Quercetin, Main Active Ingredient of Moutan Cortex, Alleviates Chronic Orofacial Pain via Block of Voltage-Gated Sodium Channel.

BACKGROUND: Chronic orofacial pain (COP) therapy is challenging, as current medical treatments are extremely lacking. Moutan Cortex (MC) is a traditional Chinese medicine herb widely used for chronic inflammatory diseases. However, the mechanism behind MC in COP therapy has not been well-established. The purpose of this study was to identify the active ingredients of MC and their specific underlying mechanisms in COP treatment. METHODS: In this study, the main active ingredients and compound-target network of MC in COP therapy were identified through network pharmacology and bioinformatics analysis. Adult male Sprague-Dawley rats received oral mucosa lipopolysaccharide (LPS) injection to induce COP. Pain behaviors were evaluated by orofacial mechanical nociceptive assessment after intraganglionar injection. In vitro inflammatory cytokines in LPS-pretreated human periodontal ligament stem cells (hPDLSCs) and rat primary cultural trigeminal ganglion (TG) neurons were quantified by real-time quantitative polymerase chain reaction (RT-qPCR). Schrödinger software was used to verify the molecular docking of quercetin and critical targets. Whole-cell recording electrophysiology was used to evaluate the effect of quercetin on voltage-gated sodium (Na v ) channel in rat TG neurons. RESULTS: The assembled compound-target network consisted of 4 compounds and 46 targets. As 1 of the active components of MC correlated with most related targets, quercetin alleviated mechanical allodynia in LPS-induced rat model of COP (mechanical allodynia threshold median [interquartile range (IQR) 0.5 hours after drug administration: vehicle 1.3 [0.6-2.0] g vs quercetin 7.0 [6.0-8.5] g, P = .002). Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that immune response and membrane functions play essential roles in MC-COP therapy. Five of the related targets were identified as core targets by protein-protein interaction analysis. Quercetin exerted an analgesic effect, possibly through blocking Na v channel in TG sensory neurons (peak current density median [IQR]: LPS -850.2 [-983.6 to -660.7] mV vs LPS + quercetin -589.6 [-711.0 to -147.8] mV, P = .006) while downregulating the expression level of proinflammatory cytokines-FOS (normalized messenger RNA [mRNA] level mean ± standard error of mean [SEM]: LPS [2. 22 ± 0.33] vs LPS + quercetin [1. 33 ± 0.14], P = .034) and TNF-α (normalized mRNA level mean ± SEM: LPS [8. 93 ± 0.78] vs LPS + quercetin [3. 77 ± 0.49], P < .0001). CONCLUSIONS: Identifying Na v as the molecular target of quercetin clarifies the analgesic mechanism of MC, and provides ideas for the development of novel selective and efficient chronic pain relievers.

[The characteristics of RR-Lorenz plot in persistent atrial fibrillation patients complicating with escape beats and rhythm].

OBJECTIVE: To explore the characteristics of RR-Lorenz plot in persistent atrial fibrillation (AF) patients complicating with escape beats and rhythm though ambulatory electrocardiogram. METHODS: The 24-hour ambulatory electrocardiogram of 291 persistent AF patients in second affiliated hospital of Zhengzhou university from July 2005 to April 2013 were retrospectively analyzed and the RR interval and the QRS wave were measured. Patients were divided into two groups according to the distribution of the RR-Lorenz point [AF without escape beats and rhythm group (Group A, n = 259) and AF with escape beats and rhythm group (Group B, n = 32)]. The characteristics of RR-Lorenz plot between the two groups were compared. RESULTS: (1) Fan-shaped RR-Lorenz plots were evidenced in Group A. (2)In Group B, 30 cases showed fan-shaped with L-shaped and a short dense rods along 45° line. The proportion of escape beats and rhythm was 0.28% (275/98 369) -14.06% (11 263/80 112) . The other 2 cases in group B showed no typical RR-Lorenz plots features. CONCLUSION: RR-Lorenz plot could help to quickly diagnose persistent AF complicating with escape beats and rhythm according to the typical RR-Lorenz plot characteristics in 24-hour ambulatory electrocardiogram.

