190 results on '"Ben-Zhan Zhu"'
Search Results
2. Detecting and Quantifying Polyhaloaromatic Environmental Pollutants by Chemiluminescence-Based Analytical Method
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Ben-Zhan Zhu, Miao Tang, Chun-Hua Huang, and Li Mao
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polyhaloaromatic compounds ,chemiluminescence ,analytical method ,Fenton system ,hydroxyl radicals ,Organic chemistry ,QD241-441 - Abstract
Polyhaloaromatic compounds (XAr) are ubiquitous and recalcitrant in the environment. They are potentially carcinogenic to organisms and may induce serious risks to the ecosystem, raising increasing public concern. Therefore, it is important to detect and quantify these ubiquitous XAr in the environment, and to monitor their degradation kinetics during the treatment of these recalcitrant pollutants. We have previously found that unprecedented intrinsic chemiluminescence (CL) can be produced by a haloquinones/H2O2 system, a newly-found ●OH-generating system different from the classic Fenton system. Recently, we found that the degradation of priority pollutant pentachlorophenol by the classic Fe(II)-Fenton system could produce intrinsic CL, which was mainly dependent on the generation of chloroquinone intermediates. Analogous effects were observed for all nineteen chlorophenols, other halophenols and several classes of XAr, and a novel, rapid and sensitive CL-based analytical method was developed to detect these XAr and monitor their degradation kinetics. Interestingly, for those XAr with halohydroxyl quinoid structure, a Co(II)-mediated Fenton-like system could induce a stronger CL emission and higher degradation, probably due to site-specific generation of highly-effective ●OH. These findings may have broad chemical and environmental implications for future studies, which would be helpful for developing new analytical methods and technologies to investigate those ubiquitous XAr.
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- 2021
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3. Caffeic Acid Phenyl Ester (CAPE) Protects against Iron-Mediated Cellular DNA Damage through Its Strong Iron-Binding Ability and High Lipophilicity
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Bo Shao, Li Mao, Miao Tang, Zhu-Ying Yan, Jie Shao, Chun-Hua Huang, Zhi-Guo Sheng, and Ben-Zhan Zhu
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caffeic acid phenethyl ester ,iron ,DNA damage ,hydroxyl radical ,redox-inactive iron complex ,lipophilicity ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Caffeic acid phenethyl ester (CAPE) and its structurally-related caffeic acid (CA), ferulic acid (FA) and ethyl ferulate (EF) are constituents of honeybee propolis that have important pharmacological activities. This study found that CAPE—but not CA, FA, and EF—could effectively prevent cellular DNA damage induced by overloaded iron through decreasing the labile iron pool (LIP) levels in HeLa cells. Interestingly, CAPE was found to be more effective than CA in protecting against plasmid DNA damage induced by Fe(II)–H2O2 or Fe(III)–citrate–ascorbate-H2O2 via the inhibition of hydroxyl radical (•OH) production. We further provided more direct and unequivocal experimental evidences for the formation of inactive CAPE/CA–iron complexes. CAPE was found to have a stronger iron-binding ability and a much higher lipophilicity than CA. Taken together, we propose that the esterification of the carboxylic moiety with phenethyl significantly enhanced the iron-binding ability and lipophilicity of CAPE, which is also responsible for its potent protection against iron-mediated cellular DNA damage. A study on the iron coordination mechanism of such natural polyphenol antioxidants will help to design more effective antioxidants for the treatment and prevention of diseases caused by metal-induced oxidative stress, as well as help to understand the structure–activity relationships of these compounds.
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- 2021
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4. The pentachlorophenol metabolite tetrachlorohydroquinone induces massive ROS and prolonged p-ERK expression in splenocytes, leading to inhibition of apoptosis and necrotic cell death.
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Hsiu-Min Chen, Ben-Zhan Zhu, Rong-Jane Chen, Bour-Jr Wang, and Ying-Jan Wang
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Medicine ,Science - Abstract
Pentachlorophenol (PCP) has been used extensively as a biocide and a wood preservative and has been reported to be immunosuppressive in rodents and humans. Tetrachlorohydroquinone (TCHQ) is a major metabolite of PCP. TCHQ has been identified as the main cause of PCP-induced genotoxicity due to reactive oxidant stress (ROS). However, the precise mechanisms associated with the immunotoxic effects of PCP and TCHQ remain unclear. The aim of this study was to examine the effects of PCP and TCHQ on the induction of ROS and injury to primary mouse splenocytes. Our results shown that TCHQ was more toxic than PCP and that a high dose of TCHQ led to necrotic cell death of the splenocytes through induction of massive and sudden ROS and prolonged ROS-triggered ERK activation. Inhibition of ROS production by N-acetyl-cysteine (NAC) partially restored the mitochondrial membrane potential, inhibited ERK activity, elevated caspase-3 activity and PARP cleavage, and, eventually, switched the TCHQ-induced necrosis to apoptosis. We suggest that prolonged ERK activation is essential for TCHQ-induced necrosis, and that ROS play a pivotal role in the different TCHQ-induced cell death mechanisms.
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- 2014
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5. Molecular mechanism of the metal-independent production of hydroxyl radicals by thiourea dioxide and H2O2.
