Heme oxygenase‐1 (HO‐1) is a stress‐inducible rate‐limiting enzyme in heme degradation, which confers cytoprotection against oxidative injury and provides a vital function in maintaining tissue homeostasis. Increasing reports have indicated that lipoteichoic acid (LTA) exerts as LPS as an immune system‐stimulating agent and plays a role in the pathogenesis of severe inflammatory responses induced by Gram‐positive bacteria infection. Here, we report that LTA is an inducer of HO‐1 and examine the signaling pathways by which LTA regulates HO‐1 expression in human tracheal smooth muscle cells (HTSMCs). LTA induced HO‐1 protein, mRNA expression, and HO‐1 promoter activity. LTA‐stimulated HO‐1 expression was attenuated by transfection with dominant negative mutants of Toll‐like receptor‐2 (TLR‐2) and MyD88, the NADPH oxidase inhibitor (DPI), the ROS scavenger (NAC), and transfection with siRNAs of Src and NF‐E2‐related factor 2 (Nrf2). LTA‐stimulated c‐Src phosphorylation, translocation of p47phox and Nrf2, and ROS production were attenuated by transfection with dominant negative mutants of TLR‐2, MyD88, and c‐Src, and by pretreatment with DPI or NAC. Further studies revealed that LTA induced TLR‐2, MyD88, c‐Src, and p47phox complex formation. These results demonstrated that in HTSMCs, LTA induced ROS generation through the TLR‐2/MyD88/c‐Src/NADPH oxidase pathway, in turn initiates the activation of Nrf2, and ultimately induces HO‐1 expression.

Oxidative stresses are believed to play an important role in the induction of both cell adhesion molecules and pro-inflammatory cytokines, a key event in a variety of inflammatory processes. The enzyme heme oxygenase-1 (HO-1) functions as an antioxidant and serves to protect against tissue injury. In this study, we report that HO-1 was induced in cultured human tracheal smooth muscle cells after either treatment with a potent inducer of HO-1 activity, cobalt protoporphyrin IX, or infection with a recombinant adenovirus that carries the human HO-1 gene. Overexpression of HO-1 protected against tumor necrosis factor (TNF)-␣-mediated airway inflammation via the down-regulation of oxidative stress, adhesion molecules, and interleukin-6 in both cultured human tracheal smooth muscle cells and the airways of mice. In addition, HO-1 overexpression inhibited TNF-␣-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, adherence of THP-1 cells, generation of interleukin-6, p47 phox translocation, and nuclear factor-B activation. HO-1 overexpression also attenuated TNF-␣-induced oxidative stress, which was abrogated in the presence of both the HO-1 inhibitor, zinc protoporphyrin IX, as well as a carbon monoxide scavenger. In addition, HO-1 overexpression reduced the formation of a TNFR1/c-Src/p47 phox complex. These results suggest that HO-1 functions as a suppressor of TNF-␣ signaling, not only by inhibiting the expression of adhesion molecules and generation of interleukin-6, but also by diminishing intracellular reactive oxygen species production and nuclear factor-B activation in both cultured human tracheal smooth muscle cells and the airways of mice.

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1 The effect of amphetamine on the secretion of testosterone and the production of testicular adenosine 3':5'-cyclic monophosphate (cyclic AMP) in rats was studied. 2 A single intravenous injection of amphetamine decreased the basal and human chorionic gonadotropin (hCG)-stimulated levels of plasma testosterone. Plasma LH levels were not altered by the injection of amphetamine. 3 Administration of amphetamine in vitro resulted in a dose-dependent inhibition of both basal and hCG-stimulated release of testosterone. 4 Amphetamine enhanced the basal and hCG-increased levels of cyclic AMP accumulation in vitro in rat testes. 5 These results suggest that amphetamine inhibits the spontaneous and hCG-stimulated secretion of testosterone from the testes through a mechanism involving an increase in cyclic AMP production.

