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A Practical Strategy for Exploring the Pharmacological Mechanism of Luteolin Against COVID-19/Asthma Comorbidity: Findings of System Pharmacology and Bioinformatics Analysis.

ABSTRACT: Asthma patients may increase their susceptibility to SARS-CoV-2 infection and the poor prognosis of coronavirus disease 2019 (COVID-19). However, anti-COVID-19/asthma comorbidity approaches are restricted on condition. Existing evidence indicates that luteolin has antiviral, anti-inflammatory, and immune regulation capabilities. We aimed to evaluate the possibility of luteolin evolving into an ideal drug and explore the underlying molecular mechanisms of luteolin against COVID-19/asthma comorbidity. We used system pharmacology and bioinformatics analysis to assess the physicochemical properties and biological activities of luteolin and further analyze the binding activities, targets, biological functions, and mechanisms of luteolin against COVID-19/asthma comorbidity. We found that luteolin may exert ideal physicochemical properties and bioactivity, and molecular docking analysis confirmed that luteolin performed effective binding activities in COVID-19/asthma comorbidity. Furthermore, a protein-protein interaction network of 538 common targets between drug and disease was constructed and 264 hub targets were obtained. Then, the top 6 hub targets of luteolin against COVID-19/asthma comorbidity were identified, namely, TP53, AKT1, ALB, IL-6, TNF, and VEGFA. Furthermore, the enrichment analysis suggested that luteolin may exert effects on virus defense, regulation of inflammation, cell growth and cell replication, and immune responses, reducing oxidative stress and regulating blood circulation through the Toll-like receptor; MAPK, TNF, AGE/RAGE, EGFR, ErbB, HIF-1, and PI3K-AKT signaling pathways; PD-L1 expression; and PD-1 checkpoint pathway in cancer. The possible "dangerous liaison" between COVID-19 and asthma is still a potential threat to world health. This research is the first to explore whether luteolin could evolve into a drug candidate for COVID-19/asthma comorbidity. This study indicated that luteolin with superior drug likeness and bioactivity has great potential to be used for treating COVID-19/asthma comorbidity, but the predicted results still need to be rigorously verified by experiments.

SUBMITTER: Xie YZ

PROVIDER: S-EPMC8777084 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundsAsthma and idiopathic pulmonary fibrosis (IPF) are common chronic diseases of the respiratory system in clinical practice. However, the relationship and molecular links remain unclear, and the current treatment's efficacy is disappointing. Bu-Shen-Yi-Qi (BSYQ) decoction has proven effective in treating various chronic airway inflammatory diseases, including asthma and IPF. But the underlying pharmacological mechanisms are still to be elucidated.MethodsThis study searched the proteins related to asthma and IPF via TTD, CTD, and DisGeNET databases and then submitted to the STRING to establish the protein-protein interaction (PPI) network. The co-bioinformatics analysis was conducted by Metascape. The active ingredients of BSYQ decoction were screened from TCMSP, ETCM, BATMAN-TCM databases, and HPLC/MS experiment. The corresponding targets were predicted based on TCMSP, ETCM, and BATMAN-TCM databases. The shared targets for asthma and IPF treatment were recognized, and further GO and KEGG analyses were conducted with the DAVID platform. Finally, molecule docking via Autodock Vina was employed to predict the potential binding mode between core potential compounds and targets.ResultsFinally, 1333 asthma-related targets and 404 IPF-related proteins were retrieved, 120 were overlapped between them, and many of the asthma-related proteins fall into the same statistically significant GO terms with IPF. Moreover, 116 active ingredients of BSYQ decoction were acquired, and 1535 corresponding targets were retrieved. Eighty-three potential compounds and 56 potential targets were recognized for both asthma and IPF treatment. GO and KEGG analysis indicated that the inflammation response, cytokine production, leukocyte differentiation, oxygen level response, etc., were the common pathological processes in asthma and IPF, which were regulated by BSYQ decoction. Molecule docking further predicted the potential binding modes between the core potential compounds and targets.ConclusionThe current study successfully clarified the complex molecule links between asthma and IPF and found the potential common targets. Then we demonstrated the efficacy of BSYQ decoction for asthma and IPF treatment from the angle of network pharmacology, which may provide valuable references for further studies and clinical use.

