Objective:Triple-negative breast cancer(TNBC)is highly metastatic,and there is an urgent unmet need to develop novel therapeutic strategies leading to the new drug discoveries against metastasis.The transforming growt...Objective:Triple-negative breast cancer(TNBC)is highly metastatic,and there is an urgent unmet need to develop novel therapeutic strategies leading to the new drug discoveries against metastasis.The transforming growth factor-β(TGF-β)is known to promote the invasive and migratory potential of breast cancer cells through induction of epithelial–mesenchymal transition(EMT)via the ERK/NF-κB/Snail signaling pathway,leading to breast cancer metastasis.Targeting this pathway to revert the EMT would be an attractive,novel therapeutic strategy to halt breast cancer metastasis.Methods:Effects of enterolactone(EL)on the cell cycle and apoptosis were investigated using flow cytometry and a cleaved caspase-3 enzyme-linked immunosorbent assay(ELISA),respectively.Effects of TGF-βinduction and EL treatment on the functional malignancy of MDA-MB-231 breast cancer cells were investigated using migration and chemo-invasion assays.The effects of EL on EMT markers and the ERK/NF-κB/Snail signaling pathway after TGF-βinduction were studied using confocal microscopy,quantitative reverse transcription polymerase chain reaction(q RT-PCR),Western blot,and flow cytometry.Results:Herein,we report that EL exhibits a significant antimetastatic effect on MDA-MB-231 cells by almost reverting the TGF-β-induced EMT in vitro.EL downregulates the mesenchymal markers N-cadherin and vimentin,and upregulates the epithelial markers E-cadherin and occludin.It represses actin stress fiber formation via inhibition of mitogen-activated protein kinase p-38(MAPK-p38)and cluster of differentiation 44(CD44).EL also suppresses ERK-1/2,NF-κB,and Snail at the m RNA and protein levels.Conclusions:Briefly,EL was found to inhibit TGF-β-induced EMT by blocking the ERK/NF-κB/Snail signaling pathway,which is a promising target for breast cancer metastasis therapy.展开更多
The antioxidant activity of ortho and meta substituted Enterolactone derivatives has been investigated in the gas phase and water.The reaction enthalpies of antioxidant activity of the studied derivatives have been ca...The antioxidant activity of ortho and meta substituted Enterolactone derivatives has been investigated in the gas phase and water.The reaction enthalpies of antioxidant activity of the studied derivatives have been calculated and compared with the corresponding values of Enterolactone.Results show that EWG substituents increase the BDE and IP,while the EDG ones rise in the PA.The Enterolactone derivatives with the lowest BDE,IP and PA values were identified as the compounds with high antioxidant activity.Results show that the substituents in the ortho position have high potential for the synthesis of novel Enterolactone derivatives.Results show that Enterolactone derivatives can processes their protective role via HAT and SPLET mechanism in gas phase and solvent,respectively.The calculated reaction enthalpies of the substituted Enterolactones have linear dependence with Hammett constants and EHOMO that can be utilized in the selection of suitable substituents for the synthesis of novel antioxidants based on Enterolactone.展开更多
Triple-negative breast cancer(TNBC)is an aggressive subtype characterized by resistance to conventional treatments and high recurrence rates.Cancer stem cells(CSCs)within TNBC contribute significantly to tumor progres...Triple-negative breast cancer(TNBC)is an aggressive subtype characterized by resistance to conventional treatments and high recurrence rates.Cancer stem cells(CSCs)within TNBC contribute significantly to tumor progression,metastasis,and therapy resistance.This study explores Enterolactone(EL),a bioactive phenolic metabolite from dietary lignans,as a potential therapeutic agent against TNBC-CSCs.The investigation began by identifying potential therapeutic targets for EL against TNBC-CSCs using predictive databases.A PPI network was constructed in STRING to emphasize top hub targets.Insights were derived from mRNA expression patterns,tumor stage differentials,and survival analysis via UALCAN and GEPIA2.Molecular docking and dynamics simulations were carried out to explore EL’s interactions with hub targets.GeneMANIA was employed to expand the target pool,generating two datasets.Preliminary FGN analysis and clustering of the second dataset were executed using GeneMANIA and MCODE plugins in CytoScape to enhance potential therapeutic avenues for EL against TNBC-CSCs.Employing network pharmacology,53 potential EL targets against TNBC-CSCs were identified,highlighting the top 15 hub targets,including ESR1,AKT1,JUN,EGFR,and others.Functional analysis unveiled their involvement in critical pathways like PI3K/AKT/mTOR,Wnt-βcatenin,and MAPK,essential for CSC self-renewal,metastasis,and therapy resistance.GO and KEGG analyses illuminated the biological significance of these targets,elucidating EL’s potential mechanisms.Analysis of GMFA-ED1 and-ED2 datasets expanded understanding,revealing novel targets of EL against TNBC-CSCs.In conclusion,EL demonstrates therapeutic potential against TNBC-CSCs by influencing crucial CSCs related molecular targets and Wnt-βcatenin and PI3K-AKT pathways,offering promising avenues in TNBC.展开更多
