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Drug target identification using network analysis: Taking active components in Sini decoction as an example.

Chen S, Jiang H, Cao Y, Wang Y, Hu Z, Zhu Z, Chai Y - Sci Rep (2016)

Bottom Line: The key enriched processes, pathways and related diseases of these target proteins were analyzed by STRING database.Among the 25 targets predicted by network analysis, tumor necrosis factor α (TNF-α) was firstly experimentally validated in molecular and cellular level.Results indicated that hypaconitine, mesaconitine, higenamine and quercetin in SND can directly bind to TNF-α, reduce the TNF-α-mediated cytotoxicity on L929 cells and exert anti-myocardial cell apoptosis effects.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.

ABSTRACT
Identifying the molecular targets for the beneficial effects of active small-molecule compounds simultaneously is an important and currently unmet challenge. In this study, we firstly proposed network analysis by integrating data from network pharmacology and metabolomics to identify targets of active components in sini decoction (SND) simultaneously against heart failure. To begin with, 48 potential active components in SND against heart failure were predicted by serum pharmacochemistry, text mining and similarity match. Then, we employed network pharmacology including text mining and molecular docking to identify the potential targets of these components. The key enriched processes, pathways and related diseases of these target proteins were analyzed by STRING database. At last, network analysis was conducted to identify most possible targets of components in SND. Among the 25 targets predicted by network analysis, tumor necrosis factor α (TNF-α) was firstly experimentally validated in molecular and cellular level. Results indicated that hypaconitine, mesaconitine, higenamine and quercetin in SND can directly bind to TNF-α, reduce the TNF-α-mediated cytotoxicity on L929 cells and exert anti-myocardial cell apoptosis effects. We envisage that network analysis will also be useful in target identification of a bioactive compound.

No MeSH data available.


Related in: MedlinePlus

The active components in SND protected Rat cardiac H9C2 cell line from DOX-induced cell death.Cells were incubated with active components in SND (6.25–100 μM) in DMEM supplemented with 0.5% fetal bovine serum at 37 °C for 2 h followed by incubation with or without DOX (2 μM) for another 24 h. Cell viability was determined by CCK8 assay. Results were expressed as percentages of control group. Data are shown as mean ± SD from three independent experiments. ###p < 0.001 DOX group versus control group, *p < 0.05, **p < 0.01, ***p < 0.001 treatment group versus DOX group.
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f7: The active components in SND protected Rat cardiac H9C2 cell line from DOX-induced cell death.Cells were incubated with active components in SND (6.25–100 μM) in DMEM supplemented with 0.5% fetal bovine serum at 37 °C for 2 h followed by incubation with or without DOX (2 μM) for another 24 h. Cell viability was determined by CCK8 assay. Results were expressed as percentages of control group. Data are shown as mean ± SD from three independent experiments. ###p < 0.001 DOX group versus control group, *p < 0.05, **p < 0.01, ***p < 0.001 treatment group versus DOX group.

Mentions: We then investigated whether these small molecule inhibitors of TNF-α have cardiotonic effect. As shown in Fig. 7, SND, aconitine, hypaconitine, mesaconitine and higenamine (6.25–200 μM) alone had a slight promoting proliferation but there were no significant differences from the control group (p > 0.05). Whereas quercetin alone had a promoting proliferation and there are significant differences from the control group (p < 0.05). To analyze the effects of SND, aconitine, hypaconitine, mesaconitine, higenamine and quercetin (6.25–200 μM) on DOX-induced cytotoxicity in H9C2 cells, cell viability was examined after incubation with these compounds in the presence of DOX (2 μM). Above compounds pretreatments all provided good protective effects on DOX-mediated cell death in a dose-dependent manner (p < 0.05, compared to DOX group) (Fig. 7). These results confirmed the cardioprotective effect and noncytotoxicity of these six compounds in vitro.


Drug target identification using network analysis: Taking active components in Sini decoction as an example.

Chen S, Jiang H, Cao Y, Wang Y, Hu Z, Zhu Z, Chai Y - Sci Rep (2016)

The active components in SND protected Rat cardiac H9C2 cell line from DOX-induced cell death.Cells were incubated with active components in SND (6.25–100 μM) in DMEM supplemented with 0.5% fetal bovine serum at 37 °C for 2 h followed by incubation with or without DOX (2 μM) for another 24 h. Cell viability was determined by CCK8 assay. Results were expressed as percentages of control group. Data are shown as mean ± SD from three independent experiments. ###p < 0.001 DOX group versus control group, *p < 0.05, **p < 0.01, ***p < 0.001 treatment group versus DOX group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4837341&req=5

f7: The active components in SND protected Rat cardiac H9C2 cell line from DOX-induced cell death.Cells were incubated with active components in SND (6.25–100 μM) in DMEM supplemented with 0.5% fetal bovine serum at 37 °C for 2 h followed by incubation with or without DOX (2 μM) for another 24 h. Cell viability was determined by CCK8 assay. Results were expressed as percentages of control group. Data are shown as mean ± SD from three independent experiments. ###p < 0.001 DOX group versus control group, *p < 0.05, **p < 0.01, ***p < 0.001 treatment group versus DOX group.
Mentions: We then investigated whether these small molecule inhibitors of TNF-α have cardiotonic effect. As shown in Fig. 7, SND, aconitine, hypaconitine, mesaconitine and higenamine (6.25–200 μM) alone had a slight promoting proliferation but there were no significant differences from the control group (p > 0.05). Whereas quercetin alone had a promoting proliferation and there are significant differences from the control group (p < 0.05). To analyze the effects of SND, aconitine, hypaconitine, mesaconitine, higenamine and quercetin (6.25–200 μM) on DOX-induced cytotoxicity in H9C2 cells, cell viability was examined after incubation with these compounds in the presence of DOX (2 μM). Above compounds pretreatments all provided good protective effects on DOX-mediated cell death in a dose-dependent manner (p < 0.05, compared to DOX group) (Fig. 7). These results confirmed the cardioprotective effect and noncytotoxicity of these six compounds in vitro.

Bottom Line: The key enriched processes, pathways and related diseases of these target proteins were analyzed by STRING database.Among the 25 targets predicted by network analysis, tumor necrosis factor α (TNF-α) was firstly experimentally validated in molecular and cellular level.Results indicated that hypaconitine, mesaconitine, higenamine and quercetin in SND can directly bind to TNF-α, reduce the TNF-α-mediated cytotoxicity on L929 cells and exert anti-myocardial cell apoptosis effects.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.

ABSTRACT
Identifying the molecular targets for the beneficial effects of active small-molecule compounds simultaneously is an important and currently unmet challenge. In this study, we firstly proposed network analysis by integrating data from network pharmacology and metabolomics to identify targets of active components in sini decoction (SND) simultaneously against heart failure. To begin with, 48 potential active components in SND against heart failure were predicted by serum pharmacochemistry, text mining and similarity match. Then, we employed network pharmacology including text mining and molecular docking to identify the potential targets of these components. The key enriched processes, pathways and related diseases of these target proteins were analyzed by STRING database. At last, network analysis was conducted to identify most possible targets of components in SND. Among the 25 targets predicted by network analysis, tumor necrosis factor α (TNF-α) was firstly experimentally validated in molecular and cellular level. Results indicated that hypaconitine, mesaconitine, higenamine and quercetin in SND can directly bind to TNF-α, reduce the TNF-α-mediated cytotoxicity on L929 cells and exert anti-myocardial cell apoptosis effects. We envisage that network analysis will also be useful in target identification of a bioactive compound.

No MeSH data available.


Related in: MedlinePlus