Ferroptosis of chondrocytes is a significant contributor to osteoarthritis(OA),for which there is still a lack of safe and effective therapeutic drugs targeting ferroptosis.Here,we screen for anti-ferroptotic drugs in...Ferroptosis of chondrocytes is a significant contributor to osteoarthritis(OA),for which there is still a lack of safe and effective therapeutic drugs targeting ferroptosis.Here,we screen for anti-ferroptotic drugs in Food and Drug Administration(FDA)-approved drug library via a high-throughput manner in chondrocytes.We identified a group of FDA-approved anti-ferroptotic drugs,among which vitamin K showed the most powerful protective effect.Further study demonstrated that vitamin K effectively inhibited ferroptosis and alleviated the extracellular matrix(ECM)degradation in chondrocytes.Intra-articular injection of vitamin K inhibited ferroptosis and alleviated OA phenotype in destabilization of the medial meniscus(DMM)mouse model.Mechanistically,transcriptome sequencing and knockdown experiments revealed that the anti-ferroptotic effects of vitamin K depended on growth arrest-specific 6(Gas6).Furthermore,exogenous expression of Gas6 was found to inhibit ferroptosis through the AXL receptor tyrosine kinase(AXL)/phosphatidylinositol 3-kinase(PI3K)/AKT serine/threonine kinase(AKT)axis.Together,we demonstrate that vitamin K inhibits ferroptosis and alleviates OA progression via enhancing Gas6 expression and its downstream pathway of AXL/PI3K/AKT axis,indicating vitamin K as well as Gas6 to serve as a potential therapeutic target for OA and other ferroptosis-related diseases.展开更多
Methylene blue(MB)is an FDA(Food and Drug Administration)-approved contrast agent with donor−acceptor(D−A)structure integrated with carbonyl-containing nitrogen-heterocycles.MB can be converted into MBH(protonated MB)...Methylene blue(MB)is an FDA(Food and Drug Administration)-approved contrast agent with donor−acceptor(D−A)structure integrated with carbonyl-containing nitrogen-heterocycles.MB can be converted into MBH(protonated MB)by protonation,which not only induces the fluorescence emission redshifted from the first near-infrared window(NIR-I,650−950 nm)to the second near-infrared window(NIR-II,1000−1700 nm)but also achieves ACQ-to-AIE conversion.MB has been successfully demonstrated in hyperacidemia imaging with an extremely low pH value(<1).展开更多
基金supported by grants from the Wenzhou Science and Technology Bureau Foundation,China(Grant No.:ZY2019014)“Pioneer”and“Leading Goose”R&D Program of Zhejiang,China(Grant No.:2022C03144)National Natural Science Foundation of China(Grant Nos.:82172494,and 82372461).
文摘Ferroptosis of chondrocytes is a significant contributor to osteoarthritis(OA),for which there is still a lack of safe and effective therapeutic drugs targeting ferroptosis.Here,we screen for anti-ferroptotic drugs in Food and Drug Administration(FDA)-approved drug library via a high-throughput manner in chondrocytes.We identified a group of FDA-approved anti-ferroptotic drugs,among which vitamin K showed the most powerful protective effect.Further study demonstrated that vitamin K effectively inhibited ferroptosis and alleviated the extracellular matrix(ECM)degradation in chondrocytes.Intra-articular injection of vitamin K inhibited ferroptosis and alleviated OA phenotype in destabilization of the medial meniscus(DMM)mouse model.Mechanistically,transcriptome sequencing and knockdown experiments revealed that the anti-ferroptotic effects of vitamin K depended on growth arrest-specific 6(Gas6).Furthermore,exogenous expression of Gas6 was found to inhibit ferroptosis through the AXL receptor tyrosine kinase(AXL)/phosphatidylinositol 3-kinase(PI3K)/AKT serine/threonine kinase(AKT)axis.Together,we demonstrate that vitamin K inhibits ferroptosis and alleviates OA progression via enhancing Gas6 expression and its downstream pathway of AXL/PI3K/AKT axis,indicating vitamin K as well as Gas6 to serve as a potential therapeutic target for OA and other ferroptosis-related diseases.
基金supported by National Key R&D Programs(China)(2021YFA0910001,2023YFA0915400)Guangdong Provincial Key Area R&D Program(2020B111-1540001)+7 种基金Shenzhen Basic Research(key project)(China)(JCYJ20210324120011030,JCYJ20210324115804013,and JCYJ20200109114616534)the Shenzhen Science and Technology Program(KQTD20210811090115019)the Major Instrumentation Development Program of the Chinese Academy of Sciences(Project Number:ZDKYYQ20220008)Shenzhen-Macao Technology Plan(SGDX202011030928-0301)Technological Cooperation Projects(China)(2020-A0505100047)Guangdong Basic and Applied Basic Research Fund Project(China)(2021A1515110699)Zhuhai Innovation and Entrepreneurship Team Project(ZH011104-05180056PWC)All animal experiments were performed under the protocols approved by the Animal Care and Use Committee(Shenzhen Institutes of Advanced Technology,Chinese Academy of Sciences)(Serial number:SIAT-IACUC-210701-YYS-GP-A1974).
文摘Methylene blue(MB)is an FDA(Food and Drug Administration)-approved contrast agent with donor−acceptor(D−A)structure integrated with carbonyl-containing nitrogen-heterocycles.MB can be converted into MBH(protonated MB)by protonation,which not only induces the fluorescence emission redshifted from the first near-infrared window(NIR-I,650−950 nm)to the second near-infrared window(NIR-II,1000−1700 nm)but also achieves ACQ-to-AIE conversion.MB has been successfully demonstrated in hyperacidemia imaging with an extremely low pH value(<1).
