Accumulated oxidative damage may lead to irreversible retinal pigmented epithelium(RPE)cell death,which is considered to be the primary cause of dry age-related macular degeneration(AMD),leading to blindness in the el...Accumulated oxidative damage may lead to irreversible retinal pigmented epithelium(RPE)cell death,which is considered to be the primary cause of dry age-related macular degeneration(AMD),leading to blindness in the elderly.However,an effective therapy for this disease is lacking.Here,we described a robust high-content screening procedure with a library of 814 protective compounds and found that D609 strongly protected RPE cells from sodium iodate(SI)-induced oxidative cell death and prolonged their healthy survival.D609 effectively attenuated excessive reactive oxygen species(ROS)and prevented severe mitochondrial loss due to oxidative stress in the RPE cells.Surprisingly,the potent antioxidative effects of D609 were not achieved through its own reducibility but were primarily dependent on its ability to increase the expression of metallothionein.The injection of this small water-soluble molecule also showed an explicit protective effect of the RPE layer in an SI-induced AMD mouse model.These findings suggested that D609 could serve as a novel antioxidative protector of RPE cells both in vitro and in vivo and unveiled a novel antioxidative mechanism of D609,which may ultimately have clinical applications for the treatment of AMD.展开更多
Antibiotic resistance in gram-negative pathogens has become one of the most serious global public health threats.The role of the N-acyl homoserine lactone(AHL)-mediated signaling pathway,which is widespread in gram-ne...Antibiotic resistance in gram-negative pathogens has become one of the most serious global public health threats.The role of the N-acyl homoserine lactone(AHL)-mediated signaling pathway,which is widespread in gram-negative bacteria,in the bacterial resistance process should be studied in depth.Here,we report a degrading enzyme of AHLs,MomL,that inhibits the antibiotic resistance of Pseudomonas aeruginosa through a novel mechanism.The MomL-mediated reactivation of kanamycin is highly associated with the relA-mediated starvation stringent response.The degradation of AHLs by MomL results in the inability of LasR to activate relA,which,in turn,stops the activation of downstream rpoS.Further results show that rpoS directly regulates the type VI secretion system H2-T6SS.Under MomL treatment,inactivated RpoS fails to regulate H2-T6SS;therefore,the expression of effector phospholipase A is reduced,and the adaptability of bacteria to antibiotics is weakened.MomL in combination with kanamycin is effective against a wide range of gram-negative pathogenic bacteria.Therefore,this study reports a MomL-antibiotic treatment strategy on antibiotic-resistant bacteria and reveals its mechanism of action.展开更多
基金The National Key Research and Development(R&D)Program of China(2016YFA0101700)National Natural Science Foundation of China(81700805,81622012 and 81870633)+1 种基金Fundamental Research Funds for the Central Universities(17ykjc28)Fundamental Research Funds of the State Key Laboratory of Ophthalmology.Guangdong Innovative and Entrepreneurial Research Team Program(2016ZT06S029).
文摘Accumulated oxidative damage may lead to irreversible retinal pigmented epithelium(RPE)cell death,which is considered to be the primary cause of dry age-related macular degeneration(AMD),leading to blindness in the elderly.However,an effective therapy for this disease is lacking.Here,we described a robust high-content screening procedure with a library of 814 protective compounds and found that D609 strongly protected RPE cells from sodium iodate(SI)-induced oxidative cell death and prolonged their healthy survival.D609 effectively attenuated excessive reactive oxygen species(ROS)and prevented severe mitochondrial loss due to oxidative stress in the RPE cells.Surprisingly,the potent antioxidative effects of D609 were not achieved through its own reducibility but were primarily dependent on its ability to increase the expression of metallothionein.The injection of this small water-soluble molecule also showed an explicit protective effect of the RPE layer in an SI-induced AMD mouse model.These findings suggested that D609 could serve as a novel antioxidative protector of RPE cells both in vitro and in vivo and unveiled a novel antioxidative mechanism of D609,which may ultimately have clinical applications for the treatment of AMD.
基金the National Natural Science Foundation of China(Nos.42176108 and 31870023)the Young Taishan Scholars Program of Shandong Province(No.tsqn202103029)+2 种基金the Marine S&T Fund of Shandong Province for Pilot National Laboratory for Marine Science and Technology(Qingdao)(No.2018SDKJ0406-4)the Fundamental Research Funds for the Central Universities(No.201941009)the open research funds of the State Key Laboratory of Ophthalmology(No.303060202400368).
文摘Antibiotic resistance in gram-negative pathogens has become one of the most serious global public health threats.The role of the N-acyl homoserine lactone(AHL)-mediated signaling pathway,which is widespread in gram-negative bacteria,in the bacterial resistance process should be studied in depth.Here,we report a degrading enzyme of AHLs,MomL,that inhibits the antibiotic resistance of Pseudomonas aeruginosa through a novel mechanism.The MomL-mediated reactivation of kanamycin is highly associated with the relA-mediated starvation stringent response.The degradation of AHLs by MomL results in the inability of LasR to activate relA,which,in turn,stops the activation of downstream rpoS.Further results show that rpoS directly regulates the type VI secretion system H2-T6SS.Under MomL treatment,inactivated RpoS fails to regulate H2-T6SS;therefore,the expression of effector phospholipase A is reduced,and the adaptability of bacteria to antibiotics is weakened.MomL in combination with kanamycin is effective against a wide range of gram-negative pathogenic bacteria.Therefore,this study reports a MomL-antibiotic treatment strategy on antibiotic-resistant bacteria and reveals its mechanism of action.