Chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway

Ketamine, a rapid-acting antidepressant drug, has been used to treat major depressive disorder and bipolar disorder(BD). Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in patients. Ketamine has also been applied to establish animal models of mania. At present, however, the underlying mechanism is still unclear. In the current study, we found that chronic lithium exposure attenuated ketamine-induced mania-like behavior and c-Fos expression in the medial prefrontal cortex(mPFC) of adult male mice. Transcriptome sequencing was performed to determine the effect of lithium administration on the transcriptome of the PFC in ketamine-treated mice, showing inactivation of the phosphoinositide 3-kinase(PI3K)-protein kinase B(AKT) signaling pathway. Pharmacological inhibition of AKT signaling by MK2206(40 mg/kg), a selective AKT inhibitor, reversed ketamine-induced mania.Furthermore, selective knockdown of AKT via AAVAKT-sh RNA-EGFP in the mPFC also reversed ketamine-induced mania-like behavior. Importantly,pharmacological activation of AKT signaling by SC79(40 mg/kg), an AKT activator, contributed to mania in low-dose ketamine-treated mice. Inhibition of PI3K signaling by LY294002(25 mg/kg), a specific PI3K inhibitor, reversed the mania-like behavior in ketamine-treated mice. However, pharmacological inhibition of mammalian target of rapamycin(mTOR)signaling with rapamycin(10 mg/kg), a specific mTOR inhibitor, had no effect on ketamine-induced mania-like behavior. These results suggest that chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway, which may be a novel target for the development of BD treatment.

Targeted suppression of miRNA-21 inhibit K562 cells growth through PTEN-PI3K/AKT signaling pathway

Objective To investigate the K562 cells biological function and related molecular changes in PTEN-PI3K/AKT signaling pathway of leukemia K562 cells by inhibiting the miRNA-21 expression to explore its pathogenesis of leukemia.Methods The chemical synthetic miRNA-

Regulatory effects of antitumor agent matrine on FOXO and PI3K-AKT pathway in castration-resistant prostate cancer cells

We previously demonstrated that matrine could inhibit the proliferating, migrating, as well as invading processes of both PC-3 and DU145 cells. However, the underlying molecular mechanisms have not yet been clearly defined. In this study, using various techniques such as high throughput sequencing technology, bioinformatics, quantitative real-time PCR, and immunoblot analysis,we aimed to understand whether matrine serves as a novel regulator of FOXO and PI3K-AKT signaling pathway. DU145 and PC-3 cell lines were cultured for 24 h in vitro. Cells were treated with either matrine or control serum for 48 h, followed by extraction of total RNA. The RNA was sequenced using HiSeq 2500 high-throughput sequencing platform (Illumina). A gene library was established and quality analysis of read data carried out. Integrated database from the website DAVID was used to analyze Gene Ontology (GO), and Kyoto encyclopedia of genes and genomes (KEGG) pathway of differential genes was used for pathway analysis, screening for fold differences of more than two times. The FOXO and PI3K-AKT signaling pathways were screened, and expression levels of mRNA and core protein detected by real-time PCR and immunoblotting, respectively. High throughput sequencing and GO analysis revealed that differentially expressed genes before and after treatment played an important role in cell metabolic process, growth process, anatomical structure formation, cellular component organization, and biological regulation. KEGG signal pathway analysis revealed that FOXO and PI3K-AKT signal pathways had a significant difference between before and after matrine-treated androgen-independent prostate cancer cells PC-3 and DU145. Real-time PCR showed that matrine treatment led to a significant increase in the expression levels of FOXO1A, FOXO3A, FOXO4, and FOXO6 in DU145 and PC-3 cells (P<0.01 or P<0.05), whereas the PI3K expression levels decreased (P<0.01). Similarly, immunoblotting revealed a significant increase (P<0.05) in the expression levels of FOXO1A FOXO3A, FOXO4, and FOXO6 in both PC-3 and DU145 cells, whereas PI3K expression levels decreased (P<0.05). Matrine had a broad regulating effect on the mRNA expression profiles of both PC-3 and DU145 cells. Matrine may inhibit cell proliferation, migration, as well as invasion, and induce apoptosis in both PC-3 and DU145 cells through FOXO and PI3K-AKT signaling pathways. Matrine could therefore be used as a complementary drug to present chemotherapeutic agents, for treating androgen-independent prostate cancer.

