FREE RADICAL BIOLOGY AND MEDICINE
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2024
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IF 7.1
Ya-Long Zheng,Yuan Ji,Yan Li,Shuai Yan,Xiao-Rong Ren,Wei Tang,Fang Dai,Bo Zhou
The development of Cu(II) ionophores for targeted disruption of aberrant redox homeostasis in cancer cells has been considered an appealing strategy in the field of anticancer research. This study presents the first identification of tanshinone I ( Ts1 ), a natural o -quinone, as a Cu(II) ionophore. Structure-activity relationship studies on tanshinones and mechanistic investigations reveal that the presence of Cu(II) effectively promotes the tautomerization of Ts1 from its diketo to keto-enol forms, thereby facilitating its sequential proton-loss Cu(II) chelation, and enabling it to function as a Cu(II) ionophore due to its structural features including the presence of an o -quinone moiety, a benzyl hydrogen, and a large conjugated system. The unique property allows Ts1 to preferentially induce copper accumulation in human hepatoma HepG2 cells over human umbilical vein endothelial cells, by releasing copper driven by reduced glutathione (GSH). This copper accumulation leads to a reduction in the GSH-to-oxidized glutathione ratio and the generation of reactive oxygen species, ultimately triggering apoptosis of HepG2 cells. The findings not only provide support for o -quinones as innovative types of anticancer Cu(II) ionophores, but also shed light on the previously unrecognized role of Ts1 as a potent Cu(II) ionophore for eradicating cancer cells by selectively disrupting their redox regulation programs, resembling a "Trojan horse".
研究领域:
肿瘤学
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药理学
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化学生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
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2022
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IF 3.973
Mingyu Zhang,Yaodong Hu,Wei Li,Chen Sun,Chunjing Guan,Ying Peng,Jiang Zheng
2,6-Dimethylphenol (2,6-DMP) is an environmental pollutant found in industrial wastewater. Exposure to 2,6-DMP is of increasing concern as it endangered reportedly some aquatic animals. In this study, we investigated the metabolic activation and hepatotoxicity of 2,6-DMP. 2,6-DMP was metabolized to an o-quinone methide intermediate in vitro and in vivo. The electrophilic metabolite was reactive to the sulfhydryl groups of glutathione, N-acetyl cysteine, and cysteine. NADPH was required for the formation of the reactive metabolite. The quinone methide intermediate reacted with cysteine residues to form hepatic protein adduction. A single dose of 2,6-DMP induced marked elevation of serum ALT and AST in mice. Both the protein adduction and hepatotoxicity of 2,6-DMP showed dose dependency.
研究领域:
毒理学
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环境科学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD CHEMISTRY
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2023
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IF 8.8
Haolin Zhang,Shiye Lin,Ruiwei Xie,Weizhi Zhong,Hui Wang,Mohamed A. Farag,Hidayat Hussain,Randolph R.J. Arroo,Xiaojia Chen,Jianbo Xiao
In the field of thermal degradation of flavonoids, current studies mainly focused on flavonols. However, the thermal degradation of dihydroflavonols in aqueous solution has received limited attention compared to flavonols. The single C2-C3 bonds of dihydroflavonols, which differs from the C2-C3 double bond in flavonols, may cause different degradation mechanisms. Dihydromyricetin (DMY) is a typical dihydroflavonol with six hydroxyl groups, and possesses various health effects. We explored the thermal degradation of DMY in neutral aqueous solution (pH 7) at 100 ℃. Ultra-performance liquid chromatography combined with photodiode array and electrospray ionization quadrupole-time-of-flight tandem mass spectrometric detection (UPLC-PDA-ESI-QTOF–MS/MS) provided suitable platform for exploring DMY degradation pathways, and negative ion mode was applied. Thermal treatment led to a decline in DMY level with time, accompanied by the appearance of various degradation products of DMY. Degradation mechanisms of DMY included isomerization, oxidation, hydroxylation, dimerization and ring cleavage. The pyrogallol-type ring B of DMY might be initially oxidized into ortho -quinone, which could further attack another DMY to form dimers. In addition, hydroxylation is likely to occur at C-2, C-3 of DMY or DMY dimers, which then further yields ring-cleavage products via breakage of the O1-C2 bond, C2-C3 bond, or C3-C4 bond. The 3-hydroxy-5-(3,3,5,7-tetrahydroxy-4-oxochroman-2-yl) cyclohexa-3,5-diene-1, 2-dione ( m / z 333.0244) and unknown compound m / z 435.0925 were annotated as key intermediates in DMY degradation. Four phenolic acids, including 3,4,5-trihydroxybenzoic acid ( m / z 169.0136, RT 1.4 min), 2,4,6-trihydroxyphenylglyoxylic acid ( m / z 197.0084, RT 1.7 min), 2-oxo-2-(2,4,6-trihydroxyphenyl) acetaldehyde ( m / z 181.0132, RT 2.4 min), and 2,4,6-trihydroxybenzoic acid ( m / z 169.0139, RT 2.5 min) were identified as the major end products of DMY degradation. In addition, 5-((3,5dihydroxyphenoxy) methyl)-3-hydroxycyclohexa-3,5-diene-1,2-dione (m / z 261.0399, RT 11.7 min) and unidentified compound with m / z 329.0507 (RT 1.0 min) were also suggested to be end products of DMY degradation. These results provide novel insights on DMY stability and degradation products. Moreover, the heat treatment of DMY aqueous solution was found to gradually reduce the antioxidant activities of DMY, and even destroy the beneficial effect of DMY on the gut microbiota composition.
研究领域:
药学化学
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分析化学
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食品科学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）