Qingyihuaji Formula promotes apoptosis and autophagy through inhibition of MAPK/ERK and PI3K/Akt/mTOR signaling pathway on pancreatic cancer in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Qingyihuaji Formula (QYHJ), a widely used traditional Chinese medicine (TCM), has been used to treat patients with cancer in China. However, the effect and mechanism of QYHJ on pancreatic ductal adenocarcinoma (PDAC) remains unclear. AIM OF THE STUDY: This study aimed to explore the roles and evaluate the possible underlying molecular mechanisms of QYHJ and its core component in PDAC using label-free quantitative proteomics in conjunction with network pharmacology-based analysis. MATERIALS AND METHODS: By screening differentially expressed proteins (DEPs) in proteomics and QYHJ-predicted gene sets, we identified QYHJ-related PDAC targets annotated with bioinformatic analysis. A subcutaneous tumor model was established to assess the role of QYHJ in vivo. The effects of quercetin (Que), a core component of QYHJ, on cell proliferation, migration, invasion, apoptosis, and autophagy in SW1990 and PANC-1 cells were investigated in vitro. Immunohistochemistry, western blotting, mRFP-GFP-LC3 adenovirus, and kinase analysis were used to determine the underlying mechanisms. RESULTS: Bioinformatics analysis revealed that 41 QYHJ-related PDAC targets were closely related to the cellular response to nitrogen compounds, positive regulation of cell death, regulation of epithelial cell apoptotic processes, and chemokine signaling pathways. CASP3, SRC, STAT1, PTPN11, PKM, and PAK1 with high expression were identified as hub DEPs in the PPI network, and these DEPs were associated with poor overall survival and STAT 1, MAPK/ERK, and PI3K/Akt/mTOR signaling pathways in PDAC patients. QYHJ significantly promoted tumor death in nude mice. Moreover, quercetin inhibited the proliferation, migration, and invasion of PDAC cells. Additionally, Que induced apoptosis and autophagy in PDAC cells. Mechanistically, QYHJ and Que significantly activated STAT 1 and remarkably inhibited the MAPK/ERK and PI3K/Akt/mTOR signaling pathways in vivo and in vitro, respectively. Importantly, ERK1/2 inactivation contributes to que-induced apoptosis in SW1990 and PANC-1 cells. CONCLUSIONS: These results suggest that QYHJ and Que are promising anti-PDAC avenues that benefit from their multiform mechanisms.

Stroke severity modified the effect of chronic atrial fibrillation on the outcome of thrombolytic therapy.

There is conflicting information regarding the impact of chronic atrial fibrillation (AF) on the outcomes of thrombolyzed patients with stroke. This study was designed to identify high-risk patients with chronic AF who had undergone thrombolysis treatment and to explore whether the baseline National Institutes of Health Stroke Scale (NIHSS) could be used to distinguish poor clinical outcomes in thrombolyzed patients. A total of 164 acute ischemic stroke patients with chronic AF were enrolled in this study. The patients were categorized as having poor or favorable outcomes. A favorable 90-day outcome was defined as a modified Rankin Scale (mRS) score ≤2. Our study showed that the baseline NIHSS score of patients with poor functional recovery (mRS >2) was significantly higher than that of patients with favorable outcomes (median 16 vs 12). Receiver operating characteristic (ROC) curve analysis of mRS score showed that a baseline NIHSS score of 14 was the optimal threshold for predicting unfavorable outcomes in patients with chronic AF. Multivariate logistic regression analysis showed that baseline NIHSS score >14 was independently associated with poor outcomes (odds ratio = 4.182, 95% confidence interval 2.092-8.361). Our study showed that stroke severity modified the effect of chronic AF on the outcome of thrombolytic therapy. The approach of stratifying stroke severity may be used to evaluate treatment strategies for decision making in intravenous thrombolytic therapy for acute stroke with chronic AF.