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Li Mao, Zhuo Quan, Zhi-Sheng Liu, Chun-Hua Huang, Zi-Han Wang, Tian-Shu Tang, Pei-Lin Li, Jie Shao, Ya-Jun Liu, and Ben-Zhan Zhu
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HYDROXYL group ,THIOUREA ,SULFINIC acids ,RADIOLABELING ,DENSITY functional theory - Abstract
It is well-known that highly reactive hydroxyl radicals (HO) can be produced by the classic Fenton system and our recently discovered haloquinone/H
2 O2 system, but rarely from thiol-derivatives. Here, we found, unexpectedly, that HO can be generated from H2 O2 and thiourea dioxide (TUO2 ), a widely used and environmentally friendly bleaching agent. A carbon-centered radical and sulfite were detected and identified as the transient intermediates, and urea and sulfate as the final products, with the complementary application of electron spin-trapping, oxygen-18 isotope labeling coupled with HPLC/ MS analysis. Density functional theory calculations were conducted to further elucidate the detailed pathways for HO production. Taken together, we proposed that the molecular mechanism for HO generation by TUO2 /H O2 2 : TUO2 tautomerizes from sulfinic acid into ketone isomer (TUO2 -K) through proton transfer, then a nucleophilic addition of H2 O2 on the S atom of TUO2 -K, forming a S-hydroperoxide intermediate TUO2 -OOH, which dissociates homolytically to produce HO. Our findings represent the first experimental and computational study on an unprecedented new molecular mechanism of HO production from simple thiol-derived sulfinic acids, which may have broad chemical, environmental, and biomedical significance for future research on the application of the well-known bleaching agent and its analogs. [ABSTRACT FROM AUTHOR]- Published
- 2024
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6. Molecular mechanism for the activation of the potent hepatotoxin acetylhydrazine: Identification of the initial N-centered radical and the secondary C-centered radical intermediates
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Li Qin, Chun-Hua Huang, Cui-Qing Liu, Chuan-Fang Zhao, Pei-Lin Li, Tian-Shu Tang, Jun Li, Lin-Na Xie, Bo Shao, Jie Shao, Li Mao, Ran Li, Lu Zhang, and Ben-Zhan Zhu
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Physiology (medical) ,Biochemistry - Published
- 2023
7. Unusual enantioselective cytoplasm-to-nucleus translocation and photosensitization of the chiral Ru(II) cationic complex via simple ion-pairing with lipophilic weak acid counter-anions
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Xi-Juan Chao, Chun-Hua Huang, Miao Tang, Zhu-Ying Yan, Rong Huang, Yan Li, and Ben-Zhan Zhu
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Genetics - Abstract
Targeted and enantioselective delivery of chiral diagnostic-probes and therapeutics into specific compartments inside cells is of utmost importance in the improvement of disease detection and treatment. The classical DNA ‘light-switch’ ruthenium(II)-polypyridyl complex, [Ru(DIP)2(dppz)]Cl2 (DIP = 4,7-diphenyl-1,10-phenanthroline, dppz = dipyridophenazine) has been shown to be accumulated only in the cytoplasm and membrane, but excluded from its intended nuclear DNA target. In this study, the cationic [Ru(DIP)2(dppz)]2+ is found to be redirected into live-cell nucleus in the presence of lipophilic 3,5-dichlorophenolate or flufenamate counter-anions via ion-pairing mechanism, while maintaining its original DNA recognition characteristics. Interestingly and unexpectedly, further studies show that only the Δ-enantiomer is selectively translocated into nucleus while the Λ-enantiomer remains trapped in cytoplasm, which is found to be mainly due to their differential enantioselective binding affinities with cytoplasmic proteins and nuclear DNA. More importantly, only the nucleus-relocalized Δ-enantiomer can induce obvious DNA damage and cell apoptosis upon prolonged visible-light irradiation. Thus, the use of Δ-enantiomer can significantly reduce the dosage needed for maximal treatment effect. This represents the first report of enantioselective targeting and photosensitization of classical Ru(II) complex via simple ion-pairing with suitable weak acid counter-anions, which opens new opportunities for more effective enantioselective cancer treatment.
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- 2023
8. Molecular mechanism of the unusual biphasic effects of the natural compound hinokitiol on iron-induced cellular DNA damage
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Miao Qin, Bo Shao, Li Lin, Zhao-Qiang Zhang, Zhi-Guo Sheng, Li Qin, Jie Shao, and Ben-Zhan Zhu
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Physiology (medical) ,Biochemistry - Abstract
Hinokitiol is a natural monoterpene compound found in the heartwood of cupressaceous plants that have anticancer and anti-inflammatory properties. However, few studies have focused on its effect on iron-mediated cellular DNA damage. Here we show that hinokitiol exhibited unusual biphasic effects on iron-induced DNA damage in a molar ratio (hinokitiol/iron) dependent manner in HeLa cells. Under low ratios (3:1), hinokitiol markedly enhanced DNA damage induced by Fe(II) or Fe(II)-H
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- 2023
9. An unprecedented free radical mechanism for the formation of DNA adducts by the carcinogenic N-sulfonated metabolite of aristolochic acids
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Pei-Lin Li, Chun-Hua Huang, Li Mao, Jun Li, Zhi-Guo Sheng, and Ben-Zhan Zhu
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Physiology (medical) ,Biochemistry - Published
- 2023
10. The critical role of unique azido-substituted chloro-O-semiquinone radical intermediates in the synergistic toxicity between sodium azide and chlorocatecholic carcinogens
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Bo Shao, Pei-Lin Li, Tian-Shu Tang, Chun-Hua Huang, Miao Tang, Dan Xu, Ben-Zhan Zhu, and Li Qin
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Semiquinone ,Radical ,Electron Spin Resonance Spectroscopy ,Quinones ,Cleavage (embryo) ,Biochemistry ,Decomposition ,Medicinal chemistry ,law.invention ,Quinone ,chemistry.chemical_compound ,chemistry ,law ,Physiology (medical) ,Benzoquinones ,Carcinogens ,Sodium azide ,heterocyclic compounds ,Sodium Azide ,Electron paramagnetic resonance ,Oxidation-Reduction ,Carcinogen - Abstract
We have shown previously that exposing bacteria to tetrachlorocatechol (TCC) and sodium azide (NaN3) together causes synergistic cytotoxicity in a biphasic mode. However, the underlying chemical mechanism remains unclear. In this study, an unexpected ring-contraction 3(2H)-furanone and two quinoid-compounds were identified as the major and minor reaction products, respectively; and two unusual azido-substituted chloro-O-semiquinone radicals were detected and characterized as the major radical intermediates by complementary applications of direct ESR, HPLC/ESI-Q-TOF and high-resolution MS studies with nitrogen-15 isotope-labeled NaN3. Taken together, we proposed a novel molecular mechanism for the reaction of TCC/NaN3: N3- may attack on tetrachloro-O-semiquinone radical, forming two transient 4-azido-3,5,6-trichloro- and 4,5-diazido-3,6-dichloro-O-semiquinone radicals, consecutively. The second-radical intermediate may either undergo an unusual zwitt-azido cleavage to form the less-toxic ring-contraction 3(2H)-furanone product, or further oxidize to form the more toxic quinoid-product 4-amino-5-azido-3,6-dichloro-O-benzoquinone. A good correlation was observed between the biphasic formation of this toxic quinone due to the two competing decomposition pathways of the radical intermediate and the biphasic synergism between TCC and NaN3, which are dependent on their molar-ratios. This is the first report of detection and identification of two unique azido-substituted chloro-O-semiquinone radicals, and an unprecedented ring-contraction mechanism via an unusually mild and facile zwitt-azido rearrangement.
