Prediction of the Mechanism of Sodium Butyrate against Radiation-Induced Lung Injury in Non-Small Cell Lung Cancer Based on Network Pharmacology and Molecular Dynamic Simulations

Abstract

BackgroundRadiation-induced lung injury (RILI) is a severe side effect of radiotherapy for non-small cell lung cancer (NSCLC) ,and one of the major hindrances to improve the efficacy of radiotherapy. Previous studies have confirmed that sodium butyrate (NaB) has potential of anti-radiation toxicity. However, the mechanism of the protective effect of NaB against RILI has not yet been clarified. This study aimed to explore the underlying protective mechanisms of NaB against RILI in NSCLC through network pharmacology, molecular docking, molecular dynamic simulations and in vivo experiments.MethodsThe predictive target genes of NaB were obtained from the PharmMapper database and the literature review. The involved genes of RILI and NSCLC were predicted using OMIM and GeneCards database. The intersectional genes of drug and disease were identified using the Venny tool and uploaded to the Cytoscape software to identify 5 core target genes of NaB associated with RILI. The correlations between the 5 core target genes and EGFR, PD-L1, immune infiltrates, chemokines and chemokine receptors were analyzed using TIMER 2.0, TIMER and TISIDB databases. We constructed the mechanism maps of the 3 key signaling pathways using the KEGG database based on the results of GO and KEGG analyses from Metascape database. The 5 core target genes and drug were docked using the AutoDock Vina tool and visualized using PyMOL software. GROMACS software was used to perform 100 ns molecular dynamics simulation. Irradiation-induced lung injury model in mice were established to assess the therapeutic effects of NaB.ResultsA total of 51 intersectional genes involved in NaB against RILI in NSCLC were identified. The 5 core target genes were AKT1, TP53, NOTCH1, SIRT1, and PTEN. The expressions of the 5 core target genes were significantly associated with EGFR, PD-L1, immune infiltrates, chemokines and chemokine receptors, respectively. The results from GO analysis of the 51 intersectional genes revealed that the biological processes were focused on the regulation of smooth muscle cell proliferation, oxidative stress and cell death, while the three key KEGG pathways were enriched in PI3K-Akt signal pathway, p53 signal pathway, and FOXO signal pathway. The docking of NaB with the 5 core target genes showed affinity and stability, especially AKT1. In vivo experiments showed that NaB treatment significantly protected mice from RILI, with reduced lung histological damage. In addition, NaB treatment significantly inhibited the PI3K/Akt signaling pathway.ConclusionsNaB may protect patients from RILI in NSCLC through multiple target genes including AKT1, TP53, NOTCH1, SIRT1 and PTEN, with multiple signaling pathways involving, including PI3K-Akt pathway, p53 pathway, and FOXO pathways. Our findings effectively provide a feasible theoretical basis to further elucidate the mechanism of NaB in the treatment of RILI.

Anticancer Effects of Gut Microbiota-Derived Short-Chain Fatty Acids in Cancers

“…Additionally, the expression of thioredoxin-interacting protein (TXNIP) was significantly increased by NaB treatment to induce apoptosis and caspase 3/7 activity in the A549 cell line [ 51 ]. In conjunction with radiation therapy, NaB treatment of LC induced antiradiation toxicity and changed the expression of 5 core targets (AKT serine/threonine kinase 1 (AKT1), tumor protein P53 (TP53), Sirtuin 1 (SIRT1), Notch receptor 1 (NOTCH), and phosphatase and tensin homolog (PTEN)), protecting cells against radiation-induced lung injury [ 52 ]. In immune response, the mice fed VSL#3 probiotics exhibited increased concentrations of propionate and butyrate in the blood and gut.…”

Sodium butyrate supresses malignant human mast cell proliferation, downregulates expression of KIT and promotes differentiation

“…Some very recent studies show that butyrate can also regulate miroRNA (miRNA) expression, and miRNA target genes that ultimately cause enhanced apoptosis, decreased proliferation, and promote cell-cycle arrest of colorectal cancer cells (14). For this reason, NaBu has been suggested as a combinational therapy to treat colon and other cancers (15)(16)(17)(18).…”