The interaction of oxidized FAD radical with dGMP, dAMP and single-stranded DNA (ssDNA) was investigated in neutral aqueous solution using time-resolved 248 nm laser flash photolysis aimed at elucidation of the initia...The interaction of oxidized FAD radical with dGMP, dAMP and single-stranded DNA (ssDNA) was investigated in neutral aqueous solution using time-resolved 248 nm laser flash photolysis aimed at elucidation of the initial photosensitization mechanism. The characterized absorption spectra of transient species were observed. Moreover, direct observation of stabilized DNA guanyl radical has provided transient evidence for site-selective photosensitized damage of DNA at guanine moiety, which has simulated the major initial species produced by the direct effect of ionizing radiation or UV light on DNA.展开更多
Mitochondrial redox states provide important information about energy-linked biological processes and signaling events in tissues for various disease phenotypes including cancer.The redox scanning method developed at ...Mitochondrial redox states provide important information about energy-linked biological processes and signaling events in tissues for various disease phenotypes including cancer.The redox scanning method developed at the Chance laboratory about 30 years ago has allowed 3D highresolution(∼50×50×10µm^(3))imaging of mitochondrial redox state in tissue on the basis of the fluorescence of NADH(reduced nicotinamide adenine dinucleotide)and Fp(oxidized flavoproteins including flavin adenine dinucleotide,i.e.,FAD).In this review,we illustrate its basic principles,recent technical developments,and biomedical applications to cancer diagnostic and therapeutic studies in small animal models.Recently developed calibration procedures for the redox imaging using reference standards allow quantification of nominal NADH and Fp concentrations,and the concentration-based redox ratios,e.g.,Fp/(Fp+NADH)and NADH/(Fp+NADH)in tissues.This calibration facilitates the comparison of redox imaging results acquired for different metabolic states at different times and/or with different instrumental settings.A redox imager using a CCD detector has been developed to acquire 3D images faster and with a higher in-plane resolution down to 10µm.Ex vivo imaging and in vivo imaging of tissue mitochondrial redox status have been demonstrated with the CCD imager.Applications of tissue redox imaging in small animal cancer models include metabolic imaging of glioma and myc-induced mouse mammary tumors,predicting the metastatic potentials of human melanoma and breast cancer mouse xenografts,differentiating precancerous and normal tissues,and monitoring the tumor treatment response to photodynamic therapy.Possible future directions for the development of redox imaging are also discussed.展开更多
Histone lysine specific demethylase 1(LSD1)has become a potential therapeutic target for the treatment of cancer.Discovery and develop novel and potent LSD1 inhibitors is a challenge,although several of them have alre...Histone lysine specific demethylase 1(LSD1)has become a potential therapeutic target for the treatment of cancer.Discovery and develop novel and potent LSD1 inhibitors is a challenge,although several of them have already entered into clinical trials.Herein,for the first time,we reported the discovery of a series of 5-cyano-6-phenylpyrimidine derivatives as LSD1 inhibitors using flavin adenine dinucleotide(FAD)similarity-based designing strategy,of which compound 14 q was finally identified to repress LSD1 with IC50=183 nmol/L.Docking analysis suggested that compound 14 q fitted well into the FAD-binding pocket.Further mechanism studies showed that compound 14 q may inhibit LSD1 activity competitively by occupying the FAD binding sites of LSD1 and inhibit cell migration and invasion by reversing epithelial to mesenchymal transition(EMT).Overall,these findings showed that compound14 q is a suitable candidate for further development of novel FAD similarity-based LSD1 inhibitors.展开更多
Choline dehydrogenase contains the prosthetic group FAD, non-haem iron and acid labile sulfur. However, the absorption spectra of the purified enzyme do not change after adding substrate. The reduced absorption spectr...Choline dehydrogenase contains the prosthetic group FAD, non-haem iron and acid labile sulfur. However, the absorption spectra of the purified enzyme do not change after adding substrate. The reduced absorption spectra of choline dehydrogenase can only be determined after the addition of dithionite. Those choline dehydrogenases situated in the mitochondrial inner membrane can be reduced by substrate and exist in the reduced state. When cholate was used to solubilize the substrate-reduced choline dehydrogenase, the reduced spectra will gradually disappear. However, if solubilization is carried out under anaerobic conditions, the reduced spectra can be retained, suggesting that the solubilized choline dehydrogenase can use oxygen as an acceptor.展开更多
文摘The interaction of oxidized FAD radical with dGMP, dAMP and single-stranded DNA (ssDNA) was investigated in neutral aqueous solution using time-resolved 248 nm laser flash photolysis aimed at elucidation of the initial photosensitization mechanism. The characterized absorption spectra of transient species were observed. Moreover, direct observation of stabilized DNA guanyl radical has provided transient evidence for site-selective photosensitized damage of DNA at guanine moiety, which has simulated the major initial species produced by the direct effect of ionizing radiation or UV light on DNA.
