Publications

Transforming growth factor (TGF)-beta family members regulate multiple aspects of wound repair through effects on cell proliferation, matrix production, and tissue inflammation, but the effects of TGF-beta on wound closure itself have been controversial. We found that blocking antibodies to TGF-beta enhanced the degree of closure of scratch wounds in primary airway epithelial monolayers, while addition of exogenous TGF-beta1 inhibited the degree of closure, suggesting that endogenous activation of TGF-beta normally serves as a brake on the degree of wound closure. Although these cells secreted large amounts of TGF-beta2 and small amounts of TGF-beta1, blockade of TGF-beta1 enhanced the degree of wound closure, whereas blockade of TGF-beta2 had no effect. TGF-beta1 (but not TGF-beta2) can be activated by two members of the integrin family, alphavbeta6 and alphavbeta8, which are both expressed on airway epithelial cells. Wounding induced activation of TGF-beta through effects of both integrins, but antibodies against alphavbeta8 enhanced the degree of wound closure, whereas antibodies against alphavbeta6 did not.

OBJECTIVES

We investigated associations between perceived neighborhood problems and quality of life (QOL), physical functioning, and depressive symptoms among adults with asthma.

METHODS

Using cross-sectional data from adults with asthma in northern California (n=435), we examined associations between 5 types of perceived neighborhood problems (traffic, noise, trash, smells, and fires) and asthma-specific QOL (Marks instrument), physical functioning (Short Form-12 physical component summary), and depressive symptoms (Center for Epidemiological Studies-Depression). We used multivariate regression analysis.

RESULTS

When asthma severity and sociodemographics were taken into account, people reporting a score of 8 or higher on a scale of 0 to 25 for serious problems (the top quartile of seriousness) in their neighborhoods had significantly poorer QOL scores (mean difference=5.91; standard error [SE]=1.63), poorer physical functioning (mean difference=-3.04; SE=1.27), and almost a fivefold increase in depressive symptoms (odds ratio=4.79; 95% confidence interval=2.41, 9.52).

CONCLUSIONS

A high level of perceived neighborhood problems was associated with poorer QOL, poorer physical functioning, and increased depressive symptoms among people with asthma when disease severity and sociodemographic factors were taken into account.

BACKGROUND

The enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT) esterifies cholesterol in a variety of tissues. In some animal models, ACAT inhibitors have antiatherosclerotic effects.

METHODS

We performed intravascular ultrasonography in 408 patients with angiographically documented coronary disease. All patients received usual care for secondary prevention, including statins, if indicated. Patients were randomly assigned to receive the ACAT inhibitor pactimibe (100 mg per day) or matching placebo. Ultrasonography was repeated after 18 months to measure the progression of atherosclerosis.

RESULTS

The primary efficacy variable analyzing the progression of atherosclerosis--the change in percent atheroma volume--was similar in the pactimibe and placebo groups (0.69 percent and 0.59 percent, respectively; P=0.77). However, both secondary efficacy variables assessed by means of intravascular ultrasonography showed unfavorable effects of pactimibe treatment. As compared with baseline values, the normalized total atheroma volume showed significant regression in the placebo group (-5.6 mm3, P=0.001) but not in the pactimibe group (-1.3 mm3, P=0.39; P=0.03 for the comparison between groups). The atheroma volume in the most diseased 10-mm subsegment regressed by 3.2 mm3 in the placebo group, as compared with a decrease of 1.3 mm3 in the pactimibe group (P=0.01). The combined incidence of adverse cardiovascular outcomes was similar in the two groups (P=0.53).

CONCLUSIONS

For patients with coronary disease, treatment with an ACAT inhibitor did not improve the primary efficacy variable (percent atheroma volume) and adversely affected two major secondary efficacy measures assessed by intravascular ultrasonography. ACAT inhibition is not an effective strategy for limiting atherosclerosis and may promote atherogenesis. (ClinicalTrials.gov number, NCT00268515.).

The monotopic, endoplasmic reticulum (ER)-anchored cytochromes P450 (P450s) undergo variable proteolytic turnover. CYP3A4, the dominant human liver drug-metabolizing enzyme, is degraded via a ubiquitin (Ub)-dependent 26S proteasomal pathway after heterologous expression in Saccharomyces cerevisiae. This turnover involves the Ub-conjugating enzyme Ubc7p and the 19S proteasomal subunit Hrd2p but is independent of Hrd1p/Hrd3p, a major Ub-ligase (E3) involved in ER protein degradation. We now show that CYP3A4 ERAD also involves the Ubc7p-ER anchor Cue1p, because CYP3A4 is significantly stabilized at the stationary growth phase in Cue1p-deficient yeast. To determine whether the other major Ub-ligase Doa10p or Rsp5p involved in ER protein degradation functions in CYP3A4 ERAD, wild type and Doa10p- or Rsp5p-deficient yeast strains were also similarly examined. No appreciable CYP3A4 stabilization was detected in either Doa10p- or Rsp5p-deficient yeast, thereby excluding these E3s and revealing that CYP3A4 ERAD involves a novel or yet to be identified E3. Similar studies also revealed that the Cdc48p-Ufd1p-Hrd4p complex, responsible for the translocation of polyubiquitinated ER proteins was critical for CYP3A4 ERAD. We previously reported that grafting of the C-terminal (CT) CYP3A4 heptapeptide onto the CYP2B1 C terminus switched its proteolytic susceptibility from predominantly vacuolar to proteasomal degradation. To determine the relevance of this CT heptapeptide to CYP3A4 ERAD, CYP3A4 degradation after CT heptapeptide-deletion (CYP3A4DeltaCT) was similarly examined in yeast. These findings revealed that CYP3A4DeltaCT was also degraded by Ubc7p-26S proteasomal pathway, thereby indicating that this CT heptapeptide is not critical for CYP3A4 proteasomal degradation. Thus, unlike CYP2B1, CYP3A4 harbors additional/multiple structural degrons for its recruitment into the Ubproteasomal pathway.