The present study aimed to explore the targets and mechanism of Mailuo Shutong Pills(MSP) in the treatment of ischemic stroke by network pharmacology, and verify the key targets through molecular docking and animal experiment, so as to provide a theoretical basis for the clinical application of MSP. The main chemical ingredients of MSP were obtained by searching against the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) and relevant literature. The potential targets of the ingredients of MSP in treating ischemic stroke were obtained from SwissTargetPrediction and DisGeNET. Protein-protein interaction(PPI) network was analyzed in STRING and plotted in Cytoscape. Gene Ontology(GO) annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis were carried out with DAVID. Molecular docking was simulated to determine the binding activity of active ingredients to key targets in AutoDock Vina. The mouse model of ischemic stroke was established. The mice were classified into a sham group, a model group, and an MSP group. After the administration, cerebral infarction volume was detected by 2,3,5-triphenyltetrazoliumchloride(TTC) staining, and Western blot was performed to determine the levels of phosphatidylinositol 3-kinase(PI3 K), protein kinase B(AKT), nuclear factor-κB(NF-κB) and their phosphorylated proteins. A total of 222 ingredients of MSP were screened out, including beta-sitosterol, quercetin, licochalcone B, and lupiwighteone, which acted on 701 targets. Totally 1 079 targets associated with ischemic stroke were retrieved, among which 192 common targets were shared by MSP and ischemic stroke. The key targets included AKT1, phosphatidylinositol 3-kinase catalytic subunit alpha(PIK3 CA), phosphatidylinositol 3-kinase regulatory subunit 1(PIK3 R1), and nuclear factor-κB p65 subunit(RELA), which were mainly involved in PI3 K/AKT, tumor necrosis factor(TNF), and NF-κB signaling pathways. The results of molecular docking revealed that PI3 K, AKT1, and RELA had good binding ability to the active ingredients of MSP. The animal experiment results showed that compared with the model group, MSP decreased cerebral infarction volume, down-regulated the expression of p-NF-κB, and up-regulated the expression of p-PI3 K and p-AKT in mouse brain. In summary, the active ingredients in MSP may treat cerebral injury by activating PI3 K/AKT signaling pathway and inhibiting NF-κB signaling pathway.

2021-11-01·International Immunopharmacology2区 · 医学

Licochalcone B attenuates neuronal injury through anti-oxidant effect and enhancement of Nrf2 pathway in MCAO rat model of stroke

2区 · 医学

Article

作者: Wang, Honglin ; Zhang, Lianlian ; Zhou, Baosheng ; Zhang, Bo

BACKGROUNDInvestigating anti-oxidant therapies that lead to the diminution of oxidative injury is priority in clinical. We herein aimed to explore whether and how Licochalcone B (Lico B) act as an anti-oxidant in the stroke model.METHODSMiddle cerebral artery occlusion (MCAO) was constructed as stroke model and exposed to various doses of Lico B. Behavioral tests and neurological behavior status were detected for neurological function examination. Histological staining was used for evaluating cerebral injury, and neuronal apoptosis or damage. Levels of oxidative stress and inflammation were also assessed by biochemical analysis and expression analysis. Nrf2 knockdown induced by lentiviral vector was used for the research on mechanism.RESULTSLico B had improvement effects on cerebral infarction size, memory impairments, and neurological deficits after MCAO. Histological evaluation also revealed the amelioration of neuronal injury and apoptosis by Lico B, along with down-regulation of apoptosis-related proteins. Additionally, Lico B rescued the down-regulation of BDNF and NGF after MCAO. Moreover, Lico B suppressed the oxidative stress and inflammation, manifesting as the enhancement of SOD, GSH and IL-4, but the decline of MDA, iNOS, and TNF-α. Finally, Nrf2 knockdown reversed the Lico B-caused improvement in neuronal injury, apoptosis and oxidative stress levels.CONCLUSIONSThe present study revealed the neuroprotective effects of Lico B in MCAO rats. Importantly, we proposed a potential mechanism that Lico B activated the Nrf2 pathway, thereby acting as anti-oxidant to attenuate neuronal injury and apoptosis after stroke. The proposed mechanism provided an encouraging possibility for anti-oxidant therapy of stroke.

Chinese Medicine

Protective effect of Huashi Baidu formula against AKI and active ingredients that target SphK1 and PAI-1

Article

作者: Xu, Haiyu ; Zhong, Yute ; Wang, Ping ; Wu, Dan ; Huang, Luqi ; Xia, Cong ; Du, Xia ; Jiang, Hong ; Li, Weijie

AbstractBackgroundHuashi Baidu Formula (HBF) is a clinical formula known for its efficacy against coronavirus disease 2019 (COVID-19). HBF may reduce the number of patients with abnormal serum creatinine while improving respiratory symptoms, suggesting that this formula may have potential for treating acute kidney injury (AKI). However, the protective effect of HBF on AKI has not been definitively confirmed, and the mechanism remains unclear. Therefore, the present study explored the renoprotective effects and molecular mechanisms of HBF and screened for its active ingredients to identify new potential applications of renoprotection by HBF.MethodsThe present study first assessed the protective effects of HBF on AKI in a DOX-induced mouse model. Then, RNA-seq and bioinformatics analyses were used to explore the related pathological processes and potential molecular mechanisms, which were subsequently validated using qRT-PCR and Western blotting. Furthermore, candidate compounds with potential binding affinity to two pivotal targets, sphingosine kinase 1 (SphK1) and plasminogen activator inhibitor-1 (PAI-1), were screened from the 29 constituents present in the blood using Microscale Thermophoresis (MST). Finally, to identify the active ingredients, the candidate components were re-screened using the SphK1 kinase activity detection system or the uPA/PAI-1 substrate colorimetric assay system.ResultsIn the DOX-induced AKI mouse model, therapeutic administration of HBF significantly reduced the levels of CRE, BUN, TNF-α, IL-1β, IL-6, and UA in plasma and the levels of MDA, T-CHO, and TG in kidney tissue. Additionally, the levels of TP and Alb in plasma and SOD and CAT in the kidney tissue were significantly increased. Histopathological assessment revealed that HBF reduced tubular vacuolation, renal interstitial inflammatory cell infiltration, tubular atrophy, and positive staining of renal interstitial collagen. RNA-seq and bioinformatics analyses showed that oxidative stress, the immune-inflammatory response, and extracellular matrix (ECM) formation could be the pathological processes that HBF targets to exerts its renoprotective effects. Furthermore, HBF regulated the APJ/SPHK1/NF-κB and APJ/PAI-1/TGFβ signaling axes and reduced the phosphorylation levels of NF-κB p65 and SMAD2 and the expression of cytokines and the ECM downstream of the axis. Finally, six SphK1 inhibitors (paeoniflorin, astragalin, emodin, glycyrrhisoflavone, quercetin, and liquiritigenin) and three PAI-1 inhibitors (glycyrrhisoflavone, licochalcone B, and isoliquiritigenin) were identified as potentially active ingredients in HBF.ConclusionIn brief, our investigation underscores the renoprotective effect of HBF in a DOX-induced AKI model mice, elucidating its mechanisms through distinct pathological processes and identifying key bioactive compounds. These findings offer new insights for broadening the clinical applications of HBF and unravelling its molecular mode of action.

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