Publications

The acute-phase response (APR) leads to alterations in lipid metabolism and type II nuclear hormone receptors, which regulate lipid metabolism, are suppressed, in liver, heart, and kidney. Here, we examine the effect of the APR in adipose tissue. In mice, lipopolysaccharide produces a rapid, marked decrease in mRNA levels of nuclear hormone receptors [peroxisome proliferator-activated receptor gamma (PPARgamma), liver X receptor alpha (LXRalpha) and LXRbeta, thyroid receptor alpha (TRalpha) and TRbeta, and retinoid X receptor alpha (RXRalpha) and RXRbeta] and receptor coactivators [cAMP response element binding protein, steroid receptor coactivator 1 (SRC1) and SRC2, thyroid hormone receptor-associated protein, and peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC1alpha) and PGC1beta] along with decreased expression of target genes (adipocyte P2, phosphoenolpyruvate carboxykinase, glycerol-3-phosphate acyltransferase, ABCA1, apolipoprotein E, sterol-regulatory element binding protein-1c, glucose transport protein 4 (GLUT4), malic enzyme, and Spot14) involved in triglyceride (TG) and carbohydrate metabolism. We show that key TG synthetic enzymes, 1-acyl-sn-glycerol-3-phosphate acyltransferase-2, monoacylglycerol acyltransferase 1, and diacylglycerol acyltransferase 1, are PPARgamma-regulated genes and that they also decrease in the APR. In 3T3-L1 adipocytes, tumor necrosis factor-alpha (TNF-alpha) significantly decreases PPARgamma, LXRalpha and LXRbeta, RXRalpha and RXRbeta, SRC1 and SRC2, and PGC1alpha and PGC1beta mRNA levels, which are associated with a marked reduction in receptor-regulated genes. Moreover, TNF-alpha significantly reduces PPAR and LXR response element-driven transcription. Thus, the APR suppresses the expression of many nuclear hormone receptors and their coactivators in adipose tissue, which could be a mechanism to coordinately downregulate TG biosynthesis and thereby redirect lipids to other critical organs during the APR.

We explored the evolution from cigarette product attributes to psychosocial needs in advertising campaigns for low-tar cigarettes. Analysis of previously secret tobacco industry documents and print advertising images indicated that low-tar brands targeted smokers who were concerned about their health with advertising images intended to distract them from the health hazards of smoking. Advertising first emphasized product characteristics (filtration, low tar) that implied health benefits. Over time, advertising emphasis shifted to salient psychosocial needs of the target markets. A case study of Vantage cigarettes in the USA and Canada showed that advertising presented images of intelligent, upward-striving people who had achieved personal success and intentionally excluded the act of smoking from the imagery, while minimal product information was provided. This illustrates one strategy to appeal to concerned smokers by not describing the product itself (which may remind smokers of the problems associated with smoking), but instead using evocative imagery to distract smokers from these problems. Current advertising for potential reduced-exposure products (PREPs) emphasizes product characteristics, but these products have not delivered on the promise of a healthier alternative cigarette. Our results suggest that the tobacco control community should be on the alert for a shift in advertising focus for PREPs to the image of the user rather than the cigarette. Global Framework Convention on Tobacco Control-style advertising bans that prohibit all user imagery in tobacco advertising could preempt a psychosocial needs-based advertising strategy for PREPs and maintain public attention on the health hazards of smoking.

BACKGROUND

The effect of raloxifene, a selective estrogen-receptor modulator, on coronary heart disease (CHD) and breast cancer is not established.

METHODS

We randomly assigned 10,101 postmenopausal women (mean age, 67.5 years) with CHD or multiple risk factors for CHD to 60 mg of raloxifene daily or placebo and followed them for a median of 5.6 years. The two primary outcomes were coronary events (i.e., death from coronary causes, myocardial infarction, or hospitalization for an acute coronary syndrome) and invasive breast cancer.

RESULTS

As compared with placebo, raloxifene had no significant effect on the risk of primary coronary events (533 vs. 553 events; hazard ratio, 0.95; 95 percent confidence interval, 0.84 to 1.07), and it reduced the risk of invasive breast cancer (40 vs. 70 events; hazard ratio, 0.56; 95 percent confidence interval, 0.38 to 0.83; absolute risk reduction, 1.2 invasive breast cancers per 1000 women treated for one year); the benefit was primarily due to a reduced risk of estrogen-receptor-positive invasive breast cancers. There was no significant difference in the rates of death from any cause or total stroke according to group assignment, but raloxifene was associated with an increased risk of fatal stroke (59 vs. 39 events; hazard ratio, 1.49; 95 percent confidence interval, 1.00 to 2.24; absolute risk increase, 0.7 per 1000 woman-years) and venous thromboembolism (103 vs. 71 events; hazard ratio, 1.44; 95 percent confidence interval, 1.06 to 1.95; absolute risk increase, 1.2 per 1000 woman-years). Raloxifene reduced the risk of clinical vertebral fractures (64 vs. 97 events; hazard ratio, 0.65; 95 percent confidence interval, 0.47 to 0.89; absolute risk reduction, 1.3 per 1000).

CONCLUSIONS

Raloxifene did not significantly affect the risk of CHD. The benefits of raloxifene in reducing the risks of invasive breast cancer and vertebral fracture should be weighed against the increased risks of venous thromboembolism and fatal stroke. (ClinicalTrials.gov number, NCT00190593 [ClinicalTrials.gov].).

Protein kinase C epsilon (PKCepsilon) is an important intracellular signaling molecule in primary afferent nociceptors, implicated in acute and chronic inflammatory as well as neuropathic pain. In behavioral experiments inflammatory mediators produce PKCepsilon-dependent hyperalgesia only in male rats. The mechanism underlying this sexual dimorphism is unknown. We show that the hormone environment of female rats changes the nociceptive signaling in the peripheral sensory neuron. This change is maintained in culture also in the absence of a gender-simulating environment. Stimulation of beta(2)-adrenergic receptors (beta(2)-AR) leads to PKCepsilon activation in cultured dorsal root ganglia (DRG) neurons derived from male but not from female rats. Addition of estrogen to male DRG neurons produces a switch to the female phenotype, namely abrogation of beta(2)-AR-initiated activation of PKCepsilon. Estrogen interferes downstream of the beta(2)-AR with the signaling pathway leading from exchange protein activated by cAMP (Epac) to PKCepsilon. The interfering action is fast indicating a transcriptional-independent mechanism. Estrogen has a dual effect on PKCepsilon. If applied before beta(2)-AR or Epac stimulation, estrogen abrogates the activation of PKCepsilon. In contrast, estrogen applied alone leads to a brief translocation of PKCepsilon. Also in vivo the activity of estrogen depends on the stimulation context. In male rats, intradermal injection of an Epac activator or estrogen alone induces mechanical hyperalgesia through a PKCepsilon-dependent mechanism. In contrast, injection of estrogen preceding the activation of Epac completely abrogates the Epac-induced mechanical hyperalgesia. Our results suggest that gender differences in nociception do not reflect the use of generally different mechanisms. Instead, a common set of signaling pathways can be modulated by hormones.