Ferroptosis is a type of cell death accompanied by iron-dependent lipid peroxidation,thus stimulating ferroptosis may be a potential strategy for treating gastric cancer,therapeutic agents against which are urgently r...Ferroptosis is a type of cell death accompanied by iron-dependent lipid peroxidation,thus stimulating ferroptosis may be a potential strategy for treating gastric cancer,therapeutic agents against which are urgently required.Jiyuan oridonin A(JDA) is a natural compound isolated from Jiyuan Rabdosia rubescens with anti-tumor activity,unclear anti-tumor mechanisms and limited water solubility hamper its clinical application.Here,we showed a2,a new JDA derivative,inhibited the growth of gastric cancer cells.Subsequently,we discovered for the first time that a2 induced ferroptosis.Importantly,compound a2 decreased GPX4 expression and overexpressing GPX4 antagonized the anti-proliferative activity of a2.Furthermore,we demonstrated that a2 caused ferrous iron accumulation through the autophagy pathway,prevention of which rescued a2 induced ferrous iron elevation and cell growth inhibition.Moreover,a2 exhibited more potent anti-cancer activity than 5-fluorouracil in gastric canc er cell line-derived xenograft mice models.Patient-derived tumor xenograft models from different patients displayed varied sensitivity to a2,and GPX4 downregulation indicated the sensitivity of tumors to a2.Finally,a2 exhibited well pharmacokinetic characteristic s.Overall,our data suggest that inducing ferroptosis is the major mechanism mediating anti-tumor activity of a2,and a2 will hopefully serve as a promising compound for gastric cancer treatment.展开更多
Endophytic fungi are promising producers of bioactive small molecules.Bioinformatic analysis of the genome of an endophytic fungus Penicillium dangeardii revealed 43 biosynthetic gene clusters,exhibited its strong abi...Endophytic fungi are promising producers of bioactive small molecules.Bioinformatic analysis of the genome of an endophytic fungus Penicillium dangeardii revealed 43 biosynthetic gene clusters,exhibited its strong ability to produce numbers of secondary metabolites.However,this strain mainly produce rubratoxins alone with high yield in varied culture conditions,suggested most gene clusters are silent.Efforts for mining the cryptic gene clusters in P.dangeardii,including epigenetic regulation and one-strain-many-compounds(OSMAC)approach were failed probably due to the high yield of rubratoxins.A metabolic shunting strategy by deleting the key gene for rubratoxins biosynthesis combining with optimization of culture condition successfully activated multiple silent genes encoding for other polyketide synthases(PKSs),and led to the trace compounds detectable.As a result,a total of 23 new compounds including azaphilone monomers,dimers,turimers with unprecedented polycyclic bridged heterocycle and spiral structures,as well as siderophores were identified.Some compounds showed significant cytotoxicities,anti-inflammatory or antioxidant activities.The attractive dual PKS s gene clusters for azaphilones biosynthesis were mined by bioinformatic analysis and overexpression of a pathway specific transcription factor.Our work therefor provides an efficient approach to mine the chemical diversity of endophytic fungi.展开更多
The EtOH extracts of the whole plants of Euphorbia helioscopia afforded 17 new jatrophane diterpenoid esters, helioscopianoids A–Q(1–17), along with eight known compounds(18–25). Their structures were elucidated by...The EtOH extracts of the whole plants of Euphorbia helioscopia afforded 17 new jatrophane diterpenoid esters, helioscopianoids A–Q(1–17), along with eight known compounds(18–25). Their structures were elucidated by extensive spectroscopic methods and Mo_2(OAc)_4-induced ECD analysis,and the structures of compounds 1, 2, and 7 were confirmed by X-ray crystallography. Compounds 1–17 were evaluated for inhibitory effects on P-glycoprotein(P-gp) in an adriamycin(ADM)-resistant human breast adenocarcinoma cell line(MCF-7/ADR) and neuroprotective effects against serum deprivationinduced and rotenone-induced PC12 cell damage. Compounds 8 and 16 increased the accumulation of ADM in MCF-7/ADR cells by approximately 3-fold at a concentration of 20 μmol/L. Compound 8 could attenuate rotenone-induced PC12 cell damage, and compounds 2, 8, and 12 showed neuroprotective activities against serum deprivation-induced PC12 cell damage.展开更多
New Delhi metallo-b-lactamase-1(NDM-1)is capable of hydrolyzing nearly allβ-lactam antibiotics,posing an emerging threat to public health.There are currently less effective treatment options for treating NDM-1 positi...New Delhi metallo-b-lactamase-1(NDM-1)is capable of hydrolyzing nearly allβ-lactam antibiotics,posing an emerging threat to public health.There are currently less effective treatment options for treating NDM-1 positive"superbug",and no promising NDM-1 inhibitors were used in clinical practice.In this study,structure eactivity relationship based on thiosemicarbazone derivatives wassystematically characterized and their potential activities combined with meropenem(MEM)were evaluated.Compounds 19 bg and 19 bh exhibited excellent activity against 10 NDM-positive isolate clinical isolates in reversing MEM resistance.Further studies demonstrated compounds 19 bg and 19 bh were uncompetitive NDM-1 inhibitors with Ki Z 0.63 and 0.44 mmol/L,respectively.Molecular docking speculated that compounds 19 bg and 19 bh were most likely to bind in the allosteric pocket which would affect the catalytic effect of NDM-1 on the substrate meropenem.Toxicity evaluation experiment showed that no hemolysis activities even at concentrations of 1000 mg/m L against red blood cells.In vivo experimental results showed combination of MEM and compound 19 bh was markedly effective in treating infections caused by NDM-1 positive strain and prolonging the survival time of sepsis mice.Our finding showed that compound 19 bh might be a promising lead in developing new inhibitor to treat NDM-1 producing superbug.展开更多