基金the Susan G.Komen Foundation Grant KG081069(PI:L.Z.Li)The Center for Magnietic Resonance and Optical Imaging,and an NIH supported research resource(P41-RR02305,PI:R.Reddy).
文摘Mitochondrial redox states provide important information about energy-linked biological processes and signaling events in tissues for various disease phenotypes including cancer.The redox scanning method developed at the Chance laboratory about 30 years ago has allowed 3D highresolution(∼50×50×10µm^(3))imaging of mitochondrial redox state in tissue on the basis of the fluorescence of NADH(reduced nicotinamide adenine dinucleotide)and Fp(oxidized flavoproteins including flavin adenine dinucleotide,i.e.,FAD).In this review,we illustrate its basic principles,recent technical developments,and biomedical applications to cancer diagnostic and therapeutic studies in small animal models.Recently developed calibration procedures for the redox imaging using reference standards allow quantification of nominal NADH and Fp concentrations,and the concentration-based redox ratios,e.g.,Fp/(Fp+NADH)and NADH/(Fp+NADH)in tissues.This calibration facilitates the comparison of redox imaging results acquired for different metabolic states at different times and/or with different instrumental settings.A redox imager using a CCD detector has been developed to acquire 3D images faster and with a higher in-plane resolution down to 10µm.Ex vivo imaging and in vivo imaging of tissue mitochondrial redox status have been demonstrated with the CCD imager.Applications of tissue redox imaging in small animal cancer models include metabolic imaging of glioma and myc-induced mouse mammary tumors,predicting the metastatic potentials of human melanoma and breast cancer mouse xenografts,differentiating precancerous and normal tissues,and monitoring the tumor treatment response to photodynamic therapy.Possible future directions for the development of redox imaging are also discussed.
基金supported by National Natural Science Foundation of China(Project Nos.81430085 and 81773562 for Hongmin Liu,No.81602961 for Yichao Zheng and No.81703328 for Liying Ma)National Key Research Program(Nos.2018YFE0195100 and 2016YFA0501800 for Hongmin Liu,China)+1 种基金Science and Technology Innovation Talents of Henan Provincial Education Department(19IRTSTHN001,China)Scientific Program of Henan Province(No.182102310070,for Liying Ma,China)
文摘Histone lysine specific demethylase 1(LSD1)has become a potential therapeutic target for the treatment of cancer.Discovery and develop novel and potent LSD1 inhibitors is a challenge,although several of them have already entered into clinical trials.Herein,for the first time,we reported the discovery of a series of 5-cyano-6-phenylpyrimidine derivatives as LSD1 inhibitors using flavin adenine dinucleotide(FAD)similarity-based designing strategy,of which compound 14 q was finally identified to repress LSD1 with IC50=183 nmol/L.Docking analysis suggested that compound 14 q fitted well into the FAD-binding pocket.Further mechanism studies showed that compound 14 q may inhibit LSD1 activity competitively by occupying the FAD binding sites of LSD1 and inhibit cell migration and invasion by reversing epithelial to mesenchymal transition(EMT).Overall,these findings showed that compound14 q is a suitable candidate for further development of novel FAD similarity-based LSD1 inhibitors.
基金Project supported by the National Natural Science Foundation of China.
文摘Choline dehydrogenase contains the prosthetic group FAD, non-haem iron and acid labile sulfur. However, the absorption spectra of the purified enzyme do not change after adding substrate. The reduced absorption spectra of choline dehydrogenase can only be determined after the addition of dithionite. Those choline dehydrogenases situated in the mitochondrial inner membrane can be reduced by substrate and exist in the reduced state. When cholate was used to solubilize the substrate-reduced choline dehydrogenase, the reduced spectra will gradually disappear. However, if solubilization is carried out under anaerobic conditions, the reduced spectra can be retained, suggesting that the solubilized choline dehydrogenase can use oxygen as an acceptor.