- Published
- 2021
11. Mechanistic investigation of the differential synergistic neurotoxicity between pesticide metam sodium and copper or zinc
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Chen Shen, Zhi-Guo Sheng, Jie Shao, Miao Tang, Li Mao, Chun-Hua Huang, Zhi-Hui Zhang, and Ben-Zhan Zhu
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Environmental Engineering ,Health, Toxicology and Mutagenesis ,Public Health, Environmental and Occupational Health ,Environmental Chemistry ,General Medicine ,General Chemistry ,Pollution - Published
- 2023
12. Generation mechanism of singlet oxygen from the interaction of peroxymonosulfate and chloride in aqueous systems
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Anna Wang, Ben-Zhan Zhu, Chun-Hua Huang, Wei-Xian Zhang, Mengye Wang, Xuchun Li, Li Ling, Jun Ma, and Jingyun Fang
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Environmental Engineering ,Ecological Modeling ,Pollution ,Waste Management and Disposal ,Water Science and Technology ,Civil and Structural Engineering - Published
- 2023
13. Ultrafast excited state dynamics and light-switching of [Ru(phen)2(dppz)]2+ in G-quadruplex DNA
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Hongmei Su, Hongmei Zhao, Chun-Hua Huang, Chunfan Yang, Qian Zhou, Ben-Zhan Zhu, and Ze-Qing Jiao
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010405 organic chemistry ,Ligand ,Stacking ,chemistry.chemical_element ,General Chemistry ,Nanosecond ,010402 general chemistry ,Photochemistry ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Ruthenium ,Chemistry ,Dark state ,chemistry ,Excited state ,Materials Chemistry ,Environmental Chemistry ,Molecule ,Luminescence ,QD1-999 - Abstract
The triplet metal to ligand charge transfer (3MLCT) luminescence of ruthenium (II) polypyridyl complexes offers attractive imaging properties, specifically towards the development of sensitive and structure-specific DNA probes. However, rapidly-deactivating dark state formation may compete with 3MLCT luminescence depending on different DNA structures. In this work, by combining femtosecond and nanosecond pump-probe spectroscopy, the 3MLCT relaxation dynamics of [Ru(phen)2(dppz)]2+ (phen = 1,10-phenanthroline, dppz = dipyridophenazine) in two iconic G-quadruplexes has been scrutinized. The binding modes of stacking of dppz ligand on the terminal G-quartet fully and partially are clearly identified based on the biexponential decay dynamics of the 3MLCT luminescence at 620 nm. Interestingly, the inhibited dark state channel in ds-DNA is open in G-quadruplex, featuring an ultrafast picosecond depopulation process from 3MLCT to a dark state. The dark state formation rates are found to be sensitive to the content of water molecules in local G-quadruplex structures, indicating different patterns of bound water. The unique excited state dynamics of [Ru(phen)2(dppz)]2+ in G-quadruplex is deciphered, providing mechanistic basis for the rational design of photoactive ruthenium metal complexes in biological applications. Photoactive ruthenium metal complexes are relevant luminescent DNA markers, but deciphering their local excited state dynamics in complex biochemical environments is challenging. Here the authors combine femtosecond and nanosecond pump-probe spectroscopy to elucidate the local hydration effects and 3MLCT relaxation dynamics of [Ru(phen)2(dppz)]2+ in two G-quadruplexes.
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- 2021
14. Structure–Activity Relationship Investigation on Reaction Mechanism between Chlorinated Quinoid Carcinogens and Clinically-Used Aldoxime Nerve-Agent Antidote under Physiological Condition
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Li Qin, Li Mao, Dong Cao, Guo-Qiang Shan, Lin-Na Xie, Zhi-Sheng Liu, Fang-Lan Geng, Dan Xu, Jie Shao, Zhi-Guo Sheng, Feng Li, Chun-Hua Huang, and Ben-Zhan Zhu
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Reaction mechanism ,Pralidoxime ,Halogenation ,medicine.medical_treatment ,Metabolite ,Reaction intermediate ,010501 environmental sciences ,Toxicology ,01 natural sciences ,Medicinal chemistry ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Oximes ,Benzoquinones ,medicine ,Antidote ,030304 developmental biology ,0105 earth and related environmental sciences ,0303 health sciences ,Molecular Structure ,Chemistry ,Hydrolysis ,General Medicine ,Hydrogen-Ion Concentration ,Homolysis ,Carcinogens ,Pyridinium ,Nerve Agents ,medicine.drug - Abstract
Pyridinium aldoximes are best-known therapeutic antidotes used for clinical treatment of poisonings by organophosphorus nerve-agents and pesticides. Recently, we found that pralidoxime (2-PAM, a currently clinically used nerve-agent antidote) could also detoxify tetrachloro-1,4-benzoquinone (TCBQ), which is a carcinogenic quinoid metabolite of the widely used wood preservative pentachlorophenol under normal physiological conditions, via an unusually mild and facile Beckmann fragmentation mechanism accompanied by radical homolysis. However, it is not clear whether the less-chlorinated benzoquinones (CnBQs, n ≤ 3) act similarly; if so, what is the structure-activity relationship? In this study, we found that (1) The stability of reaction intermediates produced by different CnBQs and 2-PAM was dependent not only on the position but also the degree of Cl-substitution on CnBQs, which can be divided into TCBQ- and DCBQ (dichloro-1,4-benzoquinone)-subgroup; (2) The pKa value of hydroxlated quinones (Cn-1BQ-OHs, the hydrolysis products of CnBQs), determined the stability of corresponding intermediates, that is, the decomposition rate of the intermediates depended on the acidity of Cn-1BQ-OHs; (3) The pKa value of the corresponding Cn-1BQ-OHs could also determine the reaction ratio of Beckmann fragmentation to radical homolysis in CnBQs/2-PAM. These new findings on the structure-activity relationship of the halogenated quinoid carcinogens detoxified by pyridinium aldoxime therapeutic agents via Beckmann fragmentation and radical homolysis reaction may have broad implications on future biomedical and environmental research.
- Published
- 2021
15. Mechanistic Study on Chemiluminescence of Chloranilic Acid by Co(II)-Mediated Fenton-like System
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Ben-Zhan Zhu, Li Mao, Yi-Qi Tang, and Ya-Jun Liu
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010405 organic chemistry ,Organic Chemistry ,Conical intersection ,010402 general chemistry ,Photochemistry ,01 natural sciences ,Potential energy ,Dioxetane ,0104 chemical sciences ,law.invention ,chemistry.chemical_compound ,chemistry ,Chloranilic acid ,Dihydroxylation ,law ,Moiety ,Luminescence ,Chemiluminescence - Abstract
Reacting with H2O2, tetrachloro-1,4-benzoquinone (TCBQ) produces chemiluminescence (CL), but chloranilic acid (CA), the dihydroxylation product of TCBQ, does not. However, an unprecedented strong CL generates from CA/H2O2 in the presence of Co(II). Why? We performed quantum chemical calculations on the entire reaction process of CA/H2O2 and CA/H2O2/Co(II) systems. The computational results indicate: for CA/H2O2 system, the reason leading to non-CL as: there is no free •OH produced by CA/H2O2, which prevents the subsequent reaction from taking place; for CA/H2O2/Co(II) system, the chemical process resulting in the CL as: First, a neutral dioxetane is formed via six sequential reactions. Then, the neutral dioxetane decomposes to generate a neutral excited-state (S1) product via a gradually reversible charge transfer initiated luminescence mechanism. A conical intersection of the ground and the S1-state potential energy surfaces facilitates the production of the S1-state product. Ultimately, the neutral S1-state product emits light as a practical light emitter. The key component for forming dioxetane and the following CL is the intrinsically generated •OH, which is roaming around at the region of C2 atoms of the CA moiety, instead of being free. The quantum chemical calculations supported the experimental observation and conclusion by providing the mechanistic explanation in detail.