Ten serratene-type triterpenoids including two new ones,named 3β-hydroxyserrat-14-en-21β-yl-formate(1)and 21β-hydroxyserrat-14-en-3β-yl-formate(2),were isolated from Lycopodium japonicum Thunb.Their structures wer...Ten serratene-type triterpenoids including two new ones,named 3β-hydroxyserrat-14-en-21β-yl-formate(1)and 21β-hydroxyserrat-14-en-3β-yl-formate(2),were isolated from Lycopodium japonicum Thunb.Their structures were established by means of spectroscopic analysis.Both of these two new compounds are formates of serratene-type triterpenoids.展开更多
One new sesquiterpene lactone, corialactone E （1）, one new neolignan, coriarianeolignan A （2）, together with three known apocarotenoids （3-5） and one known neolignan （6） have been isolated from a CHCI3 extract...One new sesquiterpene lactone, corialactone E （1）, one new neolignan, coriarianeolignan A （2）, together with three known apocarotenoids （3-5） and one known neolignan （6） have been isolated from a CHCI3 extract of the roots of Coriaria nepalensis. The structures including absolute configurations of 1-6 were elucidated through extensive NMR, HR-ESIMS, and CD data analysis. Structurally, compound I possessed novel variations in the structure, including the newly formed ether ring of C-3/O/C-9 and the lactone ring connecting C-13 and C-5. Compound 5 showed cytotoxic activity against SKOV3 （human ovarian cancer） cells with IC50 values of 4.67 μmol/L. In vivo system, compound 3 showed anti-convulsant activity by 34% at the dose of 5 mg/kg.展开更多
基金supported by grants from the National Natural Science Foundation of China (Nos. 81773562, 82020108030, and U1904163)National Key Research and Development Project (No. 2018YFE0195100, China)the Science and Technology Program of Henan Province (No. 202102310152, China)。
文摘Ferroptosis is a type of cell death accompanied by iron-dependent lipid peroxidation,thus stimulating ferroptosis may be a potential strategy for treating gastric cancer,therapeutic agents against which are urgently required.Jiyuan oridonin A(JDA) is a natural compound isolated from Jiyuan Rabdosia rubescens with anti-tumor activity,unclear anti-tumor mechanisms and limited water solubility hamper its clinical application.Here,we showed a2,a new JDA derivative,inhibited the growth of gastric cancer cells.Subsequently,we discovered for the first time that a2 induced ferroptosis.Importantly,compound a2 decreased GPX4 expression and overexpressing GPX4 antagonized the anti-proliferative activity of a2.Furthermore,we demonstrated that a2 caused ferrous iron accumulation through the autophagy pathway,prevention of which rescued a2 induced ferrous iron elevation and cell growth inhibition.Moreover,a2 exhibited more potent anti-cancer activity than 5-fluorouracil in gastric canc er cell line-derived xenograft mice models.Patient-derived tumor xenograft models from different patients displayed varied sensitivity to a2,and GPX4 downregulation indicated the sensitivity of tumors to a2.Finally,a2 exhibited well pharmacokinetic characteristic s.Overall,our data suggest that inducing ferroptosis is the major mechanism mediating anti-tumor activity of a2,and a2 will hopefully serve as a promising compound for gastric cancer treatment.
基金supported financially by the National Key Research and Development Program of China(2018YFA0901900)the CAMS Innovation Fund for Medical Sciences(CIFMS,2016-I2M-1-010,2017-I2M-4-004)+1 种基金Fundamental Research Funds for the Central Universities(2017PT35001)supported by the Drug Innovation Major Project(2018ZX09711001-008-001)
文摘Endophytic fungi are promising producers of bioactive small molecules.Bioinformatic analysis of the genome of an endophytic fungus Penicillium dangeardii revealed 43 biosynthetic gene clusters,exhibited its strong ability to produce numbers of secondary metabolites.However,this strain mainly produce rubratoxins alone with high yield in varied culture conditions,suggested most gene clusters are silent.Efforts for mining the cryptic gene clusters in P.dangeardii,including epigenetic regulation and one-strain-many-compounds(OSMAC)approach were failed probably due to the high yield of rubratoxins.A metabolic shunting strategy by deleting the key gene for rubratoxins biosynthesis combining with optimization of culture condition successfully activated multiple silent genes encoding for other polyketide synthases(PKSs),and led to the trace compounds detectable.As a result,a total of 23 new compounds including azaphilone monomers,dimers,turimers with unprecedented polycyclic bridged heterocycle and spiral structures,as well as siderophores were identified.Some compounds showed significant cytotoxicities,anti-inflammatory or antioxidant activities.The attractive dual PKS s gene clusters for azaphilones biosynthesis were mined by bioinformatic analysis and overexpression of a pathway specific transcription factor.Our work therefor provides an efficient approach to mine the chemical diversity of endophytic fungi.
