scholarly journals A Network Pharmacology-based Study of the Potential Mechanism of Bushenhuoxue Formula in Treating Osteoarthritis

2020 ◽  
Author(s):  
Xiong Wen ◽  
Cai Xianhua
Keyword(s):  
Signaling Pathway ◽  
Protein Interactions ◽  
Diabetic Complications ◽  
Target Genes ◽  
Endocrine Resistance ◽  
Network Pharmacology ◽  
Potential Mechanism ◽  
Apoptosis Rate

Abstract Background: To investigate the potential mechanism underlying the efficacy of BuShenHuoXue (BSHX) formula on Osteoarthritis (OA) and its molecular mechanism. Materials and Methods: Data as for bioactive chemicals of individual herb in BSHX formula and their targets were collected from Traditional Chinese Medicine Systems Pharmacology database and OA-associated targets from Gene Expression Omnibus database, compound-disease target network and protein-protein interactions network were built, picturized and analyzed by Cytoscape. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment of key targets were carried out and analyzed to probe into the core pathway and their main functions further. The chondrocytes of SD rats were cultured in vitro, and 50μg/ml IL-1βwas added to the chondrocytes to induce apoptosis. Different concentrations of quercetin were added to the experimental group and the apoptosis rate of chondrocytes, the difference of the expression of SELE, MMP2, and COL1 genes and their protein expression level were further detected. Results: A total of 104 candidate chemicals and 42 crossing targets were screened out. Leading target genes are PTGS2, NCOA2 and HSP90AA1, whereas quercetin and luteolin are principal ingredients. Potential pathways against OA are AGE-RAGE signaling pathway in diabetic complications, Relaxin signaling pathway, IL-17 signaling pathway, Tyrosine metabolism and Endocrine resistance. Our study showed that quercetin could inhibit the apoptosis of chondrocytes induced by IL-1β, decrease SELE, MMP2 and COL1 mRNA expression, likewise decrease the expression of SELE, MMP2 and COL1 protein. Conclusion: This study investigated the bioactive chemicals, crossing targets and possible mechanisms of BSHX formula against OA by network pharmacology strategy, results suggests that quercetin in BSHX formula may target on SELE, MMP2, and COL1 genes and then inhibit the progression of OA through the AGE-RAGE signaling pathway in diabetic complications. By the mechanism of reducing the apoptosis rate of SD rat chondrocytes and down-regulation the expression of genes involved in inflammation, we made sure that quercetin as principal ingredient can protect the cartilage. In addition, the conclusion of this study still need to be confirmed by in vivo and vitro experiments.

scholarly journals Exploring the Mechanism of Action of Banxia Baizhu Tianma Decoction against Preeclampsia by a Network Pharmacology Approach

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Shuqing Cheng ◽  
Xijuan Liu ◽  
Aner Chen ◽  
Haibo Li ◽  
Lulu Yan
Keyword(s):  
Animal Model ◽  
Signaling Pathway ◽  
Target Genes ◽  
Network Pharmacology ◽  
Trophoblast Cells ◽  
Pathway Gene ◽  
Stat Signaling ◽  
Proliferation And Invasion

Background. Banxia Baizhu Tianma Decoction (BBTD) is a traditional Chinese medicine (TCM) and has been revealed to promote symptoms of preeclampsia (PE) in clinical practice. However, its mechanisms of action and molecular targets for the treatment of PE are not clear. Method. The potential mechanisms of the BBTD against PE were explored using network pharmacology approach and bioinformatic analysis. The PE animal model was induced by phosphatidylserine/dioleoyl-phosphatidylcholine. The effects of BBTD in the treatment of PE were evaluated in vitro and in vivo. The expressions of RNA and proteins were measured by quantitative real-time polymerase chain reaction and western blotting, respectively. The cell behavior was detected using the MMT assay, Transwell assay, and flow cytometry assay. Results. A total of 173 active compounds of BBTD with 346 targets were identified, and 516 target genes related to PE were also identified from databases. 195 candidate targets for BBTD were screened from the merged PPI network of BBTD-target proteins and PE-related targets. The pathway enrichment analyses showed that the BBTD had the potential to influence a variety of biological pathways. Further pathway-gene network analysis suggested BBTD may improve symptoms of PE via several genes, including MDM2, TP53, RELA, MYC, AKT1, and EGFR. The validation results demonstrated that BBTD treatment promoted pregnancy outcome in the PE animal model. Meanwhile, BBTD regulated the gene expression of MDM2, TP53, RELA, MYC, and EGFR and inhibited the EGFR-JAK/STAT signaling pathway in placental tissue and trophoblast cells. In addition, BBTD promoted the proliferation and invasion and reduced the apoptosis of trophoblast cells. Conclusion. BBTD improved PE by inhibiting the EGFR-JAK/STAT signaling pathway and promoting the proliferation and invasion and reduced the apoptosis of trophoblast cells.