Network pharmacology and molecular docking analysis reveal insights into the molecular mechanism of Gualou Qumai Wan in clear cell renal cell carcinoma

Background:To initially clarify the potential therapeutic targets and pharmacological mechanism regarding Gualou Qumai Wan(GQW),a kind of traditional Chinese medicine(TCM),in clear cell renal cell carcinoma(ccRCC)by virtue of the network pharmacology analysis and molecular docking analysis.Methods:The screening of bioactive components and targets of GQW was based on the Traditional Chinese Medicine System Pharmacology(TCMSP)and the UniProt platform served for standardizing their targets.Online Mendelian Inheritance in Man(OMIM),PharmGkb,TTD,DrugBank and GeneCards databases were searched to collect the disease targets of ccRCC.Cytoscape assisted in constructing herb-compound-target(H-C-T)networks.The STRING database was searched for constructing the target protein-protein interaction(PPI)networks,while the R programming language served for analyzing GO functional terms and the KEGG pathways related to potential targets.Analyses of core genes related to survival and tumor microenvironment(TME)were conducted respectively based on the GEPIA2 database and TIMER 2.0 database.Human Protein Atlas(HPA)and The Cancer Genome Atlas(TCGA)helped to obtain core genes’protein expression as well as transcriptome expression level.Autodock Vina software validated the molecular docking regarding GQW components and pivotal targets.Results:The constructed H-C-T networks mainly had 33 compounds and 65 targets.A topological analysis of the PPI network identified that ESR1,AKT1,HIF1A,PTGS2,TP53 and VEGFA serve as core targets in the way GQW affects ccRCC.According to the GO and KEGG pathway enrichment analyses,the effects of GQW are mediated by genes related to hypoxia and oxidative stress as well as the Chemical carcinogenesis-receptor activation and PI3K-Akt signaling pathways.AKT1 shows a close relation to the recruitment of various immune cells and can remarkably affect disease prognosis according to reports.Molecular docking and molecular dynamics simulations showed that diosgenin has higher affinity with core targets.Conclusion:The study makes a comprehensive explanation of the biological activity,potential targets,as well as molecular mechanism regarding GQW against ccRCC,which promisingly assists in revealing the action mechanism of TCM formulae in disease treatment and the respective and scientific basis.

Mechanism prediction of Astragalus mongholicus Bunge and Angelica sinensis Diels in treating interstitial lung disease based on network pharmacology and molecular docking

