The clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)is widely used for targeted genomic and epigenomic modifications and imaging in cells and organisms,and holds trem...The clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)is widely used for targeted genomic and epigenomic modifications and imaging in cells and organisms,and holds tremendous promise in clinical applications.The efficiency and accuracy of the technology are partly determined by the target binding affinity and residence time of Cas9-single-guide RNA(sgRNA)at a given site.However,little attention has been paid to the effect of target binding affinity and residence duration on the repair of Cas9-induced DNA double-strand breaks(DSBs).We propose that the choice of DSB repair pathway may be altered by variation in the binding affinity and residence duration of Cas9-sgRNA at the cleaved target,contributing to significantly heterogeneous mutations in CRISPR/Cas9 genome editing.Here,we discuss the effect of Cas9-sgRNA target binding and residence on the choice of DSB repair pathway in CRISPR/Cas9 genome editing,and the opportunity this presents to optimize Cas9-based technology.展开更多
There are numerous evaluations of natural products,of which majority are food bioactives,performed up to date for their various health beneficial activities via targeting specific proteins.However,the direct identific...There are numerous evaluations of natural products,of which majority are food bioactives,performed up to date for their various health beneficial activities via targeting specific proteins.However,the direct identification of a targeted protein remains unexplored for natural occurring compounds.Proteolysis targeting chimera(PROTAC)is a type of bifunctional chimeric molecules that can directly degrade the binding proteins targeted by bioactive molecules in an ubiquitin-proteasome pathway.As the agents in protein degradation dependent on ubiquitin ligase,the bifunctional molecule connects the target protein ligand and E3 ligase ligand together via an appropriate linker.It is highly selective and efficient to induce the ubiquitin-mediated degradation of targeted binding proteins.Therefore,it has been demonstrated that the PROTAC technology has broad application in the modulation of the target protein level.In this review,we outlined the advances in PROTAC combined molecule compounds,summarized its quantitative structure-activity relationship,and finally reviewed the methods applied in identifying the target proteins of natural products.We hope it will provide an insightful application of PROTAC techniques in the target protein identification of natural products including food bioactive molecules.展开更多
In the 1920s,Dr Otto Warburg first suggested the significant difference in energy metabolism between malignant cancer cells and adjacent normal cells.Tumor cells mainly adopt the glycolysis as energy source to maintai...In the 1920s,Dr Otto Warburg first suggested the significant difference in energy metabolism between malignant cancer cells and adjacent normal cells.Tumor cells mainly adopt the glycolysis as energy source to maintain tumor cell growth and biosynthesis under aerobic conditions.Investigation on energy metabolism pathway in cancer cells has aroused the interest of cancer researchers all around the world.In recent years,plentiful studics suggest that targeting the peculiar cancer energy metabolic pathways,including glycolysis,mitochondrial respiration,amino acid metabolism,and fatty acid oxidation may be an effective strategy to starve cancer cells by blocking essential nutrients.Natural products (NPs)are considered as the “treasure trove of small molecules drugs” and have played an extremely remarkable role in the discovery and development of anticancer drugs.And numerous NPs have been reported to act on cancer energy metabolism targets.Herein,a comprehensive overview about cancer energy metabolism targets and their natural-occurring inhibitors is prepared.展开更多
Follicle stimulating hormone (FSH) is a kind of glycoprotein gonadotropin, and plays an important role in the diagnosis and treatment of infertility. Follicle stimulating hormone receptor (FSHR) is a kind of G protein...Follicle stimulating hormone (FSH) is a kind of glycoprotein gonadotropin, and plays an important role in the diagnosis and treatment of infertility. Follicle stimulating hormone receptor (FSHR) is a kind of G protein coupled receptor (GPCR), found in the ovary and testes, and its activation is required for the hormonal operation during the breeding period. In this study, an experimental model of FSHR mediated FSH into cell membrane, which exhibited a phenomenon of fluorescent localized on cell surfaces internalized into cell interior, was established to verify biological activity of FSH.展开更多
The epidermal growth factor receptor (EGFR) has become an important target protein in anticancer drug development. Meanwhile, peptide-Au cluster has been proposed as potential targeted nano-drug assembled by targeti...The epidermal growth factor receptor (EGFR) has become an important target protein in anticancer drug development. Meanwhile, peptide-Au cluster has been proposed as potential targeted nano-drug assembled by targeting peptide. Here, we designed and synthesized a novel peptide-Au cluster as AuloPeptides to target to EGFR. We found AumPeptides could target to the natural binding sites of all EGFRs at mem- brane in both active and inactive states by molecular simulations. Its targeted ability was further verified by the co-localization and blocking experiments. We also study the configuration modifications of both active and inactive EGFRs after binding by AumPeptides. For active EGFR, the absorbed AuloPeptide5 might replace the natural ligand in EGFR endocytosis process. Then, the peptide-Au cluster in endochylema could inhibit the cancer relating enzyme activity including thioredoxin reductasel (TrxR1) and induce the oxidative stress mediated apoptosis in tumor cells. For inactive EGFR, it was retained in inactive state by Au10 Peptides binding to inhibit dimerization of EGFR for anticancer. Both pathways might be applied in anticancer drug development based on the theoretical and experimental study here.展开更多
基金supported by the National Natural Science Foundation of China(Nos.31671385 and 31870806)the Zhejiang Provincial Natural Science Foundation of China(Nos.LY18C050001 and LQ20C050004)the Fundamental Research Funds for the Central Universities in China(No.2019QNA7031)。
文摘The clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)is widely used for targeted genomic and epigenomic modifications and imaging in cells and organisms,and holds tremendous promise in clinical applications.The efficiency and accuracy of the technology are partly determined by the target binding affinity and residence time of Cas9-single-guide RNA(sgRNA)at a given site.However,little attention has been paid to the effect of target binding affinity and residence duration on the repair of Cas9-induced DNA double-strand breaks(DSBs).We propose that the choice of DSB repair pathway may be altered by variation in the binding affinity and residence duration of Cas9-sgRNA at the cleaved target,contributing to significantly heterogeneous mutations in CRISPR/Cas9 genome editing.Here,we discuss the effect of Cas9-sgRNA target binding and residence on the choice of DSB repair pathway in CRISPR/Cas9 genome editing,and the opportunity this presents to optimize Cas9-based technology.