scholarly journals Ways into Understanding HIF Inhibition

Cancers ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 159
Author(s):  
Tina Schönberger ◽  
Joachim Fandrey ◽  
Katrin Prost-Fingerle
Keyword(s):  
Protein Interactions ◽  
Target Genes ◽  
Protein Protein Interactions ◽  
Low Oxygen ◽  
Drug Candidates ◽  
Open Questions ◽  
Wide Range ◽  
Hif Pathway

Hypoxia is a key characteristic of tumor tissue. Cancer cells adapt to low oxygen by activating hypoxia-inducible factors (HIFs), ensuring their survival and continued growth despite this hostile environment. Therefore, the inhibition of HIFs and their target genes is a promising and emerging field of cancer research. Several drug candidates target protein–protein interactions or transcription mechanisms of the HIF pathway in order to interfere with activation of this pathway, which is deregulated in a wide range of solid and liquid cancers. Although some inhibitors are already in clinical trials, open questions remain with respect to their modes of action. New imaging technologies using luminescent and fluorescent methods or nanobodies to complement widely used approaches such as chromatin immunoprecipitation may help to answer some of these questions. In this review, we aim to summarize current inhibitor classes targeting the HIF pathway and to provide an overview of in vitro and in vivo techniques that could improve the understanding of inhibitor mechanisms. Unravelling the distinct principles regarding how inhibitors work is an indispensable step for efficient clinical applications and safety of anticancer compounds.

scholarly journals HPV-18 E6 Oncoprotein and Its Spliced Isoform E6*I Regulate the Wnt/β-Catenin Cell Signaling Pathway through the TCF-4 Transcriptional Factor

2018 ◽  
Vol 19 (10) ◽  
pp. 3153 ◽  
Author(s):  
J. Muñoz-Bello ◽  
Leslie Olmedo-Nieva ◽  
Leonardo Castro-Muñoz ◽  
Joaquín Manzo-Merino ◽  
Adriana Contreras-Paredes ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Promote Cell Proliferation ◽  
E6 And E7 ◽  
Hpv 18

The Wnt/β-catenin signaling pathway regulates cell proliferation and differentiation and its aberrant activation in cervical cancer has been described. Persistent infection with high risk human papillomavirus (HR-HPV) is the most important factor for the development of this neoplasia, since E6 and E7 viral oncoproteins alter cellular processes, promoting cervical cancer development. A role of HPV-16 E6 in Wnt/β-catenin signaling has been proposed, although the participation of HPV-18 E6 has not been previously studied. The aim of this work was to investigate the participation of HPV-18 E6 and E6*I, in the regulation of the Wnt/β-catenin signaling pathway. Here, we show that E6 proteins up-regulate TCF-4 transcriptional activity and promote overexpression of Wnt target genes. In addition, it was demonstrated that E6 and E6*I bind to the TCF-4 (T cell factor 4) and β-catenin, impacting TCF-4 stabilization. We found that both E6 and E6*I proteins interact with the promoter of Sp5, in vitro and in vivo. Moreover, although differences in TCF-4 transcriptional activation were found among E6 intratype variants, no changes were observed in the levels of regulated genes. Furthermore, our data support that E6 proteins cooperate with β-catenin to promote cell proliferation.

scholarly journals A Network Pharmacology Approach to Predict the Proangiogenesis Mechanism of Huangqi-Honghua Herb Pair after Cerebral Ischemia

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Jinyi Cao ◽  
Lu Lei ◽  
Kai Wang ◽  
Jing Sun ◽  
Yi Qiao ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Signaling Pathway ◽  
Target Genes ◽  
Blood Stasis ◽  
Blood Stasis Syndrome ◽  
Network Pharmacology ◽  
Western Blot Assay ◽  
Medicinal Value ◽  
Pharmacological Method

