University of Tennessee Health Science Center

About: University of Tennessee Health Science Center is a education organization based out in Memphis, Tennessee, United States. It is known for research contribution in the topics: Population & Medicine. The organization has 15716 authors who have published 26884 publications receiving 1176697 citations.

Prooxidant-Antioxidant Shift Induced by Androgen Treatment of Human Prostate Carcinoma Cells

Abstract: Background: Prostate cancer is a disease associated with aging. Also commonly associated with increasing age is a shift in the prooxidant‐antioxidant balance of many tissues toward a more oxidative state, i.e., increased oxidative stress. We hypothesize that androgen exposure, which has long been associated with the development of prostate cancer, may be a means by which the prooxidant‐antioxidant balance of prostate cells is altered. Purpose: Using established prostate carcinoma cell lines, we studied the effect of androgens on various parameters of oxidative state (e.g., generation of hydrogen peroxide and hydroxyl radicals, lipid peroxidation, and oxygen consumption) and antioxidant defense mechanisms (e.g., the glutathione system and catalase). Methods: The androgen-responsive LNCaP and the androgen-independent DU145 prostate carcinoma cell lines were exposed to 5a-dihydrotestosterone (DHT) and to the synthetic androgen R1881. The cellular proliferation responses were measured by use of a fluorometric assay to quantitate the amount of DNA. The generation of reactive oxygen species was measured by use of 2*,7*-dichlorofluorescin diacetate, a dye that fluoresces in the presence of hydrogen peroxide or hydroxyl radicals. Lipid peroxidation was quantitated by use of a chromogen specific for malonaldehyde and 4-hydroxy-2(E)-nonenal. General mitochondrial activity was determined by assaying 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) reduction. A Clarktype electrode was used to assess oxygen consumption per cell. Intracellular glutathione concentrations and the activities of catalase and g-glutamyl transpeptidase were measured spectrophotometrically. All P values resulted from two-sided tests. Results: DHT at less than 1 to 100 nM (a concentration range encompassing the physiologic levels of DHT considering all ages) and R1881 at 0.1-1 nM concentrations were effective in inducing in LNCaP cells comparable proliferative responses and changes in oxidative stress. In contrast, neither DHT nor R1881 had any effect on the oxidative stress in DU145 cells. The mitochondrial activity in LNCaP cells, as measured by MTT reduction, was significantly elevated above the levels of the untreated controls by DHT (0.1-1000 nM) and R1881 (0.05-1 nM )( P<.001 in both). Oxygen consumption and catalase activity were increased in LNCaP cells in the presence of 1 nM R1881 by 60% and 40%, respectively, over the values in the untreated control cells (P<.03 and P<.01, respectively). The same concentration of R1881 resulted in a decrease in intracellular glutathione concentrations and an increase in g-glutamyl transpeptidase activity in LNCaP ells. Treatment with the oxidizing agents H2O2 and menadione produced an increase in g-glutamyl transpeptidase activity in LNCaP cells, whereas treatment with the antioxidant compound ascorbic acid (100 mM) reduced the oxidative stress produced in LNCaP cells by 1 nM R1881 and completely blocked the g-glutamyl transpeptidase activity. Conclusions: Physiologic levels of androgens are capable of increasing oxidative stress in androgenresponsive LNCaP prostate carcinoma cells. The evidence suggests that this result is due in part to increased mitochondrial activity. Androgens also alter intracellular glutathione levels and the activity of certain detoxification enzymes, such as g-glutamyl transpeptidase, that are important for maintenance of the cellular prooxidant‐antioxidant balance. [J Natl Cancer Inst 1997;89:40-8]

Change in Depression as a Precursor of Cardiovascular Events

Abstract: Objective: To determine the relationship between increasing depressive symptoms and cardiovascular events or mortality. Design: Cohort analytic study of data from randomized placebo-controlled double-blind clinical trial of antihypertensive therapy. Depressive symptoms were assessed semiannually with the Center for Epidemiological Studies— Depression (CES-D) scale during an average follow-up of 4.5 years. Setting: Ambulatory patients in 16 clinical centers of the Systolic Hypertension in the Elderly Program. Patients: Generally healthy men and women aged 60 years or older randomized to active antihypertensive drug therapy or placebo who were 79% white and 53% women and had follow-up CES-D scores and no outcome events during the first 6 months (N=4367). Main Outcome Measures: All-cause mortality, fatal or nonfatal stroke, or myocardial infarction. Results: Baseline depressive symptoms were not related to subsequent events; however, an increase in depression was prognostic. Cox proportional hazards regression analyses with the CES-D scale as a time-dependent variable, controlling for multiple covariates, indicated a 25% increased risk of death per 5-unit increase in the CES-D score (relative risk [RR], 1.25; 95% confidence interval [CI], 1.15 to 1.36). The RR for stroke or myocardial infarction was 1.18 (95% CI, 1.08 to 1.30). Increase in CES-D score was an independent predictor in both placebo and active drug groups, and it was strongest as a risk factor for stroke among women (RR, 1.29; 95% CI, 1.07 to 1.34). Conclusions: Among elderly persons, a significant and substantial excess risk of death and stroke or myocardial infarction was associated with an increase in depressive symptoms over time, which may be a marker for subsequent major disease events and warrants the attention of physicians to such mood changes. However, further studies of causal pathways are needed before widespread screening for depression in clinical practice is to be recommended. (Arch Intern Med. 1996;156:553-561)