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- 2021
16. The critical role of superoxide anion radicals on delaying tetrachlorohydroquinone autooxidation by penicillamine
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Jie Shao, Bo Shao, Li Qin, Zhi-Guo Sheng, Ben-Zhan Zhu, Zhu-Ying Yan, Chun-Hua Huang, Zhi-Sheng Liu, Li Mao, and Miao Tang
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0301 basic medicine ,Biochemistry ,Redox ,Antioxidants ,Superoxide dismutase ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Superoxides ,Physiology (medical) ,medicine ,Mode of action ,chemistry.chemical_classification ,Autoxidation ,biology ,Superoxide Dismutase ,Chemistry ,Superoxide ,Penicillamine ,030104 developmental biology ,Toxicity ,Biophysics ,biology.protein ,Thiol ,Oxidation-Reduction ,030217 neurology & neurosurgery ,medicine.drug - Abstract
We have recently found that penicillamine, a classic copper-chelating thiol-drug for Wilson's disease, can delay tetrachlorohydroquinone (TCHQ) autooxidation via a previously unrecognized redox-activity. However, its underlying molecular mechanism remains not fully understood. In this study, we found, interestingly and unexpectedly, that superoxide dismutase (SOD) can significantly shorten the delay of TCHQ autooxidation by penicillamine, but not by ascorbate; SOD can also markedly increase the yields of the oxidized form of penicillamine. Similar effects were observed with a recently-developed specific and sensitive superoxide anion radical (O2•-) probe CT-02H, which was also employed to successfully measure O2•- generated from both TCHQ and TCHQ/penicillamine systems for the first time. More importantly, addition of extra O2•- (KO2/18-crown-6) can further prolong the delaying effects by penicillamine and slow down penicillamine consumption. Taken together, an unexpected critical role of O2•- in TCHQ/penicillamine interaction was proposed: O2•- may regenerate penicillamine, thereby continuously reducing TCSQ•- to TCHQ and finally delaying TCHQ autooxidation; In contrast, if O2•- were eliminated, which can not only markedly change the reaction equilibrium, accelerate the rate of interaction, and ultimately shorten the delay of TCHQ autooxidation by penicillamine, but can also accelerate penicillamine oxidation to form its corresponding disulfide solely via redox reaction without any minor nucleophilic reaction. These findings not only further support our previously-proposed redox mechanism for the protection against TCHQ-induced cytotoxicity by penicillamine, but also reveal a new mode of action for O2•- in the inhibition of haloquinoids-induced toxicity by thiol antioxidants.
- Published
- 2021
17. Potent oxidation of DNA by Ru(<scp>ii</scp>) tri(polypyridyl) complexes under visible light irradiation via a singlet oxygen-mediated mechanism
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Zhi-Guo Sheng, Bo Shao, Ben-Zhan Zhu, Jing Chen, Chun-Hua Huang, Zhu-Ying Yan, Jie Shao, and Miao Tang
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010405 organic chemistry ,Singlet oxygen ,DNA damage ,Visible light irradiation ,010402 general chemistry ,Photochemistry ,01 natural sciences ,0104 chemical sciences ,Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Irradiation ,Nucleoside ,DNA ,Visible spectrum - Abstract
Since Ru(II) tri(polypyridyl) complexes can bind DNA in the groove, the chemistry of metallo-groove-binders has been extended to many applications such as artificial photonucleases and DNA recognizers. Here we found that the major product was N-(2-deoxy-β-D-erythro-pentofuranosyl)-spiroiminodihydantoin (dSp) when the nucleoside 2′-deoxyguanosine (dG) was exposed to the visible light irradiation of Ru(II) tri(polypyridyl) complexes including Ru(bpy)32+ (bpy = 2,2′-bipyridyl), Ru(OP)32+ (OP = 1,10-phenanthroline) and Ru(DIP)32+ (DIP = 4,7-diphenyl-1,10-phenanthroline). Interestingly, we found that in the oxidation of dsDNA the major oxidation product is 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) instead of dSp. The formation of dSp and 8-oxodG increased significantly in D2O and decreased markedly with the addition of NaN3. [18O]-Labeled 8-oxodG was also found to be produced more than non-labeled 8-oxodG under an 18O2 atmosphere. The above results clearly indicated that 1O2 was the major oxidant during the oxidation of both dG and dsDNA by the irradiation of Ru(II) complexes, which was further confirmed by both ESR spin-trapping and UV methods. Among the above three Ru(II) complexes, Ru(DIP)32+ is the most efficient photosensitized generator of dG oxidation products, while in the oxidation of dsDNA, Ru(bpy)32+ is the most effective. This is the first report that the irradiation of Ru(II) polypridyl complexes with visible light can induce potent oxidation of dG and ctDNA to the more mutagenic product dSp and 8-oxodG via an 1O2-mediated mechanism. These findings should provide new perspectives for future investigations on whether ubiquitous Ru(II) complexes could cause oxidatively generated DNA damage in cellular models.
- Published
- 2021
18. Unusual Two-Step Claisen-type Rearrangement Reaction under Physiological Conditions
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Ben-Zhan Zhu, Pei-Lin Li, Dan Xu, Tian-Shu Tang, Li Qin, and Chun-Hua Huang
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Free Radicals ,Spin trapping ,010405 organic chemistry ,Chemistry ,Stereochemistry ,Organic Chemistry ,Two step ,Electron Spin Resonance Spectroscopy ,Quinones ,010402 general chemistry ,01 natural sciences ,Detoxication ,0104 chemical sciences ,Yield (chemistry) ,Carcinogens ,Nucleophilic substitution ,Rearrangement reaction ,Spin Trapping ,Reaction site - Abstract
N-aryl hydroxamic acids, which are best known for their metal-chelating properties in chemical and biomedical research, have been found to markedly detoxify carcinogenic halogenated quinones. However, the exact chemical mechanism underlying such detoxication remains unclear. Here, we show that a very fast reaction took place between N-phenylbenzohydroxamic acid (N-PhBHA) and 2,5-dichloro-1,4-benzoquinone (DCBQ), forming an unexpected new carbon-carbon bonding phenyl-quinone product with high yield. In contrast, no reaction was observed with O-benzoyl N-PhBHA. Analogous results were observed for other N-aryl hydroxamic acids and halogenated quinones, which have an ortho-hydrogen adjacent to the reaction site (DCBQ-type). Interestingly, no free radical intermediates could be detected by both ESR spin-trapping and radical-scavenging methods during the reaction process. Taken together, we proposed that nucleophilic substitution followed by an unusual two-step Claisen-type rearrangement reaction was responsible for the formation of a new C-C bonding compound and the detoxication reaction. This represents the first report of an unusually mild and facile two-step Claisen-type rearrangement, which could take place under normal physiological conditions.