Objective. Huangqi-Honghua herb pair is known for its medicinal value to treat Qi deficiency and blood stasis syndrome with a long history in clinical practice. To understand its possible mechanism in a systematic study, a network pharmacological method was addressed. Methods. Detailed information on the HH compounds was obtained from two public databases, and oral bioavailability (OB) and drug-like (DL) of the compounds were evaluated. A correlation between HH compounds, its potential targets, and known targets was extrapolated, and the herb-compound-target-disease (H-C-T-D) network was established. Next, the pathway enrichment and essential genes were analyzed. Then, three key genes (VEGFA, VEGFR2, and eNOS), highly associated with angiogenesis, were screened and verified through western blot assay. Results. Out of 276 compounds, 21 HH compounds and 78 target genes regulating the major pathways associated with CI in the network are analyzed. The bioactive compounds in HH were active in various signal transduction pathways such as the toll-like receptor signaling pathway, VEGF signaling pathway, TNF signaling pathway, and HIF-1 signaling pathway are important pathways that may regulate anti-inflammatory, antiapoptotic, immune correlation, and antioxidative effects. The core genes are PTGS2, TNF, NOS2, IL6, BCL2, IL1B, SOD2, NOS3, SOD1, MMP9, and VEGFA. The in vitro results suggested that HH treatment could significantly elevate the expression of proangiogenic genes such as VEGFA, VEGFR2, and eNOS compared with OGD groups. Conclusions. Our results predict that HH may regulate the expression of VEGFA, VEGFR2, and eNOS via the VEGF and HIF-1 signaling pathway to promote angiogenesis and alleviate cerebral ischemia injury.

RNA binding by Sxl proteins in vitro and in vivo

1994 ◽  
Vol 14 (7) ◽  
pp. 4975-4990
Author(s):  
M E Samuels ◽  
D Bopp ◽  
R A Colvin ◽  
R F Roscigno ◽  
M A Garcia-Blanco ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Target Genes ◽  
Rna Binding ◽  
Polytene Chromosomes ◽  
Regulatory Sequences ◽  
Acceptor Site ◽  
Nuclear Extracts ◽  
Preferential Binding

Sxl has been proposed to regulate splicing of specific target genes by directly interacting with their pre-mRNAs. We have therefore examined the RNA-binding properties of Sxl protein in vitro and in vivo. Gel shift and UV cross-linking assays with a purified recombinant MBP-Sxl fusion protein demonstrated preferential binding to RNAs containing poly(U) tracts, and the protein footprinted over the poly(U) region. The protein did not appear to recognize either branch point or AG dinucleotide sequences, but an adenosine residue at the 5' end of the poly(U) tract enhanced binding severalfold. MBP-Sxl formed two shifted complexes on a tra regulated acceptor site RNA; the doubly shifted form may have been stabilized by protein-protein interactions. Consistent with its proposed role in pre-mRNA processing, in nuclear extracts Sxl was found in large ribonucleoprotein (RNP) complexes which sedimented significantly faster than bulk heterogeneous nuclear RNP and small nuclear RNPs. Anti-Sxl staining of polytene chromosomes showed Sxl protein at a number of chromosomal locations, among which was the Sxl locus itself. Sxl protein could also be targeted to a new chromosomal site carrying a transgene containing splicing regulatory sequences from the Sxl gene, following transcriptional induction. After prolonged heat shock, all Sxl protein was restricted to the heat-induced puff at the hs93D locus. In contrast, a presumptive small nuclear RNP protein was observed at several heat puffs following shock.

scholarly journals Integrating Network Pharmacology with Molecular Docking to Unravel the Active Compounds and Potential Mechanism of Simiao Pill Treating Rheumatoid Arthritis

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Mengshi Tang ◽  
Xi Xie ◽  
Pengji Yi ◽  
Jin Kang ◽  
Jiafen Liao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Molecular Docking ◽  
Signaling Pathway ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Binding Activity ◽  
New Combination ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Potential Mechanism

