Objective Chronic renal failure(CRF)is a worldwide public health burden.Niaoduqing granules(NDQ)is widely used for CRF treatment in China.However,the underlying mechanism of NDQ is not fully studied.This study is aime...Objective Chronic renal failure(CRF)is a worldwide public health burden.Niaoduqing granules(NDQ)is widely used for CRF treatment in China.However,the underlying mechanism of NDQ is not fully studied.This study is aimed to investigate whether NDQ ameliorate CRF by inhibiting transforming growth factor-β1(TGF-β1)-induced EMT in human renal tubular epithelial HK-2 cells.Methods 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylterazolium bromide assay and colony formation assay were used to investigate the cytotoxicity of NDQ in HK-2 cells.Morphological changes of HK-2 cells after TGF-β1 or/and NDQ treatment were observed under a microscope.Wound-healing,migration and invasion assays were performed to determine the cell movement,migratory and invasive abilities,respectively.Western blot analysis was carried out to examine the protein levels of TGF-βreceptor I(TβRI)and epithelial-mesenchymal transition(EMT)-associated factors.Fluorescence confocal microscopy was applied to observe the organization of filamentous actin.Results NDQ suppressed TβRI expression dose-dependently.NDQ inhibited TGF-β1-stimulated EMT in HK-2 cells,supported by the evidences that NDQ prevented morphology change,attenuated cell migration and invasion,downregulated EMT factors and reorganized filamentous actin distribution in TGF-β1-stimulated HK-2 cells.Conclusions NDQ attenuates chronic renal failure which may be associated with inhibition of TβRI expression and EMT process.展开更多
Sophaloseedlines A-G(1-7),seven new matrine-based alkaloids along with two known analogues,were isolated from the seeds of Sophora alopecuroides.The new structures were determined based on extensive spectroscopic data...Sophaloseedlines A-G(1-7),seven new matrine-based alkaloids along with two known analogues,were isolated from the seeds of Sophora alopecuroides.The new structures were determined based on extensive spectroscopic data,electronic circular dichroism calculations,and X-ray crystallography.Notably,sophaloseedline A(1)represents a novel rearranged 6(5→17)-abeo-matrine alkaloid featuring unprecedented highly constructed 7/6/5/6 tetracyclic fused ring skeleton.The hypothetical biosynthetic pathways for sophaloseedli nes A-F were proposed based on co-existing precursors.Additionally,all the isolated alkaloids were screened for their antiviral activities against hepatitis B virus,and new alkaloids 1 and 2 displayed more potent activities than those of matrine(a parent alkaloid of title plant)and positive control(lamivudine).展开更多
A phytochemical investigation on the seeds of Sophora alopecuroides led to obtaining fourteen structurally diverse matrine-based alkaloids(1-14),including eight new ones(1,6,8-12,14).Notably,alopecuroide F(1)represent...A phytochemical investigation on the seeds of Sophora alopecuroides led to obtaining fourteen structurally diverse matrine-based alkaloids(1-14),including eight new ones(1,6,8-12,14).Notably,alopecuroide F(1)represents the first dimeric matrine-type skeleton assembled via unprecedent C-13-C-12'connection.The new structures were determined through extensive spectroscopic data(UV,OR,HRESIMS,1D,and 2D NMR),ECD calculations,and three instances,verified by X-ray crystallography.Biologically,all alkaloids were evaluated for cytotoxicity against four human cancer cell lines(HepG2,A549,THP-1,and MCF-7)and anti-inflammatory activities for two pro-inflammatory cytokines(TNF-αand IL-6).Alopecuroide F(1)can inhibit TNF-αand IL-6 productions in a dose-dependent manner with IC50 values of 35.6±0.5 and 41.7±0.8μmol/L,respectively.展开更多