- Published
- 2020
19. Mechanistic Investigation of H 2 O 2 ‐dependent Chemiluminescence from Tetrabromo‐1,4‐Benzoquinone
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Zhuo Quan, Li Mao, Yi‐Qi Tang, Ming Lei, Ben‐Zhan Zhu, and Ya‐Jun Liu
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Physical and Theoretical Chemistry ,Atomic and Molecular Physics, and Optics - Published
- 2022
20. Free-Radical-Mediated Photoinduced Electron Transfer between 6-Thioguanine and Tryptophan Leading to DNA-Protein-Like Cross-Link
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Junjie Dong, Chunhua Huang, Shaoshi Guo, Ye Xia, Yue Hou, Chunfan Yang, Xianwang Zhang, Jialong Jie, Ben-Zhan Zhu, and Hongmei Su
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Electron Transport ,Materials Chemistry ,Tryptophan ,Electrons ,DNA ,Physical and Theoretical Chemistry ,Thioguanine ,Surfaces, Coatings and Films - Abstract
The nucleobase analog 6-thioguanine (6-TG) has emerged as important immunosuppressant, anti-inflammatory, and anticancer drug in the past few decades, but its unique photosensitivity of absorbing strongly ultraviolet UVA light elicits photochemical hazards in many ways. The particularly intriguing yet unresolved question is whether the direct photoreaction of 6-TG can promote DNA-protein cross-links (DPCs) formation, which are large DNA adducts blocking DNA replication and physically impede DNA-related processes. Herein, by real-time observation of radical intermediates using time-resolved UV-vis absorption spectroscopy in conjunction with product analysis by HPLC-MS, we discover that UVA excitation of 6-TG triggers direct covalent cross-linking with tryptophan (TrpH) via an exquisite radical mechanism of electron transfer. The photoexcitation prepares the redox-active triplet
- Published
- 2021
21. Key factors in the ligand effects on the photo redox cycling of aqueous iron species
- Author
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Bingdang Wu, Xiaojie Song, Shujuan Zhang, Guoyang Zhang, Li Zhang, and Ben-Zhan Zhu
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Diketone ,Aqueous solution ,010504 meteorology & atmospheric sciences ,Ligand ,Acetylacetone ,Oxalic acid ,010502 geochemistry & geophysics ,01 natural sciences ,Oxalate ,Ferrous ,chemistry.chemical_compound ,chemistry ,Geochemistry and Petrology ,Salicylic acid ,0105 earth and related environmental sciences ,Nuclear chemistry - Abstract
Photochemical transformation of iron plays crucial roles in the geochemical evolution of marine, terrestrial and atmospheric systems. In the present work, the photo-conversion of ferric iron and ferrous iron were studied in the presence of four naturally abundant organic compounds (OCs): two carboxylic acids [oxalic acid, salicylic acid] and two diketones [acetylacetone (Hacac), diacetyl]. The key finding is that the two diketones significantly accelerated both the photo-reduction of Fe(III) and the photo-oxidation of Fe(II) in acidic solutions. The quantum yields (Φ) of [Fe(acac)]2+ and Fe(III)-salicylate at 254 nm were estimated to be 0.23 and 0.02, respectively. The formation of photoactive Fe(III)-OC complexes accounted for the changed photo-steady state of iron but was not the exclusive factor. The enhanced consumption of dissolved oxygen (6 and 16 times in Fe(III) and Fe(II)-initiated systems) was attributed to the effects of the nonchelating diacetyl on the photo redox cycling of iron. Although the photoactivity of Fe(III)-oxalate (Φ254 nm = 1.25) was much higher than those of Fe(III)-acac and Fe(III)-salicylate, the effect of oxalate did not last, because oxalate was rapidly depleted in several minutes. The addition of the two diketones kept either the Fe(III)-initiated system or the Fe(II)-initiated system at the Fe(II) state for hours, which is of great environmental significance, because Fe(II) is more active in both engineered and natural environments.
- Published
- 2020
22. Molecular mechanisms and potential applications of the intrinsic chemiluminescence produced from the degradation of haloaromatic pollutants during environmentally-friendly advanced oxidation processes
- Author
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Bo Shao, Hui-Ying Gao, Ben-Zhan Zhu, Li Mao, and Chun-Hua Huang
- Subjects
inorganic chemicals ,Pollutant ,Chlorophenol ,0303 health sciences ,Environmental Engineering ,Semiquinone ,Radical ,010402 general chemistry ,Photochemistry ,01 natural sciences ,0104 chemical sciences ,Pentachlorophenol ,law.invention ,03 medical and health sciences ,chemistry.chemical_compound ,chemistry ,law ,Degradation (geology) ,Phenols ,030304 developmental biology ,Water Science and Technology ,Chemiluminescence - Abstract
The ubiquitous distribution of halogenated aromatic compounds (XAr) coupled with their carcinogenicity has raised public concerns over their potential risks to both human health and our ecosystem. Recently, advanced oxidation processes (AOPs) have been considered as an “environmentally-friendly” and green technology for the degradation of such recalcitrant and highly toxic XAr. During the course of our study on metal-independent generation of hydroxyl radicals (˙OH) by halogenated quinones and H2O2, we found, unexpectedly, that an unprecedented ˙OH-dependent intrinsic chemiluminescence (CL) can be produced by H2O2 and polyhalogenated quinones. Further investigations showed that, in all ˙OH-generating AOPs, CL can also be produced not only by pentachlorophenol and all other halogenated phenols, but also by all XAr tested. A systematic structure–activity relationship study for all nineteen chlorophenol congeners showed that the CL increased with an increase in the number of chlorine-substitutions in general. More importantly, a relatively good correlation was observed between the formation of quinoid/semiquinone radical intermediates and CL emission. Moreover, for those halogenated hydroxy-quinoid pollutants, much stronger CL emission and better degradation could be induced by cobalt(II)-mediated Fenton-like systems, and ˙OH produced site-specifically was found to be responsible for this unusual CL emission. On the basis of these results, a rapid, sensitive, simple, and effective CL-based analytical method was developed not only to measure and quantify trace amounts of XAr and related haloquinoid compounds, but also to monitor their degradation kinetics and provide useful information for predicting their toxicity. These findings may have broad chemical, environmental and biological implications for future studies on halogenated aromatic persistent organic pollutants.
