Protective effects of progesterone on pulmonary artery smooth muscle cells stimulated with Interleukin 6 via blocking the shuttling and transcriptional function of STAT3.

BACKGROUND: Sex hormone paradox is a crucial but unresolved issue in the field of pulmonary artery hypertension (PAH), and is thought to be related to different pathogenic factors. Inflammation is one of pathological mechanisms of PAH development. However, effects of sex hormones on the pulmonary vasculature under the condition of inflammation are still elusive. METHODS: Interleukin-6 (IL-6) was used as a representative inflammatory stimulator. Effects of 17ß-estradiol or progesterone on human pulmonary artery smooth muscle cells (PASMCs) were measured under the condition of IL-6. Cell functions of proliferation and migration were measured by Alarmar Blue, EdU assay, wound-healing assay and transwell chambers. We explored further mechanisms using western blot, immunofluorescence, co-immunoprecipitation, qPCR and chromatin immunoprecipitation. RESULTS: Our results revealed that IL-6 promoted the proliferation of PASMCs, but progesterone could reverse the adverse effect of IL-6. The protective effect was dependent on progesterone receptor (PGR). By interacting with signal transducer and activator of transcription 3 (STAT3), activated PGR could reduce the IL-6-induced nuclear translocation of STAT3 and prevent STAT3-chromatin binding in PASMCs, leading to the decreased transcription of downstream CCND1 and BCL2. Alternatively, progesterone slightly decreased the phosphorylation of pro-proliferative Erk1/2 and Akt kinases and upregulated the anti-proliferative pSmad1-Id1/2 axis in IL-6-incubated PASMCs. CONCLUSIONS: Progesterone played a protective role on PASMCs in the context of IL-6, by blocking the functions of STAT3. Our findings might assist in explaining the clinical phenomenon of better prognosis for women with PAH.

Fasting activated histaminergic neurons and enhanced arousal effect of caffeine in mice.

Caffeine, a popular psychoactive compound, promotes wakefulness via blocking adenosine A2A receptors in the shell of the nucleus accumbens, which projects to the arousal histaminergic tuberomammillary nucleus (TMN). The TMN controls several behaviors such as wakefulness and feeding. Fasting has been reported to activate the TMN histaminergic neurons to increase arousal. Therefore, we propose that caffeine may promote greater arousal under fasting rather than normal feeding conditions. In the current study, locomotor activity recording, electroencephalogram (EEG) and electromyogram recording and c-Fos expression were used in wild type (WT) and histamine H1 receptor (H1R) knockout (KO) mice to investigate the arousal effects of caffeine under fasting conditions. Caffeine (15mg/kg) enhanced locomotor activity in fasted mice for 5h, but only did so for 3h in normally fed animals. Pretreatment with the H1R antagonist pyrilamine abolished caffeine-induced stimulation on locomotor activity in fasted mice. EEG recordings confirmed that caffeine-induced wakefulness for 3h in fed WT mice, and for 5h in fasted ones. A stimulatory effect of caffeine was not observed in fasted H1R KO mice. Furthermore, c-Fos expression was increased in the TMN under fasting conditions. These results indicate that caffeine had greater wakefulness-promoting effects in fasted mice through the mediation of H1R.

The evaluation of efficacy and safety of sunitinib on EGFR-TKI pretreated advanced non-small cell lung cancer patients in China.

BACKGROUND: Sunitinib is an oral multitargeted tyrosine kinase inhibitor (TKI) exhibiting antiagiogenic and antitumor effects. OBJECTIVE: To evaluate the efficacy and potential toxicity of sunitinib therapy in advanced non-small cell lung cancer (NSCLC) patients in China. METHODS: From January 2009 to August 2011, 30 patients with stage IV NSCLC, who were pretreated with the epidermal growth factor receptor (EGFR)-TKIs and then received sunitinib, were retrospectively reviewed. Univariate and multivariate Cox proportional hazard regression analysis was performed to determine the potential prognostic risk factors influencing NSCLC survival. RESULTS: The median progression-free survival (PFS) and median overall survival (OS) of all 30 treated patients was 1.25 months [95% confidence interval (CI): 0.90-1.9 months] and 3.40 months (95% CI: 3.00-6.80 months), respectively. Cox regression analysis suggested that Eastern Cooperative Oncology Group (ECOG) performance status (PS) is predictive of both PFS (P=0.001) and OS (P<0.001). Common adverse events (AEs) included hand-foot syndrome (53.3%), mucositis (40.0%), rash (36.7%) and diarrhea (33.3%). CONCLUSION: No sign of overall clinical benefits of sunitinib was detected in patients with pretreated EGFR-TKIs. Most patients suffered AEs from mild to moderate severity. ECOG PS is highly associated with PFS and OS rate. Further studies in NSCLC are required to determine whether sunitinib is beneficial nor not.