文摘Objective:Triple-negative breast cancer(TNBC)is highly metastatic,and there is an urgent unmet need to develop novel therapeutic strategies leading to the new drug discoveries against metastasis.The transforming growth factor-β(TGF-β)is known to promote the invasive and migratory potential of breast cancer cells through induction of epithelial–mesenchymal transition(EMT)via the ERK/NF-κB/Snail signaling pathway,leading to breast cancer metastasis.Targeting this pathway to revert the EMT would be an attractive,novel therapeutic strategy to halt breast cancer metastasis.Methods:Effects of enterolactone(EL)on the cell cycle and apoptosis were investigated using flow cytometry and a cleaved caspase-3 enzyme-linked immunosorbent assay(ELISA),respectively.Effects of TGF-βinduction and EL treatment on the functional malignancy of MDA-MB-231 breast cancer cells were investigated using migration and chemo-invasion assays.The effects of EL on EMT markers and the ERK/NF-κB/Snail signaling pathway after TGF-βinduction were studied using confocal microscopy,quantitative reverse transcription polymerase chain reaction(q RT-PCR),Western blot,and flow cytometry.Results:Herein,we report that EL exhibits a significant antimetastatic effect on MDA-MB-231 cells by almost reverting the TGF-β-induced EMT in vitro.EL downregulates the mesenchymal markers N-cadherin and vimentin,and upregulates the epithelial markers E-cadherin and occludin.It represses actin stress fiber formation via inhibition of mitogen-activated protein kinase p-38(MAPK-p38)and cluster of differentiation 44(CD44).EL also suppresses ERK-1/2,NF-κB,and Snail at the m RNA and protein levels.Conclusions:Briefly,EL was found to inhibit TGF-β-induced EMT by blocking the ERK/NF-κB/Snail signaling pathway,which is a promising target for breast cancer metastasis therapy.
文摘The antioxidant activity of ortho and meta substituted Enterolactone derivatives has been investigated in the gas phase and water.The reaction enthalpies of antioxidant activity of the studied derivatives have been calculated and compared with the corresponding values of Enterolactone.Results show that EWG substituents increase the BDE and IP,while the EDG ones rise in the PA.The Enterolactone derivatives with the lowest BDE,IP and PA values were identified as the compounds with high antioxidant activity.Results show that the substituents in the ortho position have high potential for the synthesis of novel Enterolactone derivatives.Results show that Enterolactone derivatives can processes their protective role via HAT and SPLET mechanism in gas phase and solvent,respectively.The calculated reaction enthalpies of the substituted Enterolactones have linear dependence with Hammett constants and EHOMO that can be utilized in the selection of suitable substituents for the synthesis of novel antioxidants based on Enterolactone.
文摘Triple-negative breast cancer(TNBC)is an aggressive subtype characterized by resistance to conventional treatments and high recurrence rates.Cancer stem cells(CSCs)within TNBC contribute significantly to tumor progression,metastasis,and therapy resistance.This study explores Enterolactone(EL),a bioactive phenolic metabolite from dietary lignans,as a potential therapeutic agent against TNBC-CSCs.The investigation began by identifying potential therapeutic targets for EL against TNBC-CSCs using predictive databases.A PPI network was constructed in STRING to emphasize top hub targets.Insights were derived from mRNA expression patterns,tumor stage differentials,and survival analysis via UALCAN and GEPIA2.Molecular docking and dynamics simulations were carried out to explore EL’s interactions with hub targets.GeneMANIA was employed to expand the target pool,generating two datasets.Preliminary FGN analysis and clustering of the second dataset were executed using GeneMANIA and MCODE plugins in CytoScape to enhance potential therapeutic avenues for EL against TNBC-CSCs.Employing network pharmacology,53 potential EL targets against TNBC-CSCs were identified,highlighting the top 15 hub targets,including ESR1,AKT1,JUN,EGFR,and others.Functional analysis unveiled their involvement in critical pathways like PI3K/AKT/mTOR,Wnt-βcatenin,and MAPK,essential for CSC self-renewal,metastasis,and therapy resistance.GO and KEGG analyses illuminated the biological significance of these targets,elucidating EL’s potential mechanisms.Analysis of GMFA-ED1 and-ED2 datasets expanded understanding,revealing novel targets of EL against TNBC-CSCs.In conclusion,EL demonstrates therapeutic potential against TNBC-CSCs by influencing crucial CSCs related molecular targets and Wnt-βcatenin and PI3K-AKT pathways,offering promising avenues in TNBC.
