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Systematic Understanding of the Mechanism of Baicalin against Ischemic Stroke through a Network Pharmacology Approach.

ABSTRACT: Ischemic stroke is accompanied by high mortality and morbidity rates. At present, there is no effective clinical treatment. Alternatively, traditional Chinese medicine has been widely used in China and Japan for the treatment of ischemic stroke. Baicalin is a flavonoid extracted from Scutellaria baicalensis that has been shown to be effective against ischemic stroke; however, its mechanism has not been fully elucidated. Based on network pharmacology, we explored the potential mechanism of baicalin on a system level. After obtaining baicalin structural information from the PubChem database, an approach combined with literature mining and PharmMapper prediction was used to uncover baicalin targets. Ischemic stroke-related targets were gathered with the help of DrugBank, Online Mendelian Inheritance in Man (OMIM), Genetic Association Database (GAD), and Therapeutic Target Database (TTD). Protein-protein interaction (PPI) networks were constructed through the Cytoscape plugin BisoGenet and analyzed by topological methods. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were carried out via the Database for Annotation, Visualization, and Integrated Discovery (DAVID) server. We obtained a total of 386 potential targets and 5 signaling pathways, including mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), hypoxia-inducible factor-1 (HIF-1), nuclear factor kappa B (NF-?B), and forkhead box (FOXO) signaling pathways. GO analysis showed that these targets were associated with antiapoptosis, antioxidative stress, anti-inflammation, and other physiopathological processes that are involved in anti-ischemic stroke effects. In summary, the mechanism of baicalin against ischemic stroke involved multiple targets and signaling pathways. Our study provides a network pharmacology framework for future research on traditional Chinese medicine.

SUBMITTER: Xu T

PROVIDER: S-EPMC6311886 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Systematic Understanding of the Mechanism of Baicalin against Ischemic Stroke through a Network Pharmacology Approach.

Xu Tian T Ma Chongyang C Fan Shuning S Deng Nan N Lian Yajun Y Tan Ling L Du Weizhe W Zhang Shuang S Liu Shuling S Ren Beida B Li Zhenhan Z Wang Qingguo Q Wang Xueqian X Cheng Fafeng F

Evidence-based complementary and alternative medicine : eCAM 20181217

Ischemic stroke is accompanied by high mortality and morbidity rates. At present, there is no effective clinical treatment. Alternatively, traditional Chinese medicine has been widely used in China and Japan for the treatment of ischemic stroke. Baicalin is a flavonoid extracted from Scutellaria baicalensis that has been shown to be effective against ischemic stroke; however, its mechanism has not been fully elucidated. Based on network pharmacology, we explored the potential mechanism of baical ...[more]

PMID: 30647760

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Project description:Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmissions are occurring rapidly; it is raising the alarm around the globe. Though vaccines are currently available, the evolution and mutations in the SARS-CoV-2 threaten available vaccines' significance. The drugs are still undergoing clinical trials, and certain medications are approved for "emergency use" or as an "off-label" drug during the pandemic. These drugs have been effective yet accommodating side effects, which also can be lethal. Complementary and alternative medicine is highly demanded since it embraces a holistic approach. Since ancient times, natural products have been used as drugs to treat various diseases in the medical field and are still widely practiced. Medicinal plants contain many active compounds that serve as the key to an effective drug design. The Kabasura kudineer and Nilavembu kudineer are the two most widely approved formulations to treat COVID-19. However, the mechanism of these formulations is not well known. The proposed study used a network pharmacology approach to understand the immune-boosting mechanism by the Kabasura kudineer, Nilavembu kudineer, and JACOM in treating COVID-19. The plants and phytochemical chemical compounds in the Kabasura kudineer, Nilavembu kudineer, and JACOM were obtained from the literature. The Swiss target prediction algorithm was used to predict the targets for these phytochemical compounds. The common genes for the COVID-19 infection and the drug targets were identified. The gene-gene interaction network was constructed to understand the interactions between these common genes and enrichment analyses to determine the biological process, molecular functions, cellular functions, pathways involved, etc. Finally, virtual screening and molecular docking studies were performed to identify the most potential targets and significant phytochemical compounds to treat the COVID-19. The present study identified potential targets as ACE, Cathepsin L, Cathepsin B, Cathepsin K, DPP4, EGFR, HDAC2, IL6, RIPK1, and VEGFA. Similarly, betulinic acid, 5″-(2⁗-Hydroxybenzyl) uvarinol, antofine, (S)-1'-methyloctyl caffeate, (Z)-3-phenyl-2-propenal, 7-oxo-10α-cucurbitadienol, and PLX-4720 collectively to be potential treatment agents for COVID-19.