基金supported by the key scientific research projects of Hunan Provincial Department of Education of China(No.19A513)the National Nonprofit Institute Research Grant of CAFINT,China(No.CAFYBB2018GA001)Grant from Hubei Province,China(GRANT number 2019ABA100)。
文摘There are numerous evaluations of natural products,of which majority are food bioactives,performed up to date for their various health beneficial activities via targeting specific proteins.However,the direct identification of a targeted protein remains unexplored for natural occurring compounds.Proteolysis targeting chimera(PROTAC)is a type of bifunctional chimeric molecules that can directly degrade the binding proteins targeted by bioactive molecules in an ubiquitin-proteasome pathway.As the agents in protein degradation dependent on ubiquitin ligase,the bifunctional molecule connects the target protein ligand and E3 ligase ligand together via an appropriate linker.It is highly selective and efficient to induce the ubiquitin-mediated degradation of targeted binding proteins.Therefore,it has been demonstrated that the PROTAC technology has broad application in the modulation of the target protein level.In this review,we outlined the advances in PROTAC combined molecule compounds,summarized its quantitative structure-activity relationship,and finally reviewed the methods applied in identifying the target proteins of natural products.We hope it will provide an insightful application of PROTAC techniques in the target protein identification of natural products including food bioactive molecules.
基金This work was financially supported by grants from the National Natural Science Foundation of China(No.81773594,U1703111,81473254 and 81773637,31270399)Liaoning Revitalization Talents Program(No.XLYC1807182)+2 种基金Program for Liaoning Innovation Talents in University(No.LR2016002)Liaoning Province Natural Science Foundation(No.2019-MS-299)Shenyang Planning Project of Science and Technology(No.18-013-0-46).
文摘In the 1920s,Dr Otto Warburg first suggested the significant difference in energy metabolism between malignant cancer cells and adjacent normal cells.Tumor cells mainly adopt the glycolysis as energy source to maintain tumor cell growth and biosynthesis under aerobic conditions.Investigation on energy metabolism pathway in cancer cells has aroused the interest of cancer researchers all around the world.In recent years,plentiful studics suggest that targeting the peculiar cancer energy metabolic pathways,including glycolysis,mitochondrial respiration,amino acid metabolism,and fatty acid oxidation may be an effective strategy to starve cancer cells by blocking essential nutrients.Natural products (NPs)are considered as the “treasure trove of small molecules drugs” and have played an extremely remarkable role in the discovery and development of anticancer drugs.And numerous NPs have been reported to act on cancer energy metabolism targets.Herein,a comprehensive overview about cancer energy metabolism targets and their natural-occurring inhibitors is prepared.
文摘Follicle stimulating hormone (FSH) is a kind of glycoprotein gonadotropin, and plays an important role in the diagnosis and treatment of infertility. Follicle stimulating hormone receptor (FSHR) is a kind of G protein coupled receptor (GPCR), found in the ovary and testes, and its activation is required for the hormonal operation during the breeding period. In this study, an experimental model of FSHR mediated FSH into cell membrane, which exhibited a phenomenon of fluorescent localized on cell surfaces internalized into cell interior, was established to verify biological activity of FSH.
基金supported by the National Natural Science Foundation of China(31571026,11404333)the Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund(the second phase)under Grant No.U1501501
文摘The epidermal growth factor receptor (EGFR) has become an important target protein in anticancer drug development. Meanwhile, peptide-Au cluster has been proposed as potential targeted nano-drug assembled by targeting peptide. Here, we designed and synthesized a novel peptide-Au cluster as AuloPeptides to target to EGFR. We found AumPeptides could target to the natural binding sites of all EGFRs at mem- brane in both active and inactive states by molecular simulations. Its targeted ability was further verified by the co-localization and blocking experiments. We also study the configuration modifications of both active and inactive EGFRs after binding by AumPeptides. For active EGFR, the absorbed AuloPeptide5 might replace the natural ligand in EGFR endocytosis process. Then, the peptide-Au cluster in endochylema could inhibit the cancer relating enzyme activity including thioredoxin reductasel (TrxR1) and induce the oxidative stress mediated apoptosis in tumor cells. For inactive EGFR, it was retained in inactive state by Au10 Peptides binding to inhibit dimerization of EGFR for anticancer. Both pathways might be applied in anticancer drug development based on the theoretical and experimental study here.