- Published
- 2020
23. An unexpected new pathway for nitroxide radical production via more reactve nitrogen-centered amidyl radical intermediate during detoxification of the carcinogenic halogenated quinones by N-alkyl hydroxamic acids
- Author
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Ben-Zhan Zhu, Jie Shao, Dan Xu, Chun-Hua Huang, Li Qin, Balaraman Kalyanaraman, Lin-Na Xie, and Li Mao
- Subjects
0301 basic medicine ,Nitrogen ,Radical ,Hydroxamic Acids ,Hydrogen atom abstraction ,Biochemistry ,Medicinal chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Physiology (medical) ,Carcinogen ,Alkyl ,chemistry.chemical_classification ,Hydroxamic acid ,Electron Spin Resonance Spectroscopy ,Quinones ,Homolysis ,030104 developmental biology ,chemistry ,Carcinogens ,Nitrogen Oxides ,Amine gas treating ,Oxidation-Reduction ,030217 neurology & neurosurgery ,DNA - Abstract
We found previously that nitroxide radical of desferrioxamine (DFO•) could be produced from the interaction between the classic iron chelating agent desferrioxamine (DFO, an N-alkyl trihydroxamic acid) and tetrachlorohydroquinone (TCHQ), one of the carconogenic quinoind metabolites of the widely used wood preservative pentachlorophenol. However, the underlying molecular mechanism remains unclear. Here N-methylacetohydroxamic acid (N-MeAHA) was synthesized and used as a simple model compound of DFO for further mechanistic study. As expected, direct ESR studies showed that nitroxide radical of N-MeAHA (Ac-(CH3)NO•) can be produced from N-MeAHA/TCHQ. Interestingly and unexpectedly, when TCHQ was substituted by its oxidation product tetrachloro-1,4-benzoquinone (TCBQ), although Ac-(CH3)NO• could also be produced, no concurrent formation of tetrachlorosemiquinone radical (TCSQ•) and TCHQ was detected, suggesting that Ac-(CH3)NO• did not result from direct oxidation of N-MeAHA by TCSQ• or TCBQ as proposed previously. To our surprise, a new nitrogen-centered amidyl radical was found to be generated from N-MeAHA/TCBQ, which was observed by ESR with the spin-trapping agents and further unequivacally identified as Ac-(CH3)N• by HPLC-MS. The final product of amidyl radical was isolated and identified as its corresponding amine. Analogous radical homolysis mechanism was observed with other halogenated quinoid compounds and N-alkyl hydroxamic acids including DFO. Interestingly, amidyl radicals were found to induce both DNA strand breaks and DNA adduct formation, suggesting that N-alkyl hydroxamic acids may exert their potential side-toxic effects via forming the reactive amidyl radical species. This study represents the first report of an unexpected new pathway for nitroxide radical production via hydrogen abstration reaction of a more reactive amidyl radical intermediate during the detoxification of the carcinogenic polyhalogenated quinones by N-alkyl hydroxamic acids, which provides more direct experimental evidence to better explain not only our previous finding that excess DFO can provide effective but only partial protection against TCHQ (or TCBQ)-induced biological damage, and also the potential side-toxic effects induced by DFO and other N-alkyl hydroxamic acid drugs.
- Published
- 2020
24. Unexpected activation of N-alkyl hydroxamic acids to produce reactive N-centered free radicals and DNA damage by carcinogenic chlorinated quinones under normal physiological conditions
- Author
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Lin-Na Xie, Li Mao, Guo-Qiang Shan, Dan Xu, Ben-Zhan Zhu, Pei-Lin Li, Tian-Shu Tang, Li Qin, Chun-Hua Huang, and Jie Shao
- Subjects
0301 basic medicine ,chemistry.chemical_classification ,Hydroxamic acid ,Free Radicals ,Chemistry ,DNA damage ,Radical ,Electron Spin Resonance Spectroscopy ,Quinones ,Hydroxamic Acids ,Biochemistry ,Medicinal chemistry ,Quinone ,Adduct ,Homolysis ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Lossen rearrangement ,Physiology (medical) ,Carcinogens ,030217 neurology & neurosurgery ,Alkyl ,DNA Damage - Abstract
We found recently that benzohydroxamic acid (BHA) could detoxify the chlorinated quinoid carcinogens via an unusual Lossen rearrangement reaction. However, it is not clear what would happen when the nitrogen hydrogen of BHA was substituted with methyl and other alkyl groups. Here we show that N-methyl benzohydroxamic acid (N-MeBHA, a simple model compound for the classic iron-chelator deferoxamine, which is a typical N-alkyl trihydroxamic acid) could react with 2,5-dichloro-1,4-benzoquinone (DCBQ) to form a relatively stable initial carbon-oxygen bonding conjugation intermediate CBQ-O-N-MeBHA. However, the major final product was identified, unexpectedly, as a carbon-nitrogen bonding conjugate CBQ(OH)-N(CH3)-COAr, which is the rearranged isomer of CBQ-O-N-MeBHA. Interestingly, a new 18-line nitrogen-centered radical and a carbon-centered quinone ketoxy radical were observed by the ESR spin-trapping method, which was further confirmed by HPLC-MS and 15N-isotope labeling methods. We further found that both new DNA adducts and DNA strand breaks could be produced by the reactive nitrogen-centered radical. Taken together, we propose that the reaction between DCBQ and N-MeBHA was not via the Lossen rearrangement, but rather through a novel radical homolysis and recoupling pathway. Analogous results were observed for other chlorinated quinones and N-alkyl hydroxamic acids including the widely-used trihydroxamate iron-chelating drug deferoxamine. This represents the first report of unexpected radical pathway for the reaction between chlorinated quinones and N-alkyl hydroxamic acids under normal physiological conditions, which may have broad biological and environmental significance for future study of carcinogenic chloroquinones and hydroxamic acid drugs.
- Published
- 2020
25. Sulfur-centered hemi-bond radicals as active intermediates in S-DNA phosphorothioate oxidation
- Author
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Hongmei Zhao, Ye Xia, Ben-Zhan Zhu, Chunfan Yang, Hongmei Su, Chun-Hua Huang, Kunhui Liu, Jialong Jie, and Di Song
- Subjects
DNA, Bacterial ,Guanine ,Stereochemistry ,Radical ,chemistry.chemical_element ,Phosphorothioate Oligonucleotides ,Bacterial genome size ,Biology ,010402 general chemistry ,01 natural sciences ,Adduct ,chemistry.chemical_compound ,Chemical Biology and Nucleic Acid Chemistry ,Genetics ,Moiety ,Transfer technique ,Bacteria ,010405 organic chemistry ,Spectrum Analysis ,Sulfur ,0104 chemical sciences ,chemistry ,Nucleic Acid Conformation ,Oxidation-Reduction ,DNA ,Genome, Bacterial - Abstract
Phosphorothioate (PS) modifications naturally appear in bacteria and archaea genome and are widely used as antisense strategy in gene therapy. But the chemical effects of PS introduction as a redox active site into DNA (S-DNA) is still poorly understood. Herein, we perform time-resolved spectroscopy to examine the underlying mechanisms and dynamics of the PS oxidation by potent radicals in free model, in dinucleotide, and in S-oligomer. The crucial sulphur-centered hemi-bonded intermediates -P–S∴S–P- were observed and found to play critical roles leading to the stable adducts of -P–S–S–P-, which are backbone DNA lesion products. Moreover, the oxidation of the PS moiety in dinucleotides d[GPSG], d[APSA], d[GPSA], d[APSG] and in S-oligomers was monitored in real-time, showing that PS oxidation can compete with adenine but not with guanine. Significantly, hole transfer process from A+• to PS and concomitant -P–S∴S–P- formation was observed, demonstrating the base-to-backbone hole transfer unique to S-DNA, which is different from the normally adopted backbone-to-base hole transfer in native DNA. These findings reveal the distinct backbone lesion pathway brought by the PS modification and also imply an alternative -P–S∴S–P-/-P–S–S–P- pathway accounting for the interesting protective role of PS as an oxidation sacrifice in bacterial genome.
