweight participants were less likely to cook foods differently and reported better chewing ability, and underweight persons were more likely to limit foods they eat because of mouth dryness.

CONCLUSION

Objective measures may not accurately reflect peoples' perceptions; therefore, OHRQoL determined according to response to subjective questions is important to properly assess a patient's overall health status. Older adults who are under- or overweight should be evaluated for oral health conditions that may affect their nutritional status.