Objective:To investigate the mechanism by which Astragalus mongholicus Bunge(AM),and Angelica sinensis Diels(AS)act in interstitial lung disease(ILD)based on computational prediction.Methods:We screened the ingredients of AM and AS in PubMed,the Web of Science,China National Knowledge Infrastructure(CNKI)Databases,etc.Then obtained the potential effective components.By sharing the same molecular with ILD,we got the possible target genes for ILD treatment and constructed components–targets–disease network with Cytoscape software.The CTD(Comparative Toxicogenomics Database)database was used for GO and KEGG enrichment analysis of these target genes.Results:59 active ingredients that can be druggable were chosen from AM,67 active ingredients were chosen from AS.77 overlapping target genes for AM and ILD and 36 overlapping target genes for AS and ILD were acquired.The hub targets of AM were PTGS2,PTGS1,CDK2,MAOA,ESR1,TOP2A,GSK3B,ESR2,PPARG,NOS2,The hub targets of AS were PTGS2,GABRA1,PTGS1,CHRM1,SLC6A2,ADRA1B,ADRAIA,ADRB2,CHRM3,GABRA2,CHRM2.Quercetin,kaempferol,daidzein,pavilion,7-Hydroxycoumarin,and 5-Hydroxycoumarin were the main active ingredients which have more effective targets.Prediction of the protein-protein interaction network showed PTGS2,GSK3B,PPARG,etc.,were the important predicted targets.The enriched KEGG pathways,including the Immune System,Metabolism of lipids and lipoproteins,Cytokine Signaling in the Immune system,Generic Transcription Pathway,The interleukin pathway,Metabolism of proteins,PI3K-Akt signaling pathway,Metabolic pathways,Innate Immune System,Neuroactive ligand-receptor interaction,Metabolism,GPCR downstream signaling,Amine ligand-binding receptors,Class A/1,Calcium signaling pathway.Molecular docking showed that quercetin,kaempferol,daidzein,pavilion,7-Hydroxycoumarin,5-Hydroxycoumarin had good binding activities with PTGS2 and GSK3B,which mainly mediated PI3K/Akt and other important signaling pathways in the pathogenesis of ILD.Conclusion:The components in AS and AM share some common targets,such as PTGS2.AM and AS may ameliorate ILD through the PI3K-Akt signaling pathway which is mediated by GSK3B.PTGS2,PPARG may also be vital target genes in the treatment of ILD with AM and AS.

Network pharmacology-based screening of the active ingredients and mechanisms of Cymbaria daurica against diabetes mellitus

Cymbaria daurica L.has a long history as a folk medicine and tea for the treatment of diabetes.However,the biological activity and mechanism of its hypoglycemic effect have not been fully elucidated.In this study,the potential mechanism of C.daurica against type 2 diabetes mellitus(T2DM)was postulated via pharmacological network analysis.Based on data mining techniques involving topological parameters,gene ontology,and pathway enrichment,we established a compound-target,protein-protein interaction,and target-pathway network to identify central targets and pathways.Pathway enrichment analysis revealed that the most important pathway associated with C.daurica in treating T2DM is the PI3K-Akt signaling pathway.Molecular docking was performed to validate the predicted results.Then,a HepG2 cell insulin resistance model and a high-fat,high-glucose diet combined with a streptozotocin-induced T2DM rat model was established to assess the fasting glucose changes and lipid profile after C.daurica treatment,respectively.Finally,real-time PCR and western blotting were used to verify changes in key targets.The anti-diabetic mechanism of the active ingredient in C.daurica may involve the regulation of IRS-2,Akt1,GLUT4,and GSK3β.

Study on the Mechanism of Angelica sinensis-Phellodendri Chinensis Cortex in the Treatment of Chronic Prostatitis Based on Network Pharmacology

[Objectives]To explore the mechanism of Angelica sinensis-Phellodendri Chinensis Cortex in the treatment of chronic prostatitis(CP)based on the method of network pharmacology.[Methods]The active components and action targets of Angelica sinensis-Phellodendri Chinensis Cortex were screened by(TCMSP),a systematic pharmacological analysis platform of traditional Chinese medicine,combined with literature search.The target was corrected by Uniprot database,and the disease CP target was screened by GeneCards and OMIM database.The common targets of drugs and diseases were screened by R language software,and the visual network map of drugs-active components-targets-diseases was constructed by Cytoscape 3.5.1 software.The common target protein-protein interaction(PPI)network was constructed by using STRING platform.The R language software was used to annotate and analyze the gene function and pathway of the core target through geneontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG).[Results]46 active components of Angelica sinensis-Phellodendri Chinensis Cortex were screened,and 212 related targets were predicted,of which 159 were related to disease.These targets were mainly involved in biological processes such as heterologous biological stimulation,oxidation and anti-oxidation,and were mainly concentrated in PI3K-Akt,mitogen-activated protein kinase(MAPK),hypoxia inducible factor-1(HIF-1)and other related signaling pathways.[Conclusions]The multi-component,multi-target and multi-pathway action characteristics of Angelica sinensis-Phellodendri Chinensis Cortex were confirmed by network pharmacology,and the possible mechanism of Angelica sinensis-Phellodendri Chinensis Cortex in the treatment of CP was predicted,which provided a theoretical basis for further experiments to verify its action mechanism.

