Design, Synthesis and Biological Evaluation of 6-(Imidazo[1,2-a]pyridin-6-yl)quinazoline Derivatives as Anticancer Agents via PI3Kα Inhibition.

Aberrant expression of the phosphatidylinositol 3-kinase (PI3K) signalling pathway is often associated with tumourigenesis, progression and poor prognosis. Hence, PI3K inhibitors have attracted significant interest for the treatment of cancer. In this study, a series of new 6-(imidazo[1,2-a]pyridin-6-yl)quinazoline derivatives were designed, synthesized and characterized by 1H NMR, 13C NMR and HRMS spectra analyses. In the in vitro anticancer assay, most of the synthetic compounds showed submicromolar inhibitory activity against various tumour cell lines, among which 13k is the most potent compound with IC50 values ranging from 0.09 µΜ to 0.43 µΜ against all the tested cell lines. Moreover, 13k induced cell cycle arrest at G2/M phase and cell apoptosis of HCC827 cells by inhibition of PI3Kα with an IC50 value of 1.94 nM. These results suggested that compound 13k might serve as a lead compound for the development of PI3Kα inhibitor.

Maizediterpene D from the roots of Zea mays L. alleviates hydrogen peroxide induced oxidative stress and improves cell survival by activation of TrkB/IGF-1R crosstalk pathways.

The ent-kaurane diterpenoid enriched fraction (EDEF) of maize root was isolated and purified, and 10 compounds, including 4 ent-kaurane diterpenoids, were isolated and identified. We evaluated their neuroprotective properties in vitro for the first time using an H2O2-induced oxidative damage model in SH-SY5Y cells. The results showed that pretreatment with maizediterpene D, a new ent-kaurane diterpenoid isolated from the EDEF, significantly attenuated H2O2-induced apoptosis by improving cell survival, reducing ROS production and increasing mitochondrial membrane potential. Mechanistically, the neuroprotective effect of maizediterpene D was confirmed to be related to the dual activation of IGF-1R and BDNF/TrkB crosstalk pathways. Our findings suggest that the EDEF and its active constituent maizediterpene D had good neuroprotective properties and could serve as potential candidates for the development of therapeutic drugs for oxidative stress-related diseases.

Novel Flavan-3,4-diol vernicidin B from Toxicodendron Vernicifluum (Anacardiaceae) as potent antioxidant via IL-6/Nrf2 cross-talks pathways.

BACKGROUND: Oxidative stress is considered to be a pathological factor of various neurodegenerative diseases. Studies have confirmed the antioxidant activity of T. vernicifluum. However, the main active components responsible for antioxidant activity remain unknown. OBJECTIVE: The aim of this study is to explore the activities of vernicidin B on oxidative stress injury induced by H2O2 in SH-SY5Y cells, and the underlying mechanism of vernicidin B in oxidative stress-related neurological diseases is further discussed. METHODS: Various separation methods were used to isolate and identify the compounds in an EtOAc extract of T. vernicifluum. The structures of the isolates were clarified by HR-TOF-MS and 1D/2D NMR data and compared with findings in previous literature. The MTT assay was used to evaluate the potential antioxidant activity of the isolated flavonoids. The apoptosis rate, mitochondrial reactive oxygen species (ROS) level and mitochondrial potential were measured by flow cytometry and fluorescence microscope. The levels of related proteins were detected by Western blotting. RESULTS: Four new flavan-3,4-diols (1-4, vernicidins A-D) and 11 known flavonoids (5-15) were purified from the EtOAc extract of T. vernicifluum. Among these compounds, vernicidin B showed the most promising potential for protecting SH-SY5Y cells from H2O2-induced oxidative stress. Moreover, pretreatment with vernicidin B decreased ROS production and mitochondrial membrane potential and significantly attenuated H2O2-induced apoptosis in a dose-dependent manner. Mechanistically, the antioxidant stress activities of vernicidin B were confirmed to be related to the IL-6/Nrf2 cross-talks pathway and its downstream pathways, including PI3K/Akt/mToR-Gsk3ß, JAK2/STAT3 and MAPKs. CONCLUSIONS: Our findings suggested that vernicidin B can improve the oxidative stress injury induced by H2O2 through IL-6/Nrf2 cross-talks pathway, indicating that it may be a potential candidate drug for the treatment of oxidative stress-related neurodegenerative diseases.

Does a new videolaryngoscope (glidescope) provide better glottic exposure?

BACKGROUND: The GlideScope (Saturn Biomedical Systems Inc, Burnaby, British Columbia, Canada) is a new videolaryngoscope designed as an alternative to the conventional laryngoscope. It was designed to facilitate glottic exposure during tracheal intubation. This study assessed the effectiveness of the GlideScope in providing glottic exposure. METHODS: One hundred and three patients requiring general anesthesia for elective surgery were enrolled in this study. Under full monitoring, all patients were given fentanyl, propofol or thiopentone and muscle relaxant for induction. In each patient laryngoscopy was performed first with a Macintosh blade (size 3), then with the GlideScope. The optimal view of the larynx that could be achieved with each instrument was recorded and assessed using the grading scale of Cormack and Lehane (C&L grade). Intubation was performed with the GlideScope. RESULTS: The grading decreased in the majority (93.6%, 44/47) of patients with C&L grade > 1 when using the GlideScope. Of the 22 patients who were considered as subjects of difficult intubation, 20 had an improved laryngoscopic grade with GlideScope. One hundred and one patients were intubated successfully at the first attempt. CONCLUSIONS: The laryngeal view was better in the GildeScope group using this grading system. The GlideScope provided a better view of the glottis and is a useful alternative in airway management.