基金supported by Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS,No.2016-I2M-1–010)
文摘The EtOH extracts of the whole plants of Euphorbia helioscopia afforded 17 new jatrophane diterpenoid esters, helioscopianoids A–Q(1–17), along with eight known compounds(18–25). Their structures were elucidated by extensive spectroscopic methods and Mo_2(OAc)_4-induced ECD analysis,and the structures of compounds 1, 2, and 7 were confirmed by X-ray crystallography. Compounds 1–17 were evaluated for inhibitory effects on P-glycoprotein(P-gp) in an adriamycin(ADM)-resistant human breast adenocarcinoma cell line(MCF-7/ADR) and neuroprotective effects against serum deprivationinduced and rotenone-induced PC12 cell damage. Compounds 8 and 16 increased the accumulation of ADM in MCF-7/ADR cells by approximately 3-fold at a concentration of 20 μmol/L. Compound 8 could attenuate rotenone-induced PC12 cell damage, and compounds 2, 8, and 12 showed neuroprotective activities against serum deprivation-induced PC12 cell damage.
基金supported by National Natural Science Foundation of China(Grant Nos.81903447 for Bing Zhao,81903623 for Yongfang Yao,81703328 for Liying Ma,and 81430085 for Hongmin Liu)National Key Research and Development Project of China(Nos.2016YFA0501800 and 2018YFE0195100 for Hongmin Liu)
文摘New Delhi metallo-b-lactamase-1(NDM-1)is capable of hydrolyzing nearly allβ-lactam antibiotics,posing an emerging threat to public health.There are currently less effective treatment options for treating NDM-1 positive"superbug",and no promising NDM-1 inhibitors were used in clinical practice.In this study,structure eactivity relationship based on thiosemicarbazone derivatives wassystematically characterized and their potential activities combined with meropenem(MEM)were evaluated.Compounds 19 bg and 19 bh exhibited excellent activity against 10 NDM-positive isolate clinical isolates in reversing MEM resistance.Further studies demonstrated compounds 19 bg and 19 bh were uncompetitive NDM-1 inhibitors with Ki Z 0.63 and 0.44 mmol/L,respectively.Molecular docking speculated that compounds 19 bg and 19 bh were most likely to bind in the allosteric pocket which would affect the catalytic effect of NDM-1 on the substrate meropenem.Toxicity evaluation experiment showed that no hemolysis activities even at concentrations of 1000 mg/m L against red blood cells.In vivo experimental results showed combination of MEM and compound 19 bh was markedly effective in treating infections caused by NDM-1 positive strain and prolonging the survival time of sepsis mice.Our finding showed that compound 19 bh might be a promising lead in developing new inhibitor to treat NDM-1 producing superbug.
基金This work was supported by grants from the Natural Science Foundation of China(No.21132009)the National Science and Technology Project of China(No.2012ZX09301002-002)PCSIRT(No.IRT1007).
文摘Ten serratene-type triterpenoids including two new ones,named 3β-hydroxyserrat-14-en-21β-yl-formate(1)and 21β-hydroxyserrat-14-en-3β-yl-formate(2),were isolated from Lycopodium japonicum Thunb.Their structures were established by means of spectroscopic analysis.Both of these two new compounds are formates of serratene-type triterpenoids.
基金Financial support from the National Natural Science Foundation of China(No.21132009)the National Science and Technology Project of China(No.2012ZX09301002-002)
文摘One new sesquiterpene lactone, corialactone E （1）, one new neolignan, coriarianeolignan A （2）, together with three known apocarotenoids （3-5） and one known neolignan （6） have been isolated from a CHCI3 extract of the roots of Coriaria nepalensis. The structures including absolute configurations of 1-6 were elucidated through extensive NMR, HR-ESIMS, and CD data analysis. Structurally, compound I possessed novel variations in the structure, including the newly formed ether ring of C-3/O/C-9 and the lactone ring connecting C-13 and C-5. Compound 5 showed cytotoxic activity against SKOV3 （human ovarian cancer） cells with IC50 values of 4.67 μmol/L. In vivo system, compound 3 showed anti-convulsant activity by 34% at the dose of 5 mg/kg.