Mechanism prediction of Astragalus mongholicus Bunge and Angelica sinensis Diels in treating interstitial lung disease based on network pharmacology and molecular docking

Objective:To investigate the mechanism by which Astragalus mongholicus Bunge(AM),and Angelica sinensis Diels(AS)act in interstitial lung disease(ILD)based on computational prediction.Methods:We screened the ingredients of AM and AS in PubMed,the Web of Science,China National Knowledge Infrastructure(CNKI)Databases,etc.Then obtained the potential effective components.By sharing the same molecular with ILD,we got the possible target genes for ILD treatment and constructed components–targets–disease network with Cytoscape software.The CTD(Comparative Toxicogenomics Database)database was used for GO and KEGG enrichment analysis of these target genes.Results:59 active ingredients that can be druggable were chosen from AM,67 active ingredients were chosen from AS.77 overlapping target genes for AM and ILD and 36 overlapping target genes for AS and ILD were acquired.The hub targets of AM were PTGS2,PTGS1,CDK2,MAOA,ESR1,TOP2A,GSK3B,ESR2,PPARG,NOS2,The hub targets of AS were PTGS2,GABRA1,PTGS1,CHRM1,SLC6A2,ADRA1B,ADRAIA,ADRB2,CHRM3,GABRA2,CHRM2.Quercetin,kaempferol,daidzein,pavilion,7-Hydroxycoumarin,and 5-Hydroxycoumarin were the main active ingredients which have more effective targets.Prediction of the protein-protein interaction network showed PTGS2,GSK3B,PPARG,etc.,were the important predicted targets.The enriched KEGG pathways,including the Immune System,Metabolism of lipids and lipoproteins,Cytokine Signaling in the Immune system,Generic Transcription Pathway,The interleukin pathway,Metabolism of proteins,PI3K-Akt signaling pathway,Metabolic pathways,Innate Immune System,Neuroactive ligand-receptor interaction,Metabolism,GPCR downstream signaling,Amine ligand-binding receptors,Class A/1,Calcium signaling pathway.Molecular docking showed that quercetin,kaempferol,daidzein,pavilion,7-Hydroxycoumarin,5-Hydroxycoumarin had good binding activities with PTGS2 and GSK3B,which mainly mediated PI3K/Akt and other important signaling pathways in the pathogenesis of ILD.Conclusion:The components in AS and AM share some common targets,such as PTGS2.AM and AS may ameliorate ILD through the PI3K-Akt signaling pathway which is mediated by GSK3B.PTGS2,PPARG may also be vital target genes in the treatment of ILD with AM and AS.

Hypoglycemic effect of Moringa oleifera leaf extract and its mechanism prediction based on network pharmacology

Diabetes mellitus(DM)is a chronic metabolic disease characterized by hyperglycemia,which poses a serious threat to human health.Moringa oleifera Lam.is a medicinal and edible plant with various physiological functions.However,its main hypoglycemic components and mechanisms are still unclear.In this study,network pharmacology and bioinformatics were used to analyze the potential bioactive substances of M.oleifera leaf extract(MOLE)and its hypoglycemic mechanism.Studies have shown that MOLE has the effect of increasing glucose consumption in insulin resistant-HepG2 cells.MOLE was found to contain 975 compounds by ultrahigh performance liquid chromatography-mass spectrometry(UHPLC-MS).Network pharmacology analysis indicated that the main active component was robinetin and the identified core genes were AKT1 and GAPDH.KEGG pathway enrichment analysis showed that the hypoglycemic effect of MOLE may be closely related to the PI3K-Akt signaling pathway.This study revealed the possible active components and mechanisms of action of M.oleifera for hypoglycemia,laying the theoretical foundation for subsequent studies.