Protein S-sulfenylation(protein sulfenic acid),as one of the most significant oxidative post-translational modifications(OxiPTMs),plays a vital role in regulating protein function.A variety of activity-based probes ha...Protein S-sulfenylation(protein sulfenic acid),as one of the most significant oxidative post-translational modifications(OxiPTMs),plays a vital role in regulating protein function.A variety of activity-based probes have been developed to profile sulfenic acid in living cells.However,due to the transient presence and low content of sulfenic acid in living cell,high doses of probes are needed to achieve efficient labeling.More importantly,current probes have no temporal control over sulfenic acid labeling.To overcome these limitations,two caged cysteine sulfenic acid probes DYn-2-ONB and DYn-2-Cou with either an o-nitrobenzyl or coumarin protecting group were developed in this study.Both probes can be efficiently uncaged via irradiation to produce the active C-nucleophile probe DYn-2.Labeling assay in living cells demonstrated DYn-2-ONB exhibited better labeling capacity compared with DYn-2,providing it as a powerful tool for improved monitoring of protein S-sulfenylation in living cells.展开更多
Unprecedented cycloaddition reactions of azatrienes (1) with sulfene leading to the synthesis of functionalized thiazinedioxide derivatives (5) are described. The reactions were found be highly regioselective resultin...Unprecedented cycloaddition reactions of azatrienes (1) with sulfene leading to the synthesis of functionalized thiazinedioxide derivatives (5) are described. The reactions were found be highly regioselective resulting in the formation of only [4 + 2] cycloadducts.展开更多
Tumor-targeted radiopharmaceuticals have become an attractive modality for tumor diagnosis and treatment in clinics.However;their wide clinical applications are seriously impeded by poor tumor targeting;rapid systemic...Tumor-targeted radiopharmaceuticals have become an attractive modality for tumor diagnosis and treatment in clinics.However;their wide clinical applications are seriously impeded by poor tumor targeting;rapid systemic clearance;and short tumor retention.Therefore;developing advanced radiopharmaceuticals with great tumor specificity and prolonged retention time is highly desirable for efficient tumor treatment.Herein;we report a tumor-targeted covalently anchoring strategy that selectively crosslinks the radiopharmaceuticals to intratumoral macromolecules for prolonged tumor theranostics.A covalent multi-targeted radiopharmaceutical(CMTR)d-IR-2(^(125)IRGD)that includes a sulfenic acid-reactive 1,3-cyclohexanedione group was developed.We demonstrated this probe could specifically accumulate at the tumor site and bind to the sulfenated proteins that are overexpressed within tumors;which greatly prevents the efflux of probes in tumor tissues while having faster clearance in healthy tissues resulting in 12 h longer tumor retention than conventional probes for sensitive NIR and SPECT/CT detection of tumors in vivo.More notably;the ^(131)I-labeled probe could significantly suppress the growth of lung tumor A549.We thus envision that this work may offer a promising approach to developing effective radiopharmaceuticals for precise diagnosis and treatment of various tumors.展开更多
Oxidative stress plays a crucial role in organ aging and related diseases, yet the endogenous regulators involved remain largelyunknown. This work highlights the importance of metabolic homeostasis in protecting again...Oxidative stress plays a crucial role in organ aging and related diseases, yet the endogenous regulators involved remain largelyunknown. This work highlights the importance of metabolic homeostasis in protecting against oxidative stress in the large intestine.By developing a low-input and user-friendly pipeline for the simultaneous profiling of five distinct cysteine (Cys) states, includingfree SH, total Cys oxidation (Sto), sulfenic acid (SOH), S-nitrosylation (SNO), and S-glutathionylation (SSG), we shed light on Cysredox modification stoichiometries and signaling with regional resolution in the aging gut of monkeys. Notably, the proteinsmodified by SOH and SSG were associated primarily with cell adhesion. In contrast, SNO-modified proteins were involved inimmunity. Interestingly, we observed that the Sto levels ranged from 0.97% to 99.88%, exhibiting two distinct peaks and increasingwith age. Crosstalk analysis revealed numerous age-related metabolites potentially involved in modulating oxidative stress and Cysmodifications. Notably, we elucidated the role of fumarate in alleviating intestinal oxidative stress in a dextran sulfate sodium (DSS)-induced colitis mouse model. Our findings showed that fumarate treatment promotes the recovery of several cell types, signalingpathways, and genes involved in oxidative stress regulation. Calorie restriction (CR) is a known strategy for alleviating oxidativestress. Two-month CR intervention led to the recovery of many antioxidative metabolites and reshaped the Cys redoxome. Thiswork decodes the complexities of redoxomics during the gut aging of non-human primates and identifies key metabolic regulatorsof oxidative stress and redox signaling.展开更多
基金supported by the National Natural Science Foundation of China(Nos.31871365 and 22177029)Fundamental Research Funds for the Central Universities.