Epidermal growth factor receptor(EGFR)activation plays a pivotal role in EGFR-driven non-small cell lung cancer(NSCLC)and is considered as a key target of molecular targeted therapy.EGFR tyrosine kinase inhibitors(TKI...Epidermal growth factor receptor(EGFR)activation plays a pivotal role in EGFR-driven non-small cell lung cancer(NSCLC)and is considered as a key target of molecular targeted therapy.EGFR tyrosine kinase inhibitors(TKIs)have been canonically used in NSCLC treatment.However,prevalent innate and acquired resistances and EGFR kinase-independent pro-survival properties limit the clinical efficacy of EGFR TKIs.Therefore,the discovery of novel EGFR degraders is a promising approach towards improving therapeutic efficacy and overcoming drug resistance.Here,we identified a 23-hydroxybetulinic acid derivative,namely DPBA,as a novel EGFR small-molecule ligand.It exerted potent in vitro and in vivo anticancer activity in both EGFR wild type and mutant NSCLC by degrading EGFR.Mechanistic studies disclosed that DPBA binds to the EGFR extracellular domain at sites differing from those of EGF and EGFR.DPBA did not induce EGFR dimerization,phosphorylation,and ubiquitination,but it significantly promoted EGFR degradation and repressed downstream survival pathways.Further analyses showed that DPBA induced clathrin-independent EGFR endocytosis mediated by flotillin-dependent lipid rafts and unaffected by EGFR TKIs.Activation of the early and late endosome markers rab5 and rab7 but not the recycling endosome marker rab11 was involved in DPBA-induced EGFR lysosomal degradation.The present study offers a new EGFR ligand for EGFR pharmacological degradation and proposes it as a potential treatment for EGFR-positive NSCLC,particularly NSCLC with innate or acquired EGFR TKI resistance.DPBA can also serve as a chemical probe in the studies on EGFR trafficking and degradation.展开更多
基金This work was supported by the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme(GDHVPS2018)the National Hong Kong Scholars program(XJ2016059)+2 种基金the Natural Science Foundation of Guangdong Province(2020A1515011239)the Guangzhou Science and Technology Project(202102021241)the Administration of Traditional Chinese Medicine of Guangdong Province(20211253)and the Guangzhou Consun Pharmaceuticals Co.,Ltd..These funding bodies played no role in the design of the study,collection,analysis and interpretation of data,and in writing the manuscript.
文摘Objective Chronic renal failure(CRF)is a worldwide public health burden.Niaoduqing granules(NDQ)is widely used for CRF treatment in China.However,the underlying mechanism of NDQ is not fully studied.This study is aimed to investigate whether NDQ ameliorate CRF by inhibiting transforming growth factor-β1(TGF-β1)-induced EMT in human renal tubular epithelial HK-2 cells.Methods 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylterazolium bromide assay and colony formation assay were used to investigate the cytotoxicity of NDQ in HK-2 cells.Morphological changes of HK-2 cells after TGF-β1 or/and NDQ treatment were observed under a microscope.Wound-healing,migration and invasion assays were performed to determine the cell movement,migratory and invasive abilities,respectively.Western blot analysis was carried out to examine the protein levels of TGF-βreceptor I(TβRI)and epithelial-mesenchymal transition(EMT)-associated factors.Fluorescence confocal microscopy was applied to observe the organization of filamentous actin.Results NDQ suppressed TβRI expression dose-dependently.NDQ inhibited TGF-β1-stimulated EMT in HK-2 cells,supported by the evidences that NDQ prevented morphology change,attenuated cell migration and invasion,downregulated EMT factors and reorganized filamentous actin distribution in TGF-β1-stimulated HK-2 cells.Conclusions NDQ attenuates chronic renal failure which may be associated with inhibition of TβRI expression and EMT process.
基金supported by grants from the National Natural Science Foundation of China(Nos.81803376,82074116,81973190)the Guangdong Basic and Applied Basic Research Foundation(No.2020B1515020033)+3 种基金the Natural Science Foundation of Guangdong Province(No.2018B030311020)the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(No.2017BT01Y036)the Guangdong Basic and Applied Basic Research Foundation-Regional Joint Fund(Youth Fund Project,No.2020A1515110415)the high performance public computing service platform of Ji nan Un iversity.