- Published
- 2019
26. Molecular mechanism for the activation of the anti-tuberculosis drug isoniazid by Mn(III): First detection and unequivocal identification of the critical N-centered isoniazidyl radical and its exact location
- Author
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Li Qin, Balaraman Kalyanaraman, Lin-Na Xie, Jie Shao, Ben-Zhan Zhu, Chun-Hua Huang, Li Mao, and Dan Xu
- Subjects
0301 basic medicine ,Drug ,Free Radicals ,Stereochemistry ,media_common.quotation_subject ,Antitubercular Agents ,Hydrazide ,Biochemistry ,Pyrophosphate ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Anti tuberculosis ,Physiology (medical) ,Isoniazid ,medicine ,Exact location ,Hydrazine (antidepressant) ,media_common ,Manganese ,Electron Spin Resonance Spectroscopy ,030104 developmental biology ,chemistry ,Molecular mechanism ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Isoniazid (INH), the most-widely used anti-tuberculosis drug, has been shown to be activated by Mn(III) to produce the reactive carbon-centered isonicotinic acyl radical, which was considered to be responsible for its anti-tuberculosis activity. However, it is still not clear whether the previously-proposed N-centered isoniazidyl radical intermediate can be initially produced or not; and if so, what is its exact location on the hydrazine group, distal- or proximal-nitrogen? Through complementary applications of ESR spin-trapping and HPLC/MS methods, here we show that the characteristic and transient N-centered isoniazidyl radical intermediate can be detected and identified from INH activation uniquely by Mn(III)Acetate not by Mn(III) pyrophosphate. The exact location of the radical was found to be at the distal-nitrogen of the hydrazine group by 15N-isotope-labeling techniques via using 15N-labeled INH. Diisonicotinyl hydrazine was identified as a new reaction product from INH/Mn(III). Analogous results were observed with other hydrazides. This study represents the first detection and unequivocal identification of the initial N-centered isoniazidyl radical and its exact location. These findings should provide a new perspective on the molecular mechanism of INH activation, which may have broad biomedical and toxicological significance for future research for more efficient hydrazide anti-tuberculosis drugs.
- Published
- 2019
27. Targeted live-cell nuclear delivery of the DNA ‘light-switching’ Ru(II) complex via ion-pairing with chlorophenolate counter-anions: the critical role of binding stability and lipophilicity of the ion-pairing complexes
- Author
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Zhu-Ying Yan, Jie Shao, Chun-Hua Huang, Miao Tang, Rong Huang, Xi-Juan Chao, and Ben-Zhan Zhu
- Subjects
Cell ,Trichlorophenol ,Biology ,010402 general chemistry ,01 natural sciences ,Medicinal chemistry ,Ruthenium ,Metal ,chemistry.chemical_compound ,Chemical Biology and Nucleic Acid Chemistry ,Genetics ,medicine ,Humans ,Phenols ,Cell Nucleus ,010405 organic chemistry ,Gene Transfer Techniques ,Cationic polymerization ,DNA ,humanities ,0104 chemical sciences ,Pentachlorophenol ,medicine.anatomical_structure ,chemistry ,visual_art ,Lipophilicity ,visual_art.visual_art_medium ,Hydrophobic and Hydrophilic Interactions ,Chlorophenols ,HeLa Cells - Abstract
We have found recently that nuclear uptake of the cell-impermeable DNA light-switching Ru(II)-polypyridyl cationic complexes such as [Ru(bpy)2(dppz)]Cl2 was remarkably enhanced by pentachlorophenol (PCP), by forming ion-pairing complexes via a passive diffusion mechanism. However, it is not clear whether the enhanced nuclear uptake of [Ru(bpy)2(dppz)]2+ is only limited to PCP, or it is a general phenomenon for other highly chlorinated phenols (HCPs); and if so, what are the major physicochemical factors in determining nuclear uptake? Here, we found that the nuclear uptake of [Ru(bpy)2(dppz)]2+ can also be facilitated by other two groups of HCPs including three tetrachlorophenol (TeCP) and six trichlorophenol (TCP) isomers. Interestingly and unexpectedly, 2,3,4,5-TeCP was found to be the most effective one for nuclear delivery of [Ru(bpy)2(dppz)]2+, which is even better than the most-highly chlorinated PCP, and much better than its two other TeCP isomers. Further studies showed that the nuclear uptake of [Ru(bpy)2(dppz)]2+ was positively correlated with the binding stability, but to our surprise, inversely correlated with the lipophilicity of the ion-pairing complexes formed between [Ru(bpy)2(dppz)]Cl2 and HCPs. These findings should provide new perspectives for future investigations on using ion-pairing as an effective method for delivering other bio-active metal complexes into their intended cellular targets.
- Published
- 2019
28. Enantioselective and Differential Fluorescence Lifetime Imaging of Nucleus and Nucleolus by the Two Enantiomers of Chiral Os(II) Polypyridyl Complex
- Author
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Jie Shao, Ben-Zhan Zhu, Rong Huang, and Chun-Hua Huang
- Subjects
Fluorescence-lifetime imaging microscopy ,Chemistry ,Nucleolus ,cells ,Cellular differentiation ,02 engineering and technology ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,0104 chemical sciences ,Spindle apparatus ,symbols.namesake ,medicine.anatomical_structure ,Stokes shift ,symbols ,medicine ,Biophysics ,General Materials Science ,Physical and Theoretical Chemistry ,Enantiomer ,0210 nano-technology ,Mitosis ,Nucleus - Abstract
The nucleolus is an important subnuclear structure, but very few dyes are available for nucleolar imaging. Here we show that the Λ-enantiomer of [Os(phen)2(dppz)]Cl2 can differentially distinguish the nucleolus from nucleus in living cells with tetrachlorophenolate as counteranion, while the Δ-enantiomer can do so in fixed cells by FLIM imaging. Further studies with three specific metabolic inhibitors for nucleolar protein synthesis found that the lifetime changes of the two enantiomers in the nucleolus can reflect the alteration of the cellular microenvironment, which is related to the general pathological status of the nucleolus. We then observed dynamical architecture changes of the nucleolus, chromosome and spindle apparatus during cell differentiation by these two enantiomers. The chiral Os(II) complex shows many advantages as compared to the commercially available nucleolus dye Syto 9: it displays a much larger Stokes shift value with a near-red emission and a longer lifetime, it can image spindle apparatus during mitosis, and more importantly, it is enantioselective.