Project description:Luteolin, a natural flavone compound, exists in a variety of fruits and vegetables, and its anticancer effect has been shown in many studies. However, its use in glioma treatment is hampered due to the fact that the underlying mechanism of action has not been fully explored. Therefore, we elucidated the potential antiglioma targets and pathways of luteolin systematically with the help of network pharmacology and molecular docking technology. The druggability of luteolin, including absorption, excretion, distribution, and metabolism, was assessed via the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The potential targets of luteolin and glioma were extracted from public databases, and the intersecting targets between luteolin and glioma were integrated and visualized by a Venn diagram. In addition, GO and KEGG pathway analysis was engaged in Metascape. The network of the luteolin-target-pathway was visualized by Cytoscape. Ultimately, the interactions between luteolin and predicted key targets were confirmed by Discovery studio software. According to the ADME results, luteolin shows great potential for development into a drug. 4860 glioma-associated targets and 280 targets of luteolin were identified, of which 205 were intersection targets. 6 core targets of luteolin against glioma, including AKT1, JUN, ALB, MAPK3, MAPK1, and TNF, were identified via PPI network analysis of which AKT1, JUN, ALB, MAPK1, and TNF harbor diagnostic value. The biological processes of luteolin are mainly involved in the response to inorganic substances, response to oxidative stress, and apoptotic signaling pathway. The essential pathways of luteolin against glioma involve pathways in cancer, the PI3K-Akt signaling pathway, the TNF signaling pathway, and more. Meanwhile, luteolin's interaction with six core targets was verified by molecular docking simulation and its antiglioma effect was verified by in vitro experiments. This study suggests that luteolin has a promising potential for development into a drug and, moreover, it displays preventive effects against glioma by targeting various genes and pathways.

Project description:BackgroundAsthma is a common chronic respiratory disease worldwide. Recent studies have revealed the critical effects of the ceRNA network and ferroptosis on patients with asthma. Thus, this study aimed to explore the potential ferroptosis-related ceRNA network, investigate the immune cell infiltration level in asthma through integrated analysis of public asthma microarray datasets, and find suitable diagnostic biomarkers for asthma.MethodsFirst, three asthma-related datasets which were downloaded from the Gene Expression Omnibus (GEO) database were integrated into one pooled dataset after correcting for batch effects. Next, we screened differentially expressed lncRNAs (DElncRNAs) between patients and healthy subjects, constructed a ceRNA network using the StarBase database and screened ferroptosis-related genes from the predicted target mRNAs for Disease Ontology (DO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. We also performed Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) on the batch effect-corrected mRNA expression profile. Then, Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to screen potential diagnostic biomarkers, and the diagnostic efficacy was assessed using a receiver operating characteristic (ROC) curve. Finally, we determined the proportion of 22 immune cells in patients with asthma using CIBERSORT and investigated the correlation between key RNAs and immune cells.ResultsWe obtained 19 DElncRNAs, of which only LUCAT1 and MIR222HG had corresponding target miRNAs. The differentially expressed ferroptosis-related genes were involved in multiple programmed cell death-related pathways. We also found that the mRNA expression profile was primarily enriched in innate immune system responses. We screened seven candidate diagnostic biomarkers for asthma using LASSO regression (namely, BCL10, CD300E, IER2, MMP13, OAF, TBC1D3, and TMEM151A), among which the area under the curve (AUC) value for CD300E and IER2 were 0.722 and 0.856, respectively. Finally, we revealed the infiltration ratio of different immune cells in asthma and found a correlation between LUCAT1, MIR222HG, CD300E, and IER2 with some immune cells.ConclusionThis study explored a potential lncRNA-miRNA-mRNA regulatory network and its underlying diagnostic biomarkers (CD300E and IER2) in asthma and identified the immune cells most associated with them, providing possible diagnostic markers and immunotherapeutic targets for asthma.

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A Practical Strategy for Exploring the Pharmacological Mechanism of Luteolin Against COVID-19/Asthma Comorbidity: Findings of System Pharmacology and Bioinformatics Analysis.

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