Objective. To explore the main components and unravel the potential mechanism of simiao pill (SM) on rheumatoid arthritis (RA) based on network pharmacological analysis and molecular docking. Methods. Related compounds were obtained from TCMSP and BATMAN-TCM database. Oral bioavailability and drug-likeness were then screened by using absorption, distribution, metabolism, and excretion (ADME) criteria. Additionally, target genes related to RA were acquired from GeneCards and OMIM database. Correlations about SM-RA, compounds-targets, and pathways-targets-compounds were visualized through Cytoscape 3.7.1. The protein-protein interaction (PPI) network was constructed by STRING. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed via R packages. Molecular docking analysis was constructed by the Molecular Operating Environment (MOE). Results. A total of 72 potential compounds and 77 associated targets of SM were identified. The compounds-targets network analysis indicated that the 6 compounds, including quercetin, kaempferol, baicalein, wogonin, beta-sitosterol, and eugenol, were linked to ≥10 target genes, and the 10 target genes (PTGS1, ESR1, AR, PGR, CHRM3, PPARG, CHRM2, BCL2, CASP3, and RELA) were core target genes in the network. Enrichment analysis indicated that PI3K-Akt, TNF, and IL-17 signaling pathway may be a critical signaling pathway in the network pharmacology. Molecular docking showed that quercetin, kaempferol, baicalein, and wogonin have good binding activity with IL6, VEGFA, EGFR, and NFKBIA targets. Conclusion. The integrative investigation based on bioinformatics/network topology strategy may elaborate on the multicomponent synergy mechanisms of SM against RA and provide the way out to develop new combination medicines for RA.

scholarly journals Uterine progesterone signaling is a target for metformin therapy in PCOS-like rats

2018 ◽  
Vol 237 (2) ◽  
pp. 123-137 ◽  
Author(s):  
Min Hu ◽  
Yuehui Zhang ◽  
Jiaxing Feng ◽  
Xue Xu ◽  
Jiao Zhang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Target Genes ◽  
Polycystic Ovary ◽  
Metformin Therapy ◽  
Before And After ◽  
Elevated Expression ◽  
Targeted Gene Expression ◽  
First Time

Impaired progesterone (P4) signaling is linked to endometrial dysfunction and infertility in women with polycystic ovary syndrome (PCOS). Here, we report for the first time that elevated expression of progesterone receptor (PGR) isoforms A and B parallels increased estrogen receptor (ER) expression in PCOS-like rat uteri. The aberrant PGR-targeted gene expression in PCOS-like rats before and after implantation overlaps with dysregulated expression of Fkbp52 and Ncoa2, two genes that contribute to the development of uterine P4 resistance. In vivo and in vitro studies of the effects of metformin on the regulation of the uterine P4 signaling pathway under PCOS conditions showed that metformin directly inhibits the expression of PGR and ER along with the regulation of several genes that are targeted dependently or independently of PGR-mediated uterine implantation. Functionally, metformin treatment corrected the abnormal expression of cell-specific PGR and ER and some PGR-target genes in PCOS-like rats with implantation. Additionally, we documented how metformin contributes to the regulation of the PGR-associated MAPK/ERK/p38 signaling pathway in the PCOS-like rat uterus. Our data provide novel insights into how metformin therapy regulates uterine P4 signaling molecules under PCOS conditions.

scholarly journals Network pharmacology based research into the effect and mechanism of Yinchenhao Decoction against Cholangiocarcinoma

2021 ◽  
Author(s):  
Zhiqiang Chen ◽  
Tong Lin ◽  
Xiaozhong Liao ◽  
Zeyun Li ◽  
Ruiting Lin ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Experimental Results ◽  
Network Pharmacology ◽  
Therapeutic Effects ◽  
Active Components ◽  
Active Compounds ◽  
Apoptosis Rate

Abstract Background: Cholangiocarcinoma refers to an epithelial cell malignancy with poor prognosis. Yinchenhao decoction (YCHD) showed positive effects on cancers, and associations between YCHD and cholangiocarcinoma remain unclear. This study aimed to screen out the effective active components of Yinchenhao decoction (YCHD) using network pharmacology, estimate their potential targets, screen out the pathways, as well as delve into the potential mechanisms on treating cholangiocarcinoma. Methods: By the traditional Chinese medicine system pharmacology database and analysis platform (TCMSP) as well as literature review, the major active components and their corresponding targets were estimated and screened out. Using the software Cytoscape 3.6.0, a visual network was established using the active components of YCHD and the targets of cholangiocarcinoma. Based on STRING online database, the protein interaction network of vital targets was built and analyzed. With the Database for Annotation, Visualization, and Integrated Discovery (DAVID) server, the gene ontology (GO) biological processes and the Kyoto encyclopedia of genes and genomes (KEGG) signaling pathways of the targets enrichment were performed. The AutoDock Vina was used to perform molecular docking and calculate the binding affinity. The PyMOL software was utilized to visualize the docking results of active compounds and protein targets. In vivo experiment, the IC50 values and apoptosis rate in PI-A cells were detected using CCK-8 kit and Cell Cycle Detection Kit. The predicted targets were verified by the real-time PCR and western blot methods. Results: 32 effective active components with anti-tumor effects of YCHD were sifted in total, covering 209 targets, 96 of which were associated with cancer. Quercetin, kaempferol, beta-sitosterol, isorhamnetin, and stigmasterol were identified as the vital active compounds, and AKT1, IL6, MAPK1, TP53 as well as VEGFA were considered as the major targets. The molecular docking revealed that these active compounds and targets showed good binding interactions. These 96 putative targets exerted therapeutic effects on cancer by regulating signaling pathways (e.g., hepatitis B, the MAPK signaling pathway, the PI3K-Akt signaling pathway, and MicroRNAs in cancer). Our in vivo experimental results confirmed that YCHD showed therapeutic effects on cholangiocarcinoma by decreasing IC50 values, down-regulating apoptosis rate of cholangiocarcinoma cells, and lowering protein expressions. Conclusion:As predicted by network pharmacology strategy and validated by the experimental results, YCHD exerts anti-tumor effectsthrough multiple components, targets, and pathways, thereby providing novel ideas and clues for the development of preparations and the treatment of cholangiocarcinoma.

