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Objective:To explore the mechanism of Tripterygium wilfordii in treating renal cell carcinoma using network pharmacology and experimental validation. Methods:The traditional Chinese medicine systems pharmacology (TCMSP) database and analysis platform was utilized to screen the active ingredients of T. wilfordii and predict the targets using the Swiss database. Renal cell carcinoma related targets were collected from DisGeNET, GeneCards, and OMIM databases, and intersecting targets were obtained through Venny 2.1.0. Protein-protein interaction (PPI) networks were mapped using the STRING database and Cytoscape software, and gene ontology (GO) and kyoto encyclopedia of genes and genomics (KEGG) enrichment analyses were performed. Component-target-pathway networks were constructed using Cytoscape software. To induce the subcutaneous transplantation tumor model of renal cell carcinoma, nude mice were randomly divided into a control group and a treatment group, with 5 mice in each group. In the treatment group, mice were gastrically instilled with 615 mg/ml of T. wilfordii solution (1 845 mg T. wilfordii granules dissolved into 3 ml water) 2.46 g/kg, 10 μl/time, once daily for 21 d. In the control group, mice were gastrically instilled with an equal amount of saline. Tumor volume was measured once every 5 days, and the expression of serine/threonine protein kinase 1 (AKT1), signal transduction and transcription activator 3 (STAT3), tumor necrosis factor (TNF), tumor protein p53 (TP53), JUN, mitogen-activated protein kinase 8 (MAPK8), and MAPK14 was detected by enzyme-linked immunoassay. Results:Twenty-eight active pharmaceutical ingredients and 117 potential targets of T. wilfordii were screened; 13 425 related disease targets were identified; and finally, 113 drug-disease intersecting targets were obtained. In the PPI network, AKT1, STAT3, TNF, TP53, JUN, MAPK8, and MAPK14 were the core targets. GO analysis showed that BP mainly included nuclear receptor activity, ligand-activated transcription factor activity, RNA polymerase-specific DNA-binding transcription factor binding, nuclear steroid receptor activity, and adrenergic receptor activity, etc. CC mainly included the response to hormones, the cellular response to lipids, the positive regulation of cell migration, the response to TNF, the inflammatory response, the cellular response to hormonal stimulation, the response to hypoxia, the response to metal ions, etc. MF involves membrane rafts, membrane microregions, the outer side of the plasma membrane, the lateral side of the membrane, plasma membrane rafts, presynaptic membranes, vesicles, transcriptional regulatory complexes, post-synaptic membranes, synaptic membranes, etc. KEGG analysis showed that T. wilfordii treatment of RCC involves signaling pathways such as lipid and atherosclerosis, advanced glycosylation end product-receptor for advanced glycosylation end products (AGE-RAGE), TNF, Toll-like receptor, phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt), and MAPK. The experimental validation results showed that the tumor volume was reduced after treatment with tretinoin ( P < 0.05), the expression of TP53 protein was increased ( P < 0.001), and the expression of AKT1, STAT3, TNF, JUN, MAPK8, and MAPK14 proteins were all reduced (all P < 0.001). Conclusions:In this study, the target and signaling pathways of T. wilfordii treatment of renal cell carcinoma were initially predicted, providing a reference basis for further research on its protective mechanism and clinical application.
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Objective:To investigate the effect of tidal volume (Vt DI) on pulse pressure variation (ΔPP DI) during deep inspiration maneuvers in spontaneously breathing patients with sepsis and to test if adjusting ΔPP DI by Vt DI can further improve its ability in predicting fluid responsiveness (FR). Methods:Spontaneously breathing, nonintubated sepsis or septic shock patients who were admitted to the Intensive Care Unit of the Characteristic Medical Center of Chinese People's Armed Police Force and Nanjing Gaochun People's Hospital were prospectively enrolled from October 2017 to October 2019. Volume expansion (VE) was performed by infusing 500 mL saline over 20 min. Prior to VE, measurements including pulse pressure variation and tidal volume were obtained during quiet spontaneous breathing (ΔPP TB and Vt TB, respectively) and during the deep inspiration maneuver (ΔPP DI and Vt DI, respectively). Patients were classified as responders if stroke volume (SV) increased ≥ 15% after VE, otherwise non-responders. Multiple linear regression analysis was conducted to investigate the correlation of ΔPP DI with Vt DI and VE-induced percentage changes in SV (ΔSV). Receiver operating characteristic (ROC) curve analysis and the gray zone approach were used to assess the ability of each index to predict FR. Changes in gray zone limits according to the cost ratio (R = cost[false positive (FP)]/cost[false negative (FN)]) were also evaluated. Results:Of the included 31 patients, 17 were responders. There was no significant difference in ΔPP TB between fluid responders and non-responders ( P>0.05), whereas ΔPP DI was significantly higher in responders than in non-responders [(19.1±7.4)% vs (11.2±4.5)%; P=0.001]. The area under the ROC curve (AUC) of ΔPP DI predicted FR was 0.832, sensitivity of 76.47% and specificity of 71.43%, which was significantly higher than ΔPP TB (AUC=0.580, sensitivity of 47.06% and specificity of 71.43%; P<0.05). Multiple linear regression analysis showed that both Vt DI and ΔSV were independently associated with ΔPP DI ( P<0.01), the AUC of ΔPP DI adjusted by Vt DI was signigicantly higher than that of ΔPP DI alone ( P=0.03). Among the ΔPP TB, ΔPP DI and ΔPP DI/Vt DI, ΔPP DI/Vt DI had the narrowest gray zone (12.7-14.5) for the normal fluid policy (R=1), which only included 19% of the patients. When applying "restrictive" fluid management (R=2), the gray zone for ΔPP DI/Vt DI was 12.8-14.5 and included only 2 patients (6.5%). Conclusions:In spontaneously breathing, nonintubated patients with sepsis or septic shock, the ΔPP value obtained during the deep inspiration maneuver predicts FR with moderate accuracy. Given the close correlation between Vt DI and ΔPP DI, ΔPP DI adjusted by Vt DI performs better than ΔPP DI alone in predicting FR.
ABSTRACT
@#Accumulating studies have recently shown that long noncoding RNAs (lncRNAs) are involved in the initiation and progression of myocardial fibrosis,a common histological characteristic of heart conditions and prominent global health issues. LncRNAs are prominently served as regulatory molecules via interaction with DNA,RNA and proteins in transcriptional and post-transcriptional processes. They can change morphological structure and biochemical metabolism of cardiac cells and regulate homeostasis of the cardiac extracellular matrix. Therefore,lncRNAs show great potential as diagnostic and prognostic biomarkers and therapeutic targets for anti-fibrotic treatment.