Syntheses of 3 ketolanosterol, 3 acetolanosterol, 3 oximolanosterol, 3α and 3β aminolanosterol were described The products have been fully characterized on the basis of their chromatographic (TLC R f, GLC R...Syntheses of 3 ketolanosterol, 3 acetolanosterol, 3 oximolanosterol, 3α and 3β aminolanosterol were described The products have been fully characterized on the basis of their chromatographic (TLC R f, GLC RRTc) and spectral (IR, MS, 1 H NMR, 13 C NMR) properties展开更多
Novel tetralin compounds were designed and synthesized on the three-dimensional model of lanosterol 14α-demethylase of Candida albicans. All of the lead compounds exhibited potent antifungal activities, especially co...Novel tetralin compounds were designed and synthesized on the three-dimensional model of lanosterol 14α-demethylase of Candida albicans. All of the lead compounds exhibited potent antifungal activities, especially compounds 16, 20. The mode of the action of the lead compounds was different from that of azoles. The present study affords the possibility to develop novel antifungal agents that specifically interact with the amino acid residues in the active site and avoid the serious toxicity arising from coordination binding with the heme of mammalian P450s.展开更多
Lipid composition represents a significant differentiator across the three domains(eukaryotes,bacteria,and archaea)of cellular life.Eukaryotes possess distinct lipids,such as sterols and sphingolipids,generally,these ...Lipid composition represents a significant differentiator across the three domains(eukaryotes,bacteria,and archaea)of cellular life.Eukaryotes possess distinct lipids,such as sterols and sphingolipids,generally,these are not commonly found in typical bacteria and archaea.Sterols play a pivotal role in eukaryotic cellular functions,lanosterol,a key precursor for animal and fungal steroids,has well established functions in eukaryotes,while its potential functions in bacteria remain largely uninvestigated.In this study,we genetically engineered Escherichia coli(E.coli)to reconstruct the biosynthesis of lanosterol,and successfully developed a novel E.coli strain capable of synthesizing lanosterol,although its specific location,such as whether it is incorporated into the cell mem-brane,remains to be further determined.Comprehensive characterization of the observed phenotypic changes has unveiled that,despite an unaltered growth rate under normal condition,the engineered E.coli strain dis-played notably enhanced tolerance to various stresses.Subsequent analysis has indicated that lanosterol plays a role in preserving membrane integrity,fluidity,hydrophobicity,and ATP production,mirroring the functions of sterols in eukaryotes.This study unveils the unexpected capacity of E.coli to synthesize sterols,not only un-derscores the importance of lanosterol as a precursor for essential cellular lipids but also offers fresh insights into the potential functions of sterols within bacterial systems.展开更多
Background:To evaluate the effect of lanosterol on cataractous lens of cynomolgus monkeys using a subconjunctival drug release system.Methods:Nine elder cynomolgus monkeys were used,consisting of three monkeys without...Background:To evaluate the effect of lanosterol on cataractous lens of cynomolgus monkeys using a subconjunctival drug release system.Methods:Nine elder cynomolgus monkeys were used,consisting of three monkeys without cataract as controls,three monkeys with naturally occurring cortical cataract,and three monkeys with nuclear cataract as intervention groups.Nanoparticulated thermogel with lanosterol and fluorescein was administered by subconjunctival injection in the monkeys with cataract.Fluorescence changes of injected thermogel and cataract progression were observed.Lanosterol concentration in aqueous humor,solubility changes in lens proteins,and oxidative stress levels were analyzed in the lenses of the control and intervention groups.Results:Injected thermogel showed decreased fluorescence during follow up.Lanosterol concentration in aqueous humor increased in the first 2 weeks and then gradually decreased,which was in accordance with the changes in cortical lens clarity.However,lenses with nuclear opacification showed little change.In the cortical region of lenses with cortical cataract,solubility ofα-crystallin was significantly increased after administration of lanosterol,as well as the reduction of oxidative stress.Conclusions:We demonstrated the effect of lanosterol on cataract progression based on in vivo models of primates.Lanosterol showed a short-term and reliable reversal effect on reducing cataract severity in cortical cataract in the early stages,possibly due to the increase in the solubility of lens proteins and changes in the oxidative stress status.Lanosterol administration using subconjunctival drug release system could be a promising nonsurgical approach for future clinical studies of cataract prevention and treatment.展开更多
文摘Syntheses of 3 ketolanosterol, 3 acetolanosterol, 3 oximolanosterol, 3α and 3β aminolanosterol were described The products have been fully characterized on the basis of their chromatographic (TLC R f, GLC RRTc) and spectral (IR, MS, 1 H NMR, 13 C NMR) properties
基金supported by the National Natural Science Foundation of China(No.30572257)
文摘Novel tetralin compounds were designed and synthesized on the three-dimensional model of lanosterol 14α-demethylase of Candida albicans. All of the lead compounds exhibited potent antifungal activities, especially compounds 16, 20. The mode of the action of the lead compounds was different from that of azoles. The present study affords the possibility to develop novel antifungal agents that specifically interact with the amino acid residues in the active site and avoid the serious toxicity arising from coordination binding with the heme of mammalian P450s.