scholarly journals Identification on the potential mechanism of Radix pueraria on colon cancer based on network pharmacology

2021 ◽  
Author(s):  
Yi Li ◽  
Chunli Zhang ◽  
Xiaohan Ma ◽  
Liuqing Yang ◽  
Huijun Ren
Keyword(s):  
Colon Cancer ◽  
Chinese Medicine ◽  
Target Genes ◽  
Enrichment Analysis ◽  
In Vivo Studies ◽  
Network Pharmacology ◽  
Biological Mechanism ◽  
Active Components

Abstract Radix Puerariae (RP), a dry root of the Pueraria lobata (Willd.) Ohwi, is used to treat a variety of diseases, including cancer. Several in vitro and in vivo studies have demonstrated the efficacy of RP in the treatment of colon cancer (CC). However, the biological mechanism of RP in the treatment of colon cancer remains unclear. In this study, the active component of RP and its potential molecular mechanism against CC were studied by network pharmacology and enrichment analysis. The methods adopted included screening of active ingredients of Chinese medicine, prediction of target genes of Chinese medicine and disease, construction of protein interaction network, and GO and KEGG Enrichment Analysis. Finally, the results of network pharmacology were further validated by molecular docking experiments and cell experiments. 8 active constituents and 14 potential protein targets were screened from RP, including EGFR, JAK2 and SRC. The biological mechanism of RP against CC was analyzed by studying the relationship between active components, targets, and enrichment pathway. This provides a basis for understanding the clinical application of RP in CC.

scholarly journals RNA binding by Sxl proteins in vitro and in vivo.

1994 ◽  
Vol 14 (7) ◽  
pp. 4975-4990 ◽  
Author(s):  
M E Samuels ◽  
D Bopp ◽  
R A Colvin ◽  
R F Roscigno ◽  
M A Garcia-Blanco ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Target Genes ◽  
Rna Binding ◽  
Polytene Chromosomes ◽  
Regulatory Sequences ◽  
Acceptor Site ◽  
Nuclear Extracts ◽  
Preferential Binding

Sxl has been proposed to regulate splicing of specific target genes by directly interacting with their pre-mRNAs. We have therefore examined the RNA-binding properties of Sxl protein in vitro and in vivo. Gel shift and UV cross-linking assays with a purified recombinant MBP-Sxl fusion protein demonstrated preferential binding to RNAs containing poly(U) tracts, and the protein footprinted over the poly(U) region. The protein did not appear to recognize either branch point or AG dinucleotide sequences, but an adenosine residue at the 5' end of the poly(U) tract enhanced binding severalfold. MBP-Sxl formed two shifted complexes on a tra regulated acceptor site RNA; the doubly shifted form may have been stabilized by protein-protein interactions. Consistent with its proposed role in pre-mRNA processing, in nuclear extracts Sxl was found in large ribonucleoprotein (RNP) complexes which sedimented significantly faster than bulk heterogeneous nuclear RNP and small nuclear RNPs. Anti-Sxl staining of polytene chromosomes showed Sxl protein at a number of chromosomal locations, among which was the Sxl locus itself. Sxl protein could also be targeted to a new chromosomal site carrying a transgene containing splicing regulatory sequences from the Sxl gene, following transcriptional induction. After prolonged heat shock, all Sxl protein was restricted to the heat-induced puff at the hs93D locus. In contrast, a presumptive small nuclear RNP protein was observed at several heat puffs following shock.

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