Project description:Buyang Huanwu Decoction (BYHWD) is used to promote blood circulation and is widely used in Chinese clinical practice for the treatment and prevention of ischemic cerebral vascular diseases. However, the mechanism and active compounds of BYHWD used to treat ischemic stroke are not well understood. The current study aimed to identify the potential active components of BYHWD and explore its mechanism using network pharmacology and bioinformatics analyses. The compounds of BYHWD were obtained from public databases. Oral bioavailability and drug-likeness were screened using the absorption, distribution, metabolism and excretion (ADME) criteria. Components of BYHWD, alongside the candidate targets of each component and the known therapeutic targets of ischemic stroke were collected. A network of target gene compounds and cerebral ischemia compounds was established using network pharmacology data sources. The enrichment of key targets and pathways was analyzed using STRING and DAVID databases. Moreover, three of key targets [IL6, VEGFA and hypoxia-inducible-factor-1α (HIF-1α)] were verified using western blot analysis. Network analysis determined 102 compounds in seven herbal medicines that were subjected to ADME screening. A total of 42 compounds as well as 79 genes formed the principal pathways associated with ischemic stroke. The 16 key compounds identified were baicalein, beta-carotene, baicalin, kaempferol, luteolin, quercetin, hydroxysafflor yellow A, isorhamnetin, bifendate, formononetin, calycosin, astragaloside IV, stigmasterol, sitosterol, Z-ligustilide, and dihydrocapsaicin. The core genes in this network were IL6, TNF, VEGFA, HIF-1α, MAPK1, MAPK3, JUN, STAT3, IL1B and IL10. Furthermore, the TNF, IL17, apoptosis, PI3K-Akt, toll-like receptor, MAPK, NF-κB and HIF-1 signaling pathways were identified to be associated with ischemic stroke. Compared with the control group (no treatment), BYHWD significantly inhibited the expression of IL6 and increase the expression of HIF-1α and VEGFA. Network pharmacology analyses can help to reveal close interactions between multi-components and multi-targets and enhance understanding of the potential effects of BYHWD on ischemic stroke.

Project description:Stroke is the second leading cause of death after heart disease globally and cerebral ischemic stroke accounts for approximately 70% of all incident stroke cases. We selected four main compounds from a patent Chinese medicine, Qingkailing (QKL) injection, including baicalin from Scutellaria baicalensis Georgi (Huang Qin), geniposide from Gardenia jasminoides J. Ellis (Zhizi), and cholic acid and hyodeoxycholic acid from Bovis Calculus (Niuhuang) with a ratio of 4.4:0.4:3:2.6 m/m, to develop a more efficacious and safer modern Chinese medicine injection against ischemic stroke, refined QKL (RQKL). In this study, we investigated multiple targets, levels, and pathways of RQKL by using an integrative pharm\acology combining experimental validation approach. In silica study showed that RQKL may regulate PI3K-Akt, estrogen, neurotrophin, HIF-1, MAPK, Hippo, FoxO, TGF-beta, NOD-like receptor, apoptosis, NF-kappa B, Wnt, chemokine, TNF, Toll-like receptor signaling pathways against ischemic stroke. The experimental results showed that RQKL improved neurological function and prevented infract volume and blood-brain-barrier damage. RQKL inhibited microgliosis and astrogliosis, and protected neurons from ischemic/reperfusion injury. RQKL also inhibited cell apoptosis and affecting the ratio of the anti-apoptosis protein B-cell lymphoma-2 (Bcl2) and pro-apoptosis protein Bcl2-associated X protein (Bax). Western blot analysis showed that RQKL activated AKT/PI3K signaling pathway and antibody array showed RQKL inhibited inflammatory response and decreased proinflammatory factor Tnf, Il6, and Il1b, and chemokines Ccl2, Cxcl2, and Cxcl3, and increased anti-inflammatory cytokine Il10. In conclusion, RQKL protected tissue against ischemic stroke through multiple-target, multiple signals, and modulating multiple cell-types in brain. This study not only promoted our understanding of the role of RQKL against ischemic stroke, but also provided a pattern for the study of Chinese medicine combining pharmaceutical Informatics and system biology methods.

