Epithelial ovarian carcinoma (EOC) is the most lethal gynecological malignancy. Herein, we sought to determine the efficacy of phosphoinositide 3-kinase (PI3K)/Akt inhibition using three AZD compounds in a NOD-SCID xenograft mouse model and Akt regulation in a panel of eight ovarian cancer cell lines. Elevated Akt phosphorylation on Ser473 but not on Thr308 in cancerous tissues correlated with short progression-free survival (PFS), overall survival (OS), and death. AZD8835 and AZD8186 inhibited Akt phosphorylation while AZD5363 augmented its phosphorylation on Ser473. To add, all compounds inhibited the Akt downstream effectors 4E-BP1 and p70S6 kinase. AZD8835 and AZD5363 sensitized chemoresistant ovarian cancer cells to cisplatin and paclitaxel treatment. Only AZD5363 could inhibit COL11A1 mRNA and promoter activity, which are important factors in Akt regulation and chemoresistance in ovarian cancer. By using a mouse xenograft model, AZD8835 and AZD5363, but not AZD8186, caused a significant reduction in tumor formation. AZD compounds did not change the mRNA expression of BRCA1/BRCA in ovarian cancer cells, but AZD8835 inhibited BRCA1/BRCA2 mRNA expression and p-ERK protein expression in OVCAR-8 cells with the KRAS mutation. This study highlights the importance of PI3K/Akt in ovarian tumor progression and chemoresistance and the potential application of AZD compounds, especially AZD8835 and AZD5363, as therapeutic agents for the treatment of ovarian cancer.
As a rising emerging field, synthetic biology intends to realize precise regulations of cellular network by constructing artificial synthetic circuits, and it brings great opportunities to treat diseases and discover novel drug targets. Depending on the combination mode of different logic gates, various synthetic circuits are created to carry out multilevel regulations. In given synthetic circuits, drugs often act as inputs to drive circuits operation. It is becoming available to construct drug-responsive gene circuits for experimentally treating various disease models, including metabolic disease, immunity disease, cancer and bacterial infection. Synthetic biology works well in association with the CRISPR system for drug target functional screening. Remarkably, more and more well-designed circuits are developed to discover novel drug targets and precisely regulate drug therapy for diseases.
Aims: To explore the effect and mechanism of gastrodin (GAS) on human umbilical vein endothelial cells (HUVECs) apoptosis induced by oxidative stress and its function in wound healing.
Main methods: HUVECs were incubated with tert-butyl hydroperoxide (TBHP) to induce endothelial cell dysfunction and GAS was used as a protector. Cell viability was detected by Counting Kit-8 (CCK-8). HUVECs apoptosis was evaluated by TUNEL assay and western blotting for cleaved caspase3 (C-caspase3) and other apoptosis-related proteins. Transwell migration assay, tube formation assay, and cell-matrix adhesion assay were performed to evaluated cell function of HUVECs. Transfection with nuclear factor-erythroid 2-related factor 2 (Nrf2) small interfering ribonucleic acid and western blotting for Nrf2, HO-1, and apoptosis-related proteins were performed to prove that Nrf2/HO-1 pathway is involved in the protective effects of GAS. The skin wound model of rat was used to assess the protective effects of GAS in vivo.
Key Findings: The results show that treating HUVECs with GAS attenuated TBHP-induced apoptosis and cellular dysfunction, including cellular tube formation, migration, and adhesion. Mechanistically, we found that GAS protects HUVECs from TBHP-induced cellular apoptosis by activating the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway. An in vivo study illustrated that the oral administration of GAS enhances vascularization in regenerated tissue and facilitates wound healing.
Significance: The findings of this study demonstrated that GAS may serve as a potential agent that accelerates wound healing.
Neuroinflammation is one of the important factors aggravating brain injury after ischemic stroke. We aimed to investigate the effects of cerebrolysin (CBL) on neuroinflammation in vivo and in vitro and the underlying mechanisms. The gene expressions of pro-inflammatory factors and anti-inflammatory factors were analyzed by real time PCR in rat transient middle cerebral artery occlusion (tMCAO) model, lipopolysaccharides-induced neuroinflammatory mice model and LPS-treated mouse primary microglia cells. The neuroprotective effects of CBL were evaluated by infarct size, Longa test and Rotarod test for long-term functional recovery in rats subjected to ischemia. The role of CREB/PGC-1α pathway in anti-neuroinflammatory effect of CBL was also determined by real time PCR and Western blotting. In the tMCAO model, administration of CBL at 3 h post-ischemia reduced infarct volume, promoted long-term functional recovery, decreased the gene expression of pro-inflammatory factors and increased the gene expression of anti-inflammatory factors. Correspondingly, in LPS-induced neuroinflammatory mice model, CBL treatment attenuated sickness behavior, decreased the gene expression of pro-inflammatory factors, and increased the gene expression of anti-inflammatory factors. In in vitro and in vivo experiments, CBL increased the protein expression levels of PGC-1α and phosphorylated CREB to play anti-inflammatory effect. Additionally, the application of the specific CREB inhibitor, 666-15 compound could effectively reverse the anti-inflammatory effect of CBL in primary mouse microglia cells and anti-ischemic brain injury of CBL in rats subjected to tMCAO. In conclusion, CBL ameliorated cerebral ischemia injury through reducing neuroinflammation partly via the activation of CREB/PGC-1α pathway and may play a therapeutic role as anti-neuroinflammatory agents in the brain disorders associated with neuroinflammation.
Frontiers in Pharmacology
Target Discovery for Anticancer Therapy Facilitated by Artificial IntelligenceFrontiers in Pharmacology
Inspired by Nature: Towards Novel Anti-infective AgentsFrontiers in Pharmacology
Advanced Nanotechnological Detection and Drug Delivery ConfigurationsFrontiers in Pharmacology
Innovative Pharmacometric Approaches to Inform Drug Development and Clinical Use