Correction: High expression of CTHRC1 promotes EMT of epithelial ovarian cancer (EOC) and is associated with poor prognosis.

[This corrects the article DOI: 10.18632/oncotarget.5358.].

The preoperative platelet-lymphocyte ratio versus neutrophil-lymphocyte ratio: which is better as a prognostic factor in oral squamous cell carcinoma?

OBJECTIVE: Recent studies have shown that the presence of systemic inflammation and platelet status correlate with poor survival in various cancers. The aim of this study was to evaluate the prognostic value of the preoperative platelet-lymphocyte ratio (PLR) and the neutrophil-lymphocyte ratio (NLR) in patients with oral squamous cell carcinoma (OSCC) undergoing surgery. METHODS: In this study, 306 patients with OSCC who had surgery were enrolled. The optimal cutoff value of PLR and NLR was determined by receiver operating characteristic (ROC) curve analysis. The prognostic significance of both markers was determined by uni- and multivariate analysis. RESULTS: The results showed that high NLR and PLR were classified using a cutoff value of 2.7 and 135, respectively, based on ROC curve analysis. Only PLR was associated with decreased disease-free survival [hazard ratio (HR) = 2.237; 95% confidence interval (CI): 1.401-3.571; p = 0.001] and overall survival [HR = 2.022; 95% CI: 1.266-3.228; p = 0.003] by both uni- and multivariate analysis. CONCLUSION: The preoperative PLR is superior to NLR as an independent indicator in predicting disease-free survival and overall survival in patients who undergo oral cancer resection for OSCC.

AEG-1 activates Wnt/PCP signaling to promote metastasis in tongue squamous cell carcinoma.

Despite advances in therapy, survival among patients with locally advanced squamous cell carcinoma of tongue (TSCC) and cervical lymph node metastasis remains dismal. Here, we estimated the functional effect of AEG-1 on TSCC metastasis and explored the molecular mechanism by which AEG-1 stimulates epithelial-mesenchymal transition (EMT). We initially found that AEG-1 mRNA levels were much higher in metastatic TSCC than in non-metastatic TSCC and that AEG-1 expression strongly correlates with EMT status. Receiver operating characteristic analysis showed that the combined AEG-1 and EMT statuses are predictive of the survival rate among TSCC patients. In addition, AEG-1 knockdown inhibited EMT in cultured TSCC cell lines and in a xenograft-mouse model. Recombinant AEG-1 activated Wnt/PCP-Rho signaling, and its stimulatory effects on TSCC cell invasiveness and EMT were reversed by an anti-Wnt5a neutralizing antibody or by inhibition of Rac1 or ROCK. These results highlight the critical stimulatory effect of AEG-1 on cancer cell invasiveness and EMT and indicate that AEG-1 may be a useful prognostic biomarker for TSCC patients.

High expression of CTHRC1 promotes EMT of epithelial ovarian cancer (EOC) and is associated with poor prognosis.

Collagen triple helix repeat-containing 1 (CTHRC1) is aberrantly overexpressed in multiple malignant tumors. However, the expression characteristics and function of CTHRC1 in epithelial ovarian cancer (EOC) remain unclear. We found that CTHRC1 expression was up-regulated in the paraffin-embedded EOC tissues compared to borderline or benign tumor tissues. CTHRC1 expression was positively correlated with tumor size (p = 0.008), menopause (p = 0.037), clinical stage (p = 0.002) and lymph node metastasis (p < 0.001) and was also an important prognostic factor for the overall survival of EOC patients, as revealed by Kaplan-Meier analysis. CTHRC1 increased the invasive capabilities of EOC cells in vitro by activating the Wnt/ß-catenin signaling pathway. We showed that ectopic transfection of CTHRC1 in EOC cells up-regulated the expression of EMT markers such as N-cadherin and vimentin, and EMT-associated transcriptional factor Snail. Knockdown of CTHRC1 expression in EOC cells resulted in down-regulation of N-cadherin, vimentin, Snail and translocation of ß-catenin. Collectively, CTHRC1 may promote EOC metastasis through the induction of EMT process and serve as a potential biomarker for prognosis as well as a target for therapy.