Protective effect of thioredoxin perfusion but not inhalation in warm ischemic-reperfused rat lungs

Abstract

Background: Thioredoxin is a ubiquitous protein with anti-oxidative, anti-apoptotic, and anti-inflammatory effects. It was reported [Fukuse T, Hirata T, Yokomise H et al. Attenuation of ischaemia reperfusion injury by human thioredoxin. Thorax 1995; 50: 387–391] that rhTRX protected lungs from ischemia-reperfusion injury as a radical scavenger; however, the mechanism was not elucidated. Therefore, we investigated the effect of perfusion and inhalation of rhTRX, and the associated mechanisms, by analyzing the concentrations and molecular states of the perfused rhTRX.

Materials and methods: Perfusion and inhalation studies of rhTRX were conducted with an isolated rat-lung perfusion model. The heart-lung block was perfused for 15 min and subsequently exposed to a 55-min ischemia followed by a 120-min reperfusion. Pulmonary artery pressure, weight gain, dynamic airway resistance, pulmonary compliance, and tidal volume were measured continuously. The concentrations and molecular states of the perfused rhTRX were measured.

Results: A 350-μg/ml perfusion of rhTRX decreased post-ischemic pulmonary artery pressure (P < 0.05), while a 200-μg/ml perfusion did not. Throughout the experiment, the rhTRX concentrations were constant, and the rhTRX molecules were mostly dimeric. The inhalation of rhTRX showed adverse effects on the pulmonary function compared with the control group (P < 0.05).

Conclusions: A 350-μg/ml perfusion, but not inhalation, of rhTRX protected rat lungs from ischemia-reperfusion injury. rhTRX was effective in dimeric form without transit to the lung tissue. rhTRX may be effective by some mechanism other than radical scavenging.     

Activation of Notch-1 enhances epithelial-mesenchymal transition in gefitinib-acquired resistant lung cancer cells

Despite an initial response to EGFR tyrosine kinase inhibitors (EGFR-TKI) in EGFR mutant lung cancer, most patients eventually become resistant and result in treatment failure. Recent studies have shown that epithelial to mesenchymal transition (EMT) is associated with drug resistance and cancer cell metastasis. Strong multiple gene signature data indicate that EMT acts as a determinant of insensitivity to EGFR-TKI. However, the exact mechanism for the acquisition of the EMT phenotype in EGFR-TKI resistant lung cancer cells remains unclear. In the present study, we showed that the expression of Notch-1 was highly upregulated in gefitinib-resistant PC9/AB2 lung cancer cells. Notch-1 receptor intracellular domain (N1IC), the activated form of the Notch-1 receptor, promoted the EMT phenotype in PC9 cells. Silencing of Notch-1 using siRNA reversed the EMT phenotype and restored sensitivity to gefitinib in PC9/AB2 cells. Moreover, Notch-1 reduction was also involved in inhibition of anoikis as well as colony-formation activity of PC9/AB2 cells. Taken together, these results provide strong molecular evidence that gefitinib-acquired resistance in lung cancer cells undergoing EMT occurs through activation of Notch-1 signaling. Thus, inhibition of Notch-1 can be a novel strategy for the reversal of the EMT phenotype thereby potentially increasing therapeutic drug sensitivity to lung cancer cells.     

Efficacy Comparison of Six Chemotherapeutic Combinations for Osteosarcoma and Ewing's Sarcoma Treatment: A Network Meta‐Analysis

This study aimed to address the insufficiency of traditional meta‐analysis and provide improved guidelines for the clinical practice of osteosarcoma treatment. The heterogeneity of the fixed‐effect model was calculated, and when necessary, a random‐effect model was adopted. Furthermore, the direct and indirect evidence was pooled together and exhibited in the forest plot and slash table. The surface under the cumulative ranking curve (SUCRA) value was also measured to rank each intervention. Finally, heat plot was introduced to demonstrate the contribution of each intervention and the inconsistency between direct and indirect comparisons. This network meta‐analysis included 32 trials, involving a total of 5,626 subjects reported by 28 articles. All the treatments were classified into six chemotherapeutic combinations: dual agent with or without ifosfamide (IFO), multi‐agent with or without IFO, and dual agent or multi‐agent with IFO and etoposide. For the primary outcomes, both overall survival (OS) and event‐free survival (EFS) rates were considered. The multi‐agent integrated with IFO and etoposide showed an optimal performance for 5‐year OS, 10‐year OS, 3‐year EFS, 5‐year EFS, and 10‐year EFS when compared with placebo. The SUCRA value of this treatment was also the highest of these six interventions. However, multi‐drug with IFO alone had the highest SUCRA value of 0.652 and 0.516 when it came to relapse and lung‐metastasis. It was efficient to some extent, but no significant difference was observed in both outcomes. Chemotherapy, applied as induction or adjuvant treatment with radiation therapy or surgery, is able to increase the survival rate of patients, especially by combining multi‐drug with IFO and etoposide, which demonstrated the best performance in both OS and EFS. As for relapse and the lung‐metastasis, multiple agents with IFO alone seemed to have the optimal efficiency, although no significant difference was observed here. J. Cell. Biochem. 119: 250–259, 2018. © 2017 Wiley Periodicals, Inc.