Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the pr...Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain unknown.In this study,we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis.Additionally,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,respectively.Computational simulation and BioLayer interferometry were used to confirm their binding affinity.Our results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)pathway.In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways.Moreover,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.展开更多
为探究表没食子儿茶素没食子酸酯-牛骨蛋白(Epigallocatechin-3-gallate-Bovine bone protein,EGCG-BBP)对乳化肉制品蛋白结构及贮藏氧化稳定性的影响,本文研究不同EGCG-BBP添加量对生肉糜中肌原纤维蛋白(Myofibrillar protein,MP)的理...为探究表没食子儿茶素没食子酸酯-牛骨蛋白(Epigallocatechin-3-gallate-Bovine bone protein,EGCG-BBP)对乳化肉制品蛋白结构及贮藏氧化稳定性的影响,本文研究不同EGCG-BBP添加量对生肉糜中肌原纤维蛋白(Myofibrillar protein,MP)的理化性质、结构特性以及对肉丸氧化特性的影响。结果表明:当EGCG-BBP添加量为0.8%时,肉糜中MP的巯基含量最高,达4.06 nmol/mg蛋白,且羰基含量及表面疏水性最低,能够有效提升乳化肉制品的抗氧化能力。由红外光谱分析表明,与未添加EGCG-BBP组相比,添加共价物肉糜中MP的酰胺A带峰值所对应的波数明显增大,说明MP的二级结构会随之发生改变;荧光光谱显示,随贮藏时间延长,对照组中MP的最强荧光波长发生显著红移,但随EGCG-BBP浓度的增加,红移程度显著降低,表明添加EGCGBBP能够改变MP的三级结构。此外,乳化肉丸贮藏过程中的氧化指标分析表明,添加0.8%EGCG-BBP能显著降低肉丸的过氧化值(PV)和硫代巴比妥酸值(TBARs),从而提高其氧化稳定性。综上所述,EGCG-BBP能够显著改变MP的二、三级结构,且具有良好的抗氧化性能,在提升乳化肉制品品质方面具有很大的应用潜力,为肉品抗氧化型乳化剂的应用提供新的选择。展开更多
Soluble receptor for advanced glycation end products(sRAGE)acts as a decoy sequestering of RAGE ligands,thus preventing the activation of the ligand-RAGE axis linking human diseases.However,the molecular mechanisms un...Soluble receptor for advanced glycation end products(sRAGE)acts as a decoy sequestering of RAGE ligands,thus preventing the activation of the ligand-RAGE axis linking human diseases.However,the molecular mechanisms underlying sRAGE remain unclear.In this study,THP-1 monocytes were cultured in normal glucose(NG,5.5 mmol/L)and high glucose(HG,15 mmol/L)to investigate the effects of diabetesrelevant glucose concentrations on sRAGE and interleukin-1β(IL-1β)secretion.The modulatory effects of epigallocatechin gallate(EGCG)in response to HG challenge were also evaluated.HG enhanced intracellular reactive oxygen species(ROS)generation and RAGE expression.The secretion of sRAGE,including esRAGE and cRAGE,was reduced under HG conditions,together with the downregulation of a disintegrin and metallopeptidase 10(ADAM10)and nuclear factor erythroid 2-related factor 2(Nrf2)nuclear translocation.Mechanistically,the HG effects were counteracted by siRAGE and exacerbated by siNrf2.Chromatin immunoprecipitation results showed that Nrf2 binding to the ADAM10 promoter and HG interfered with this binding.Our data reinforce the notion that RAGE and Nrf2 might be sRAGE-regulating factors.Under HG conditions,the treatment of EGCG reduced ROS generation and RAGE activation.EGCG-stimulated cRAGE release was likely caused by the upregulation of the Nrf2-ADAM10 pathway.EGCG inhibited HG-mediated NLRP3 inflammasome activation at least partly by stimulating sRAGE,thereby reducing IL-1βrelease.展开更多
基金supported by the GRF RGC&CRF,Hong Kong(Grant Nos.:475012 and C5045-20 EF)HMRF,Hong Kong(Grant No.:03141386)+3 种基金ITF,Hong Kong(Grant No.:ITS/209/12)UGC Direct Grant 2011,2012,2021.032HKOG Trust Fund 2011,2014,2019the National Natural Science Foundation of China(Grant Nos.:81974225 and 82201823)。
文摘Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain unknown.In this study,we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis.Additionally,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,respectively.Computational simulation and BioLayer interferometry were used to confirm their binding affinity.Our results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)pathway.In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways.Moreover,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.
文摘为探究表没食子儿茶素没食子酸酯-牛骨蛋白(Epigallocatechin-3-gallate-Bovine bone protein,EGCG-BBP)对乳化肉制品蛋白结构及贮藏氧化稳定性的影响,本文研究不同EGCG-BBP添加量对生肉糜中肌原纤维蛋白(Myofibrillar protein,MP)的理化性质、结构特性以及对肉丸氧化特性的影响。结果表明:当EGCG-BBP添加量为0.8%时,肉糜中MP的巯基含量最高,达4.06 nmol/mg蛋白,且羰基含量及表面疏水性最低,能够有效提升乳化肉制品的抗氧化能力。由红外光谱分析表明,与未添加EGCG-BBP组相比,添加共价物肉糜中MP的酰胺A带峰值所对应的波数明显增大,说明MP的二级结构会随之发生改变;荧光光谱显示,随贮藏时间延长,对照组中MP的最强荧光波长发生显著红移,但随EGCG-BBP浓度的增加,红移程度显著降低,表明添加EGCGBBP能够改变MP的三级结构。此外,乳化肉丸贮藏过程中的氧化指标分析表明,添加0.8%EGCG-BBP能显著降低肉丸的过氧化值(PV)和硫代巴比妥酸值(TBARs),从而提高其氧化稳定性。综上所述,EGCG-BBP能够显著改变MP的二、三级结构,且具有良好的抗氧化性能,在提升乳化肉制品品质方面具有很大的应用潜力,为肉品抗氧化型乳化剂的应用提供新的选择。
文摘Soluble receptor for advanced glycation end products(sRAGE)acts as a decoy sequestering of RAGE ligands,thus preventing the activation of the ligand-RAGE axis linking human diseases.However,the molecular mechanisms underlying sRAGE remain unclear.In this study,THP-1 monocytes were cultured in normal glucose(NG,5.5 mmol/L)and high glucose(HG,15 mmol/L)to investigate the effects of diabetesrelevant glucose concentrations on sRAGE and interleukin-1β(IL-1β)secretion.The modulatory effects of epigallocatechin gallate(EGCG)in response to HG challenge were also evaluated.HG enhanced intracellular reactive oxygen species(ROS)generation and RAGE expression.The secretion of sRAGE,including esRAGE and cRAGE,was reduced under HG conditions,together with the downregulation of a disintegrin and metallopeptidase 10(ADAM10)and nuclear factor erythroid 2-related factor 2(Nrf2)nuclear translocation.Mechanistically,the HG effects were counteracted by siRAGE and exacerbated by siNrf2.Chromatin immunoprecipitation results showed that Nrf2 binding to the ADAM10 promoter and HG interfered with this binding.Our data reinforce the notion that RAGE and Nrf2 might be sRAGE-regulating factors.Under HG conditions,the treatment of EGCG reduced ROS generation and RAGE activation.EGCG-stimulated cRAGE release was likely caused by the upregulation of the Nrf2-ADAM10 pathway.EGCG inhibited HG-mediated NLRP3 inflammasome activation at least partly by stimulating sRAGE,thereby reducing IL-1βrelease.