文摘Protein S-sulfenylation(protein sulfenic acid),as one of the most significant oxidative post-translational modifications(OxiPTMs),plays a vital role in regulating protein function.A variety of activity-based probes have been developed to profile sulfenic acid in living cells.However,due to the transient presence and low content of sulfenic acid in living cell,high doses of probes are needed to achieve efficient labeling.More importantly,current probes have no temporal control over sulfenic acid labeling.To overcome these limitations,two caged cysteine sulfenic acid probes DYn-2-ONB and DYn-2-Cou with either an o-nitrobenzyl or coumarin protecting group were developed in this study.Both probes can be efficiently uncaged via irradiation to produce the active C-nucleophile probe DYn-2.Labeling assay in living cells demonstrated DYn-2-ONB exhibited better labeling capacity compared with DYn-2,providing it as a powerful tool for improved monitoring of protein S-sulfenylation in living cells.
文摘Unprecedented cycloaddition reactions of azatrienes (1) with sulfene leading to the synthesis of functionalized thiazinedioxide derivatives (5) are described. The reactions were found be highly regioselective resulting in the formation of only [4 + 2] cycloadducts.
基金supported by the National Natural Science Foundation of China(T2325019,22077092)the Basic Research Program of Jiangsu(BK20243030)+3 种基金the Special Project of“Technological Innovation”Project of CNNC Medical Industry Co.Ltd.(ZHYLYB2021001)the Four“Batches”Innovation Project of Invigorating Medical through Science and Technology of Shanxi Province(2022XM19)the Open Project Program of the State Key Laboratory of Radiation Medicine and Protection(GZK12024016,GZK12023050,GZK12024013)a Project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘Tumor-targeted radiopharmaceuticals have become an attractive modality for tumor diagnosis and treatment in clinics.However;their wide clinical applications are seriously impeded by poor tumor targeting;rapid systemic clearance;and short tumor retention.Therefore;developing advanced radiopharmaceuticals with great tumor specificity and prolonged retention time is highly desirable for efficient tumor treatment.Herein;we report a tumor-targeted covalently anchoring strategy that selectively crosslinks the radiopharmaceuticals to intratumoral macromolecules for prolonged tumor theranostics.A covalent multi-targeted radiopharmaceutical(CMTR)d-IR-2(^(125)IRGD)that includes a sulfenic acid-reactive 1,3-cyclohexanedione group was developed.We demonstrated this probe could specifically accumulate at the tumor site and bind to the sulfenated proteins that are overexpressed within tumors;which greatly prevents the efflux of probes in tumor tissues while having faster clearance in healthy tissues resulting in 12 h longer tumor retention than conventional probes for sensitive NIR and SPECT/CT detection of tumors in vivo.More notably;the ^(131)I-labeled probe could significantly suppress the growth of lung tumor A549.We thus envision that this work may offer a promising approach to developing effective radiopharmaceuticals for precise diagnosis and treatment of various tumors.
基金supported by the National Key R&D Program of China(no.2022YFA1303200)the National Natural Science Foundation of China(nos.82073221,32201216,and 31870826)+2 种基金the Science and Technology Project of Sichuan Province(nos.2024YFFK0099,2023NSFSC1525,and 2021YFS0134)the National Clinical Research Center for Geriatrics at West China Hospital(no.Z2024JC002)the West China Hospital 135 project(nos.ZYYC23013 and ZYYC23025).
文摘Oxidative stress plays a crucial role in organ aging and related diseases, yet the endogenous regulators involved remain largelyunknown. This work highlights the importance of metabolic homeostasis in protecting against oxidative stress in the large intestine.By developing a low-input and user-friendly pipeline for the simultaneous profiling of five distinct cysteine (Cys) states, includingfree SH, total Cys oxidation (Sto), sulfenic acid (SOH), S-nitrosylation (SNO), and S-glutathionylation (SSG), we shed light on Cysredox modification stoichiometries and signaling with regional resolution in the aging gut of monkeys. Notably, the proteinsmodified by SOH and SSG were associated primarily with cell adhesion. In contrast, SNO-modified proteins were involved inimmunity. Interestingly, we observed that the Sto levels ranged from 0.97% to 99.88%, exhibiting two distinct peaks and increasingwith age. Crosstalk analysis revealed numerous age-related metabolites potentially involved in modulating oxidative stress and Cysmodifications. Notably, we elucidated the role of fumarate in alleviating intestinal oxidative stress in a dextran sulfate sodium (DSS)-induced colitis mouse model. Our findings showed that fumarate treatment promotes the recovery of several cell types, signalingpathways, and genes involved in oxidative stress regulation. Calorie restriction (CR) is a known strategy for alleviating oxidativestress. Two-month CR intervention led to the recovery of many antioxidative metabolites and reshaped the Cys redoxome. Thiswork decodes the complexities of redoxomics during the gut aging of non-human primates and identifies key metabolic regulatorsof oxidative stress and redox signaling.