基金financially supported by the National Natural Science Foundation of China(Project No.32422047,32371482,32101175)National Key R&D Program of China(Project No.2021YFC2104400)+1 种基金State Key Laboratory of Microbial Technology Open Projects Fund(Project No.M2021-02)China Postdoctoral Science Foundation(Project No.2022M712075).
文摘Lipid composition represents a significant differentiator across the three domains(eukaryotes,bacteria,and archaea)of cellular life.Eukaryotes possess distinct lipids,such as sterols and sphingolipids,generally,these are not commonly found in typical bacteria and archaea.Sterols play a pivotal role in eukaryotic cellular functions,lanosterol,a key precursor for animal and fungal steroids,has well established functions in eukaryotes,while its potential functions in bacteria remain largely uninvestigated.In this study,we genetically engineered Escherichia coli(E.coli)to reconstruct the biosynthesis of lanosterol,and successfully developed a novel E.coli strain capable of synthesizing lanosterol,although its specific location,such as whether it is incorporated into the cell mem-brane,remains to be further determined.Comprehensive characterization of the observed phenotypic changes has unveiled that,despite an unaltered growth rate under normal condition,the engineered E.coli strain dis-played notably enhanced tolerance to various stresses.Subsequent analysis has indicated that lanosterol plays a role in preserving membrane integrity,fluidity,hydrophobicity,and ATP production,mirroring the functions of sterols in eukaryotes.This study unveils the unexpected capacity of E.coli to synthesize sterols,not only un-derscores the importance of lanosterol as a precursor for essential cellular lipids but also offers fresh insights into the potential functions of sterols within bacterial systems.
基金funded by research grants from the National Natural Science Foundation of China(Grants No.82122017,81870642,81970780,81670835,and 81700819)Science and Technology Innovation Action Plan of Shanghai Science and Technology Commission(Grants No.19441900700 and 21S31904900)Clinical Science and Technology Innovation Project of Shanghai Shenkang Hospital Development Center(Grants No.SHDC12019X08 and SHDC2020CR4078)。
文摘Background:To evaluate the effect of lanosterol on cataractous lens of cynomolgus monkeys using a subconjunctival drug release system.Methods:Nine elder cynomolgus monkeys were used,consisting of three monkeys without cataract as controls,three monkeys with naturally occurring cortical cataract,and three monkeys with nuclear cataract as intervention groups.Nanoparticulated thermogel with lanosterol and fluorescein was administered by subconjunctival injection in the monkeys with cataract.Fluorescence changes of injected thermogel and cataract progression were observed.Lanosterol concentration in aqueous humor,solubility changes in lens proteins,and oxidative stress levels were analyzed in the lenses of the control and intervention groups.Results:Injected thermogel showed decreased fluorescence during follow up.Lanosterol concentration in aqueous humor increased in the first 2 weeks and then gradually decreased,which was in accordance with the changes in cortical lens clarity.However,lenses with nuclear opacification showed little change.In the cortical region of lenses with cortical cataract,solubility ofα-crystallin was significantly increased after administration of lanosterol,as well as the reduction of oxidative stress.Conclusions:We demonstrated the effect of lanosterol on cataract progression based on in vivo models of primates.Lanosterol showed a short-term and reliable reversal effect on reducing cataract severity in cortical cataract in the early stages,possibly due to the increase in the solubility of lens proteins and changes in the oxidative stress status.Lanosterol administration using subconjunctival drug release system could be a promising nonsurgical approach for future clinical studies of cataract prevention and treatment.