Project description:ObjectiveThe mechanism of action of Sanhua Decoction (SHD) in the treatment of ischemic stroke (IS) was analyzed based on the network pharmacology technology, and the pharmacodynamics and key targets were verified using the rat middle cerebral artery occlusion (MCAO) model.MethodsThe GEO database was used to collect IS-related gene set S D , and DrugBank and TTD databases were used to obtain the therapeutic drug target set S T . IS disease gene set S I was collected from DisGeNET, GeneCards, and OMIM databases. These three different gene sets obtained from various sources were merged, duplicates were removed, and the resulting IS disease gene set S IS was imported into the STRING database to establish the protein-protein interaction (PPI) network. Two methods were used to screen the key targets of IS disease based on the PPI network analysis. The TCMSP database and PubChem were applied to retrieve the main chemical components of SHD, and the ACD/Labs software and the SwissADME online system were utilized for ADMET screening. HitPick, SEA, and SwissTarget Prediction online systems were used to predict the set of potential targets for SHD to treat IS. The predicted set of potential targets and the IS disease gene set were intersected. Subsequently, the set of potential targets for SHD treatment of IS was identified, the target information was confirmed through the UniProt database, and finally, the component-target data set for SHD treatment of IS was obtained. clusterProfiler was used for GO function annotation and KEGG pathway enrichment analysis on the target set of SHD active ingredients. A rat MCAO model was established to evaluate the pharmacodynamics of SHD in the treatment of IS, and Western blot analysis assessed the level of proteins in the related pathways.ResultsThis study obtained 1,009 IS disease gene sets. PPI network analysis identified 12 key targets: AGT, SAA1, KNG1, APP, GNB3, C3, CXCR4, CXCL12, CXCL8, CXCL1, F2, and EDN1. Database analyses retrieved 40 active ingredients and 47 target genes in SHD. The network proximity algorithm was used to optimize the six key components in SHD. KEGG enrichment showed that the signaling pathways related to IS were endocrine resistance, estrogen, TNF signal pathway, and AGEs/RAGE. Compound-disease-target regulatory network analysis showed that AKT1, IL-6, TNF-α, TP53, VEGFA, and APP were related to the treatment of IS with SHD. Animal experiments demonstrated that SHD significantly reduces the neurological function of rat defect symptoms (P < 0.05), the area of cerebral avascular necrosis, and neuronal necrosis while increasing the levels of IL-6 and APP proteins (P < 0.05) and reducing the levels of AKT1 and VEGFA proteins (P < 0.05).ConclusionThe effective components of SHD may regulate multiple signaling pathways through IL-6, APP, AKT1, and VEGFA to reduce brain damage and inflammatory damage and exert a neuroprotective role in the treatment of IS diseases. Thus, this study provides a feasible method to study the pharmacological mechanism of traditional Chinese medicine compound prescriptions and a theoretical basis for the development of SHD into a new drug for IS treatment.

Dataset Information

Systematic Understanding of the Mechanism of Baicalin against Ischemic Stroke through a Network Pharmacology Approach.

Publications

Systematic Understanding of the Mechanism of Baicalin against Ischemic Stroke through a Network Pharmacology Approach.

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