-Epithelial-mesenchymal transition (EMT) plays a pivotal event in the development of pulmonary fibrosis. We have previously reported that methotrexate (MTX)-induced alveolar epithelial cell injury followed by pulmonary fibrosis as a result of the recruitment and proliferation of myofibroblasts. However, there is no data concerning whether EMT occurs in MTX-induced pulmonary fibrosis. In the present study, therefore, we investigated the expression of EMT markers such as E-cadherin, α-SMA, and vimentin by immunofluorescence analysis in mouse lung tissues after administration of MTX. We found that vimentin and α-SMA-positive cells of the MTX-induced pulmonary fibrosis were increased; on the other hand, E-cadherin was decreased, indicating that epithelial cells act as the main source of mesenchymal expansion. These results exhibited the down-regulation of E-cadherin expression and the up-regulation of α-smooth muscle actin (α-SMA) in primary mouse alveolar epithelial cells (MAECs) and A549 cell lines. Additionally, MTX-induced A549 cells exhibited an EMT-like phenotype accompanied by the elevation of the expression of interleukin-6 (IL-6) and transforming growth factor (TGF)-β1, as well as an enhancement of migration. All of these findings suggest that MTX-induced pulmonary fibrosis occurs via EMT.

Use of the ERAS protocol for the perioperative management of open AAA surgery shortened the time before recommencing oral consumption, the postoperative hospital stay, and reduced the medical costs compared to the conventional approach.

17b-Estradiol (E 2 ) serves as an anti-obesity steroid; however, the mechanism underlying this effect has not been fully clarified. The effect of E 2 on adipocytes opposes that of glucocorticoids, which potentiate adipogenesis and anabolic lipid metabolism. The key to the intracellular activation of glucocorticoid in adipocytes is 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1), which catalyses the production of active glucocorticoids (cortisol in humans and corticosterone in rodents) from inactive 11-keto steroids (cortisone in humans and 11-dehydrocorticosterone in rodents). Using differentiated 3T3-L1 adipocytes, we showed that E 2 inhibited 11b-HSD1 activity. Estrogen receptor (ER) antagonists, ICI-182 780 and tamoxifen, failed to reverse this inhibition. A significant inhibitory effect of E 2 on 11b-HSD1 activity was observed within 5-10 min. Furthermore, acetylation or a-epimerization of 17-hydroxy group of E 2 attenuated the inhibitory effect on 11b-HSD1. These results indicate that the inhibition of 11b-HSD1 by E 2 depends on neither an ER-dependent route, transcriptional pathway nor nonspecific fashion. Hexose-6-phosphate dehydrogenase, which provides the cofactor NADPH for full activation of 11b-HSD1, was unaffected by E 2 . A kinetic study revealed that E 2 acted as a non-competitive inhibitor of 11b-HSD1. The inhibitory effect of E 2 on 11b-HSD1 was reproduced in adipocytes isolated from rat mesenteric fat depots. This is the first demonstration that E 2 inhibits 11b-HSD1, thereby providing a novel insight into the anti-obesity mechanism of estrogen.

Percutaneous trans-catheter ASD closure was safely performed under the support of a surgical team. The cosmetic outcome of surgical closure is improving after initiation of partial sternotomy via limited skin incision for the pediatric population and young adult females. Prior to the treatment, the physicians must thoroughly inform patients and families of the advantages and disadvantages of both treatment options.

Inducing apoptosis is an effective treatment for cancer. Conventional cytotoxic anticancer agents induce apoptosis primarily through activation of tumor suppressor p53 by causing DNA damage and the resulting regulation of B-cell leukemia/lymphoma-2 (BCL-2) family proteins. Therefore, the effects of these agents are limited in cancers where p53 loss-of-function mutations are common, such as triple-negative breast cancer (TNBC). Here, we demonstrate that ultraviolet (UV) light-induced p53-independent transcriptional activation of NOXA, a proapoptotic factor in the BCL-2 family, results in apoptosis induction. This UV light-induced NOXA expression was triggered by extracellular signal-regulated kinase (ERK) activity. Moreover, we identified the specific UV light-inducible DNA element of the NOXA promoter and found that this sequence is responsible for transcription factor Krüppel-like factor 4 (KLF4)-mediated induction. In p53-mutated TNBC cells, inhibition of KLF4 by RNA interference reduced NOXA expression. Furthermore, treatment of TNBC cells with a KLF4-inducing small compound, APTO-253, resulted in the induction of NOXA expression and NOXA-mediated apoptosis. Therefore, our results help to clarify the molecular mechanism of DNA damage-induced apoptosis and provide support for a possible treatment method for p53-mutated cancers.

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It has been suggested that resveratrol, a polyphenol in wine, can regulate adiposity because it decreases adipose deposition in mice and rats; however, the mechanism underlying this effect has not been fully clarified. In humans and rodents, 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) is expressed in liver and adipose tissue. 11b-HSD1 converts inactive glucocorticoid into active glucocorticoid in adipocytes. Activated glucocorticoid plays an important role in the pathogenesis of central obesity. The objective of this study was to investigate the effects of resveratrol on 11b-HSD1 activity in rodent adipose tissue. 11b-HSD1 activity in microsomes from rat mesenteric adipose depots and 3T3-L1 adipocytes was determined in the presence of 11-dehydrocorticosterone with or without varying concentrations of resveratrol. Significant inhibition of 11b-HSD1 by resveratrol was observed in rat adipose microsomes and 3T3-L1 adipocytes within 10 min. Time-and dose-dependent effects were also observed. The 11b-HSD1 activity by resveratrol was also inhibited in rat epididymal adipose tissue, and this inhibition was not recovered by estrogen receptor blockers. The kinetic study revealed that resveratrol acted as a non-competitive inhibitor of 11b-HSD1. K i and IC 50 values of resveratrol were 39.6 and 35.2 mM respectively. Further, resveratrol did not affect the activities of 11b-HSD2 and hexose-6-phosphate dehydrogenase. These results suggest that the most likely mechanism of 11b-HSD1 inhibition by resveratrol is via interaction between resveratrol and 11b-HSD1 enzyme, rather than via a transcriptional pathway. We demonstrated that the antiobesity effects of resveratrol may partially be attributed to the inhibition of 11b-HSD1 activity in adipocytes.

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