文摘Sophaloseedlines A-G(1-7),seven new matrine-based alkaloids along with two known analogues,were isolated from the seeds of Sophora alopecuroides.The new structures were determined based on extensive spectroscopic data,electronic circular dichroism calculations,and X-ray crystallography.Notably,sophaloseedline A(1)represents a novel rearranged 6(5→17)-abeo-matrine alkaloid featuring unprecedented highly constructed 7/6/5/6 tetracyclic fused ring skeleton.The hypothetical biosynthetic pathways for sophaloseedli nes A-F were proposed based on co-existing precursors.Additionally,all the isolated alkaloids were screened for their antiviral activities against hepatitis B virus,and new alkaloids 1 and 2 displayed more potent activities than those of matrine(a parent alkaloid of title plant)and positive control(lamivudine).
基金This project was supported financially by grants from the National Natural Science Foundation of China(Nos.81803376,82074116,81973190)the Guangdong Basic and Applied Basic Research Foundation(No.2020B1515020033)+4 种基金the Natural Science Foundation of Guangdong Province(No.2018B030311020)the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(No.2017BT01Y036)Guangdong Basic and Applied Basic Research Foundation-Regional Joint Fund(Youth Fund Project,No.2020A1515110415)Pearl River S&T Nova Program of Guangzhou(No.201906010069)We thank the High Performance Public Computing Service Platform of Jinan University for the help of theoretical ECD calculations.
文摘A phytochemical investigation on the seeds of Sophora alopecuroides led to obtaining fourteen structurally diverse matrine-based alkaloids(1-14),including eight new ones(1,6,8-12,14).Notably,alopecuroide F(1)represents the first dimeric matrine-type skeleton assembled via unprecedent C-13-C-12'connection.The new structures were determined through extensive spectroscopic data(UV,OR,HRESIMS,1D,and 2D NMR),ECD calculations,and three instances,verified by X-ray crystallography.Biologically,all alkaloids were evaluated for cytotoxicity against four human cancer cell lines(HepG2,A549,THP-1,and MCF-7)and anti-inflammatory activities for two pro-inflammatory cytokines(TNF-αand IL-6).Alopecuroide F(1)can inhibit TNF-αand IL-6 productions in a dose-dependent manner with IC50 values of 35.6±0.5 and 41.7±0.8μmol/L,respectively.
基金supported by National Key R&D Program of China(2017YFC1703800)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y036)+3 种基金National Science Foundation of China(81630095,81973340,81903634 and 81803566)National Science and Technology Major Project(2018ZX09711001-008-008)National High-level Personnel of Special Support Program(Dongmei Zhang),Natural Science Foundation of Guangdong Province(2019A1515010144)China Postdoctoral Science Foundation-funded project(2019T120793).
文摘Epidermal growth factor receptor(EGFR)activation plays a pivotal role in EGFR-driven non-small cell lung cancer(NSCLC)and is considered as a key target of molecular targeted therapy.EGFR tyrosine kinase inhibitors(TKIs)have been canonically used in NSCLC treatment.However,prevalent innate and acquired resistances and EGFR kinase-independent pro-survival properties limit the clinical efficacy of EGFR TKIs.Therefore,the discovery of novel EGFR degraders is a promising approach towards improving therapeutic efficacy and overcoming drug resistance.Here,we identified a 23-hydroxybetulinic acid derivative,namely DPBA,as a novel EGFR small-molecule ligand.It exerted potent in vitro and in vivo anticancer activity in both EGFR wild type and mutant NSCLC by degrading EGFR.Mechanistic studies disclosed that DPBA binds to the EGFR extracellular domain at sites differing from those of EGF and EGFR.DPBA did not induce EGFR dimerization,phosphorylation,and ubiquitination,but it significantly promoted EGFR degradation and repressed downstream survival pathways.Further analyses showed that DPBA induced clathrin-independent EGFR endocytosis mediated by flotillin-dependent lipid rafts and unaffected by EGFR TKIs.Activation of the early and late endosome markers rab5 and rab7 but not the recycling endosome marker rab11 was involved in DPBA-induced EGFR lysosomal degradation.The present study offers a new EGFR ligand for EGFR pharmacological degradation and proposes it as a potential treatment for EGFR-positive NSCLC,particularly NSCLC with innate or acquired EGFR TKI resistance.DPBA can also serve as a chemical probe in the studies on EGFR trafficking and degradation.
