The mechanism of polyphyllin in the treatment of gastric cancer was verified based on network pharmacology and experimental validation.

Background: Polyphyllin is a class of saponins extracted from Paris polyphylla rhizomes and has been used in clinical application in China for more than 2000 years. However, the mechanism for treating gastric cancer (GC) is still unclear. This study was designed to predict the targets and mechanisms of total Polyphyllin from Paris polyphylla rhizomes for the treatment of GC. Method: Firstly, PubChem and Swiss Target Prediction databases were utilized to collect the 12 ingredients of total Polyphyllin from Paris polyphylla rhizomes and their targets. GC-related genes were obtained from the GEO database. Then the intersecting targets to all these molecules that identified using Venny. Secondly, the intersecting targets were imported into STRING platform for protein-protein interaction (PPI) network. Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted in DAVID website. In addition, the GEPIA was applied to perform the expression levels, transcript levels, staging, and overall survival of hub genes. In addition, we used AutoDock Vina to evaluate binding affinity of molecular docking between key ingredients and anti-GC targets. In vitro cell experiments, we detected the cell viability of gastric cancer cells at 24, 36, and 48 h using CCK-8 assay. The G0/G1 of cell cycle and apoptosis were detected by flow cytometry. Finally, quantitative real time polymerase chain reaction (qRT-PCR) was used to detect the level of hub genes, and Western blot was used to detect the changes of PI3K/Akt signal pathway. Results: Firstly, we identified 12 ingredients and 286 targets of total Polyphyllin. A total of 2653 GC-related differentially expressed genes (DEGs) were collected, including 1366 up-regulated genes and 1287 down-regulated genes. Moreover, 45 targets were obtained after intersection. Secondly, results of the GO enrichment suggested that these genes were closely related to cell proliferation, migration and aging. KEGG analysis suggested that Polyphyllin in GC therapy were mostly regulated by multiple pathways, including the pathways in cancer, calcium signaling pathway, Rap1 signaling pathway, phospholipase D signaling pathway, etc. In addition, GEPIA results exhibited that PDGFRB, KIT, FGF1, GLI1, F2R, and HIF1A were associated with GC progression, stage, and survival. Besides, the molecular docking results further confirmed that the binding energy of Polyphyllin Ⅲ with HIF1A was minimal. In vitro cell experiments, Polyphyllin Ⅲ inhibited the cell viability of gastric cancer cells, blocked the cell cycle G0/G1 phase, and induced cell apoptosis. In addition, Polyphyllin Ⅲ down-regulated the mRNA levels of PDGFRB, KIT, FGF1, GLI1, F2R, and HIF1A, and regulated the PI3K/Akt signal pathway. Conclusions: The results revealed that total Polyphyllin treated GC through multiple targets, multiple channels, and multiple pathways. In addition, Polyphyllin Ⅲ played an anti-gastric cancer role by inhibiting the proliferation of gastric cancer.

To explore the mechanism of Yigong San anti-gastric cancer and immune regulation.

BACKGROUND: Yigong San (YGS) is a representative prescription for the treatment of digestive disorders, which has been used in clinic for more than 1000 years. However, the mechanism of its anti-gastric cancer and regulate immunity are still remains unclear. AIM: To explore the mechanism of YGS anti-gastric cancer and immune regulation. METHODS: Firstly, collect the active ingredients and targets of YGS, and the differentially expressed genes of gastric cancer. Secondly, constructed a protein-protein interaction network between the targets of drugs and diseases, and screened hub genes. Then the clinical relevance, mutation and repair, tumor microenvironment and drug sensitivity of the hub gene were analyzed. Finally, molecular docking was used to verify the binding ability of YGS active ingredient and hub genes. RESULTS: Firstly, obtained 55 common targets of gastric cancer and YGS. The Kyoto Encyclopedia of Genes and Genomes screened the microtubule-associated protein kinase signaling axis as the key pathway and IL6, EGFR, MMP2, MMP9 and TGFB1 as the hub genes. The 5 hub genes were involved in gastric carcinogenesis, staging, typing and prognosis, and their mutations promote gastric cancer progression. Finally, molecular docking results confirmed that the components of YGS can effectively bind to therapeutic targets. CONCLUSION: YGS has the effect of anti-gastric cancer and immune regulation.

Review and prospects of targeted therapies for Spleen tyrosine kinase (SYK).

Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase. The dysregulation of SYK is closely related to the occurrence and development of allergic diseases, autoimmune diseases and cancer. SYK has become an attractive target for drug discovery due to its important biological functions. This article reviews the biological function of SYK, the relationship between SYK and disease, and therapies targeting SYK. In addition, inspired by new technologies such as proteolysis targeting chimeras (PROTACs) and phosphatase recruiting chimeras (PHORCs), we propose the development of new therapeutic approaches for targeting SYK, such as SYK PROTACs and SYK PHORCs, which may overcome deficiencies of existing methods.

Morbidity After Symptomatic Hemorrhage of Cerebral Cavernous Malformation: A Nomogram Approach to Risk Assessment.

BACKGROUND AND PURPOSE: Symptomatic hemorrhage contributes to an increased risk of repeated bleeding and morbidity in cerebral cavernous malformation (CCM). A better understanding of morbidity after CCM hemorrhage would be helpful to identify patients of higher risk for unfavorable outcome and tailor individualized management. METHODS: We identified 282 consecutive patients who referred to our institute from 2014 to 2018 for CCM with symptomatic hemorrhage and had an untreated follow-up period over 6 months after the first hemorrhage. The morbidity after hemorrhage was described in CCM of different features. Nomogram to predict morbidity was formulated based on the multivariable model of risk factors. The predictive accuracy and discriminative ability of nomogram were determined with concordance index (C-index) and calibration curve, and further validated in an independent CCM cohort of a prospective multicenter study from 2019 to 2020. RESULTS: The overall morbidity of CCM was 26.2% after a mean follow-up of 1.9 years (range 0.5-3.5 years) since the first hemorrhage. The morbidity during untreated follow-up was associated with hemorrhage ictus (adjusted odds ratio per ictus increase, 4.17 [95% CI, 1.86-9.33]), modified Rankin Scale score at initial hemorrhage (adjusted odds ratio per point increase, 2.57 [95% CI, 1.82-3.63]), brainstem location (adjusted odds ratio, 2.93 [95% CI, 1.28-6.68]), and associated developmental venous anomaly (adjusted odds ratio, 2.21 [95% CI, 1.01-4.83]). Subgroup analysis revealed similar findings in brainstem and non-brainstem CCM. Nomogram was contracted based on these features. The calibration curve showed good agreement between nomogram prediction and actual observation. The C-index of nomogram predicting morbidity was 0.83 (95% CI, 0.77-0.88). In validation cohort, the nomogram maintained the discriminative ability (C-index, 0.87 [95% CI, 0.78-0.96]). CONCLUSIONS: Multiple symptomatic hemorrhages, initial neurological function after hemorrhage, brainstem location, and associated developmental venous anomaly were associated with morbidity of CCM hemorrhage. The nomogram represented a practical approach to provide individualized risk assessment for CCM patients. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT04076449.

Effects of PPAR-γ in the Myocardium on the Development of Ventricular Septation.

Ventricular septum defects (VSDs) are common types of congenital heart diseases caused by developmental defect; they contribute to 25%-30% of all adult congenital heart diseases. The peroxisome proliferator-activated receptor gamma (PPAR-γ) is widely expressed in mammalian tissues and in the immune system, regulating cell differentiation and immune and inflammatory responses. The PPAR-γ gene has recently been found crucial for heart development, but the mechanism of action is not clear. This study aims to investigate the effects of the PPAR-γ gene in the myocardium on the development of ventricular septation. In this study, we applied Cre-loxP recombination enzyme (CRE) technology to downregulate the expression of the PPAR-γ gene in different cardiac tissues, RT-PCR to examine the expression of the c-fos and TGF-ß1 genes, and histology staining to check the defect of embryonic heart at embryonic day 14.5 (E14.5). We found that the downregulation of the PPAR-γ gene resulted in a ventricular membranous septation defect of the embryonic heart at E14.5. Furthermore, only conversion of a Tnt:Cre, but not Mef2c:Cre, Tie2:Cre, or Wnt:Cre PPAR-γ floxed allele to a null allele resulted in VSD. PPAR-γTnt-Cre/+ embryos showed increases in atrioventricular (AV)-cushion cells and the expression of c-fos gene but no change in the expression of TGF-ß1 at E10.5. Our study demonstrates PPAR-γ in the myocardium is required for ventricular septation through regulation of AV-cushion cell proliferation by a Tnt/c-fos signal.