1 The aim of this study was to investigate the mechanism by which amphetamine exerts its inhibitory e ect on testicular interstitial cells of male rats. 2 Administration of amphetamine (10 712 ± 10 76 M) in vitro resulted in a dose-dependent inhibition of both basal and human chorionic gonadotropin (hCG, 0.05 iu ml 71 )-stimulated release of testosterone. 3 Amphetamine (10 79 M) enhanced the basal and hCG-increased levels of adenosine 3':5'-cyclic monophosphate (cyclic AMP) accumulation in vitro (P50.05) in rat testicular interstitial cells. 4 Administration of SQ22536, an adenylyl cyclase inhibitor, decreased the basal release (P50.05) of testosterone in vitro and abolished the inhibitory e ect of amphetamine. 5 Nifedipine (10 76 M) alone decreased the secretion of testosterone (P50.01) but it failed to modify the inhibitory action of amphetamine (10 710 ± 10 76 M). 6 Amphetamine (10 710 ± 10 76 M) signi®cantly (P50.05 or P50.01) decreased the activities of 3b-hydroxysteroid dehydrogenase (3b-HSD), P450c17, and 17-ketosteroid reductase (17-KSR) as indicated by thin-layer chromatography (t.l.c.). 7 These results suggest that increased cyclic AMP production, decreased Ca 2+ channel activity and decreased activities of 3b-HSD, P450c17, and 17-KSR are involved in the inhibition of testosterone production induced by the administration of amphetamine.

Endocrine sensitivity, assessed by the expression of estrogen receptor (ER), has long been the predict factor to guide therapeutic decisions. Tamoxifen has been the most successful hormonal treatment in endocrine-sensitive breast cancer. However, in estrogen-insensitive cancer tamoxifen showed less effectiveness than in estrogen-sensitive cancer. It is interesting to develop new drugs against both hormone-sensitive and insensitive tumor. In this present study we examined anticancer effects of evodiamine extracted from the Chinese herb, Evodiae fructus, in estrogen-dependent and –independent human breast cancer cells, MCF-7 and MDA-MB-231 cells, respectively. Evodiamine inhibited the proliferation of MCF-7 and MDA-MB-231 cells in a concentration-dependent manner with concentration of 1×10−6 and 1×10−5 M. Evodiamine also induced apoptosis via up-regulation of caspase 7 activation, PARP cleavage (Bik and Bax expression). The expression of ER α and β in protein and mRNA levels was down-regulated by evodiamine according to data from immunoblotting and RT-PCR analysis. Overall, our results indicate that evodiamine mediates degradation of ER and induces caspase-dependent pathway leading to inhibit proliferation of breast cancer cell lines. It suggests that evodiamine may in part mediate through ER-inhibitory pathway to inhibit breast cancer cell proliferation.

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1 In vivo and in vitro experiments were performed to examine inhibitory e ects of digoxin on testosterone secretion and to determine possible underlying mechanisms. 2 A single intravenous injection of digoxin (1 mg kg 71 ) decreased the basal and human chorionic gonadotropin (hCG)-stimulated plasma testosterone concentrations in adult male rats. 3 Digoxin (10 77 ± 10 74 M) decreased the basal and hCG-stimulated release of testosterone from rat testicular interstitial cells in vitro. 4 Digoxin (10 77 ± 10 74 M) also diminished the basal and hCG-stimulated production of cyclic 3' : 5'-adenosine monophosphate (AMP) and attenuated the stimulatory e ects of forskolin and 8-Br-cyclic AMP on testosterone production by rat testicular interstitial cells. 5 Digoxin (10 74 M) inhibited cytochrome P450 side chain cleavage enzyme (cytochrome P450 scc ) activity (conversion of 25-hydroxy cholesterol to pregnenolone) in the testicular interstitial cells but did not in¯uence the activity of other steroidogenic enzymes. 6 These results suggest that digoxin inhibits the production of testosterone in rat testicular interstitial cells, at least in part, via attenuation of the activities of adenylyl cyclase and cytochrome P450 scc .