Connectivity map identifies luteolin as a treatment option of ischemic stroke by inhibiting MMP9 and activation of the PI3K/Akt signaling pathway

Abstract

This study aimed to explore potential new drugs in the treatment of ischemic stroke by Connectivity Map (CMap) and to determine the role of luteolin on ischemic stroke according to its effects on matrix metalloproteinase-9 (MMP9) and PI3K/Akt signaling pathway. Based on published gene expression data, differentially expressed genes were obtained by microarray analysis. Potential compounds for ischemic stroke therapy were obtained by CMap analysis. Cytoscape and gene set enrichment analysis (GSEA) were used to discover signaling pathways connected to ischemic stroke. Cell apoptosis and viability were, respectively, evaluated by flow cytometry and an MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis were used to test the expression of MMP9 and the PI3K/Akt signaling pathway-related proteins in human brain microvascular endothelial cells (HBMECs) and tissues. Additionally, the infarct volume after middle cerebral artery occlusion (MCAO) was determined by a TTC (2,3,5-triphenyltetrazolium chloride) assay. The microarray and CMap analyses identified luteolin as a promising compound for future therapies for ischemic stroke. Cytoscape and GSEA showed that the PI3K/Akt signaling pathway was crucial in ischemic stroke. Cell experiments revealed that luteolin enhanced cell viability and downregulated apoptosis via inhibiting MMP9 and activating the PI3K/Akt signaling pathway. Experiments performed in vivo also demonstrated that luteolin reduced the infarct volume. These results suggest that luteolin has potential in the treatment of ischemic stroke through inhibiting MMP9 and activating PI3K/Akt signaling pathway.

Luteolin Exerts Neuroprotection via Modulation of the p62/Keap1/Nrf2 Pathway in Intracerebral Hemorrhage

“…Numerous studies have revealed anti-inflammatory, antioxidative, anti-apoptotic, autophagic-regulatory, anti-viral, anticancer, and metabolic effects of luteolin, which have been confirmed in many different disease models (Hu et al, 2016;Zhang et al, 2016;Peng et al, 2017;Du et al, 2018;Liu et al, 2018;Tan et al, 2018b;Yang et al, 2018b;Kang et al, 2019). In addition, in studies on ischemic stroke (Qiao et al, 2012;Tan et al, 2018a;Luo et al, 2019), traumatic brain injury (Xu et al, 2014), neurodegenerative diseases (Kwon, 2017;Zhang et al, 2017), and other neurological diseases, luteolin has been shown to exert therapeutic effects.…”

“…As a member of the flavonoid family, luteolin has been shown to exhibit multiple pharmacological effects, such as antioxidative, anti-inflammatory, autophagic-regulatory, apoptotic, and antitumor effects in many disease models (Xiong et al, 2017;Luo et al, 2019;Ma et al, 2019;Yu et al, 2019). Several studies have shown that luteolin exerts neuroprotective effects both in vitro and in vivo (Xu et al, 2014;Caltagirone et al, 2016;Kwon, 2017;Luo et al, 2019). However, the effects of luteolin on ICH remain poorly understood.…”

Network pharmacology and molecular docking analysis on molecular targets and mechanisms of Buyang Huanwu Decoction in the treatment of Ischemic Stroke

“…[54] Experiments performed in vivo also demonstrated that luteolin reduced the infarct volume. It was suggested that luteolin had potential in the treatment of IS through inhibiting MMP9 and activating PI3K/Akt signaling pathway [55]. Beta-sitosterol and stigmasterol are the common components of Carthami Flos, Persicae Semen, Radix paeoniae Rubra, and Angelicae Sinensis Radix.…”

Molecular mechanism of luteolin against inflammation based on integration of network pharmacology, transcriptomics and proteomics

“…The main function of MMP9 is to degrade and reshape the homeostasis of the extracellular matrix, and plays a critical role in in ammatory response, tissue con guration, regulating matrix-bound growth factor and cytokine expression and cancer 30 . Moreover, research shows that luteolin decrease MMP9 expression to treat ischemic stroke, colon cancer and diabetes 31,32 . MAPK pathway is the intersection of signal pathways such as cell proliferation, in ammation, differentiation, functional synchronization, transformation and apoptosis, and MAPK pathway participates in cell proliferation, differentiation, canceration, metastasis, apoptosis and so on 33 .…”