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.

The improvement of periodontal tissue regeneration using a 3D-printed carbon nanotube/chitosan/sodium alginate composite scaffold.

Periodontal disease is a common disease in the oral field, and many researchers are studying periodontal disease and try to find some biological scaffold materials to make periodontal tissue regenerative. In this study, we attempted to construct a carbon nanotube/chitosan/sodium alginate (CNT/CS/AL) ternary composite hydrogel and then prepare porous scaffold by 3D printing technology. Subsequently, characterizing the materials and testing the mechanical properties of the scaffold. Additionally, its effect on the proliferation of human periodontal ligament cells (hPDLCs) and its antibacterial effect on Porphyromonas gingivalis were detected. We found that CNT/CS/AL porous composite scaffolds with uniform pores could be successfully prepared. Moreover, with increasing CNT concentration, the degradation rate and the swelling degree of scaffold showed a downward trend. The compressive strength test indicated the elastic modulus of composite scaffolds ranged from 18 to 80 kPa, and 1% CNT/CS/AL group had the highest quantitative value. Subsequently, cell experiments showed that the CNT/CS/AL scaffold had good biocompatibility and could promote the proliferation of hPDLCs. Among 0.1%-1% CNT/CS/AL groups, the biocompatibility of 0.5% CNT/CS/AL scaffold performed best. Meanwhile, in vitro antibacterial experiments showed that the CNT/CS/AL scaffold had a certain bacteriostatic effect on P. gingivalis. When the concentration of CNT was more than 0.5%, the antimicrobial activity of composite scaffold was significantly promoted, and about 30% bacteria were inactivated. In conclusion, this 3D-printed CNT/CS/AL composite scaffold, with good material properties, biocompatibility and bacteriostatic activity, may be used for periodontal tissue regeneration, providing a new avenue for the treatment of periodontal disease.

Design, Synthesis and Evaluation of Novel 1,4-Disubstituted Piperazine-2,5-dione Derivatives as Antioxidants against H2O2-Induced Oxidative Injury via the IL-6/Nrf2 Loop Pathway.

Excessive reactive oxygen species (ROS) production leads to oxidative stress in cells, impairing the function of mitochondria and finally inducing cell apoptosis. Considering the essential role of oxidative stress in the pathogenesis of various neurodegenerative diseases and psychiatric disorders, the discovery of novel antioxidants has attracted increasing attention. Herein, a series of novel 1,4-disubstituted piperazine-2,5-dione derivatives were designed, synthesized and evaluated for their antioxidative activity. The results of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay indicated that none of the tested compounds showed significant toxicity to SH-SY5Y cells at concentrations up to 80 µM. Cell counting via flow cytometry revealed that most of the tested compounds could effectively protect SH-SY5Y cells from H2O2-induced oxidative damage at 20 µM. Among these compounds, compound 9r exhibited the best antioxidative activity. Further mechanistic investigation indicated that 9r decreased ROS production and stabilized the mitochondrial membrane potential to restrain cell apoptosis, and promoted cell survival via an IL-6/Nrf2 positive-feedback loop. These results suggested the potential of compound 9r as a novel antioxidative candidate for the treatment of diseases caused by oxidative stress.

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.

Root Canal Disinfection Using Highly Effective Aggregation-Induced Emission Photosensitizer.

Root canal (RC) therapy is the primary treatment of dental-pulp and periapical diseases. The mechanical method and chemical irrigation have limitations in RC therapy. Much attention has focused on exploring more controllable and efficacious antimicrobial methods. Although the introduction of photodynamic therapy (PDT) has provided the ideas for RC debridement, the problems of low photosensitive efficiency and nonsignificant germicidal potency of traditional photosensitizers (e.g., methylene blue) have not been solved. Since the concept of "aggregation-induced emission" (AIE) was proposed, optimization of photosensitizers has been boosted considerably. Herein, an AIE photosensitizer, DPA-SCP, with a strong ability to generate singlet oxygen, is proposed for use as an antibacterial application in infected RCs. The antimicrobial activity of DPA-SCP against Enterococcus faecalis suspensions was tested. To explore the antibacterial ability of this photosensitizer against bacterial-biofilm colonization on the inner walls of RCs, we established a model of bacterial biofilm infection. PDT mediated by DPA-SCP had a significant germicidal effect on E. faecalis suspensions and 21-day biofilms in human RCs. PDT mediated by DPA-SCP could achieve efficiency equivalent to that observed using 1% NaOCl, and lead to no significant change in the dentin surface, chemical corrosion, or cytotoxicity.

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.