- Published
- 2019
29. Mechanistic Study on Oxidative DNA Damage and Modifications by Haloquinoid Carcinogenic Intermediates and Disinfection Byproducts
- Author
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Ben-Zhan Zhu, Chun-Hua Huang, Li Mao, Jie Shao, and Miao Tang
- Subjects
Radical ,010501 environmental sciences ,Toxicology ,medicine.disease_cause ,01 natural sciences ,Oxidative dna damage ,03 medical and health sciences ,chemistry.chemical_compound ,medicine ,Animals ,Humans ,Carcinogen ,030304 developmental biology ,0105 earth and related environmental sciences ,0303 health sciences ,Chemistry ,Mutagenicity Tests ,Mutagenesis ,General Medicine ,DNA ,Phenanthrenes ,Quinone ,genomic DNA ,Oxidative Stress ,Biochemistry ,Carcinogens ,Environmental Pollutants ,Genotoxicity ,DNA Damage ,Disinfectants - Abstract
Haloquinones (XQs) are a group of carcinogenic intermediates of the haloaromatic environmental pollutants and newly identified chlorination disinfection byproducts (DBPs) in drinking water. The highly reactive hydroxyl radicals/alkoxyl radicals and quinone enoxy/ketoxy radicals were found to arise in XQs and H2O2 or organic hydroperoxides system, independent of transition-metal ions. However, it was not clear whether these haloquinoid carcinogens and hydroperoxides can cause oxidative DNA damage and modifications, and if so, what are the underlying molecular mechanisms. We found that 8-oxodeoxyguanosine (8-oxodG), DNA strand breaks, and three methyl oxidation products could arise when DNA was treated with tetrachloro-1,4-benzoquinone and H2O2 via a metal-independent and intercalation-enhanced oxidation mechanism. Similar effects were observed with other XQs, which are generally more efficient than the typical Fenton system. We further extended our studies from isolated DNA to genomic DNA in living cells. We also found that potent oxidation of DNA to the more mutagenic imidazolone dIz could be induced by XQs and organic hydroperoxides such as t-butylhydroperoxide or the physiologically relevant hydroperoxide 13S-hydroperoxy-9Z,11E-octadecadienoic acid via an unprecedented quinone-enoxy radical-mediated mechanism. These findings should provide new perspectives to explain the potential genotoxicity, mutagenesis, and carcinogenicity for the ubiquitous haloquinoid carcinogenic intermediates and DBPs.
- Published
- 2021
30. The cell-impermeable Ru(II) polypyridyl complex as a potent intracellular photosensitizer under visible light irradiation via ion-pairing with suitable lipophilic counter-anions
- Author
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Zhi-Hui Zhang, Hongmei Su, Jing Chen, Li Mao, Miao Tang, Chun-Hua Huang, Jie Shao, Zhu-Ying Yan, Ze-Qing Jiao, Zhi-Guo Sheng, Ben-Zhan Zhu, Rong Huang, and Tian-Shu Tang
- Subjects
0301 basic medicine ,Tris ,Anions ,Light ,medicine.medical_treatment ,Photodynamic therapy ,Photochemistry ,Biochemistry ,Ruthenium ,HeLa ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Coordination Complexes ,Physiology (medical) ,medicine ,Humans ,Photosensitizer ,Irradiation ,Photosensitizing Agents ,biology ,Singlet oxygen ,Cationic polymerization ,biology.organism_classification ,030104 developmental biology ,Flufenamic acid ,chemistry ,030217 neurology & neurosurgery ,medicine.drug ,HeLa Cells - Abstract
Developing the cell-impermeable Ru(II) polypyridyl cationic complexes as effective photosensitizers (PS) which have high cellular uptake and photo-toxicity, but low dark toxicity, is quite challenging. Here we found that the highly reactive singlet oxygen (1O2) can be generated by the irradiation of a typical Ru(II) polypyridyl complex Ru(II)tris(tetramethylphenanthroline) ([Ru(TMP)3]2+) under visible light irradiation by ESR with TEMPO (2,2,6,6-tetramethyl-4-piperidone-N-oxyl) as 1O2 probe. Effective cellular and nuclear delivery of cationic [Ru(TMP)3]2+ was achieved through our recently developed ion-pairing method, and 2,3,4,5-tetrachlorophenol (2,3,4,5-TeCP) was found to be the most effective among all chlorophenols tested. The accelerated cellular, especially nuclear uptake of [Ru(TMP)3]2+ results in the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and DNA strand breaks, caspase 3/7 activation and cell apoptosis in HeLa cells upon light irradiation. More importantly, compared with other traditional photosensitizers, [Ru(TMP)3]2+ showed significant photo-toxicity but low dark toxicity. Similar effects were observed when 2,3,4,5-TeCP was substituted by the currently clinically used anti-inflammatory drug flufenamic acid. This represents the first report that the cell-impermeable Ru(II) polypyridyl complex ion-paired with suitable lipophilic counter-anions functions as potent intracellular photosensitizer under visible light irradiation mainly via a 1O2-mediated mechanism. These findings should provide new perspectives for future investigations on other metal complexes with similar characteristics as promising photosensitizers for potential photodynamic therapy.
- Published
- 2021
31. Reactive Nitrogen Species Are Also Involved in the Transformation of Micropollutants by the UV/Monochloramine Process
- Author
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Zihao Wu, Chunyan Chen, Ben-Zhan Zhu, Taicheng An, Fangang Meng, Jingyun Fang, and Chun-Hua Huang
- Subjects
Chloramine ,Ultraviolet Rays ,Bicarbonate ,Radical ,Chloramines ,Advanced oxidation process ,chemistry.chemical_element ,General Chemistry ,Nitroso ,010501 environmental sciences ,Reactive Nitrogen Species ,01 natural sciences ,Water Purification ,Kinetics ,chemistry.chemical_compound ,Reaction rate constant ,chemistry ,Chlorine ,Environmental Chemistry ,Hydroxyl radical ,Oxidation-Reduction ,Water Pollutants, Chemical ,0105 earth and related environmental sciences ,Nuclear chemistry - Abstract
The UV/monochloramine (NH2Cl) process is an emerging advanced oxidation process (AOP) in water treatment via radicals produced from the UV photolysis of NH2Cl. This study investigated the degradation of micropollutants by the UV/NH2Cl AOP, with ibuprofen (IBP) and naproxen (NPX) selected as representative micropollutants. Hydroxyl radical (HO•) and chlorine atom (Cl•) were identified in the process, and unexpectedly, we found that reactive nitrogen species (RNS) also played important roles in the transformation of micropollutants. The electron paramagnetic resonance (EPR) analysis proved the production of •NO as well as HO•. The concentrations of HO•, Cl•, and •NO in UV/NH2Cl remained constant at pH 6.0-8.6, resulting in the slightly changed UV fluence-based pseudo-first-order rate constants (k') of IBP and NPX, which were about 1.65 × 10-3 and 2.54 × 10-3 cm2/mJ, respectively. For IBP, the relative contribution of RNS to k' was 27.8% at pH 7 and 50 μM NH2Cl, which was higher than that of Cl• (6.5%) but lower than that of HO• (58.7%). For NPX, the relative contribution of RNS to k' was 13.6%, which was lower than both Cl• (23.2%) and HO• (46.9%). The concentrations of HO•, Cl•, and •NO increased with the increasing NH2Cl dosage. Water matrix components of natural organic matter (NOM) and bicarbonate can scavenge HO•, Cl•, and RNS. The presence of 5 mg/L NOM decreased the k' of IBP and NPX by 66.9 and 57.6%, respectively, while 2 mM bicarbonate decreased the k' of IBP by 57.4% but increased the k' of NPX by 10.5% due to the contribution of CO3•- to NPX degradation. Products containing nitroso-, hydroxyl-, and chlorine-groups were detected during the degradation of IBP and NPX by UV/NH2Cl, indicating the role of nitrogen oxide radical (•NO) as well as HO• and Cl•. Trichloronitromethane formation was strongly enhanced in the UV/NH2Cl-treated samples, further indicating the important roles of RNS in this process. This study first demonstrates the involvement of RNS in the transformation of micropollutants in UV/NH2Cl.
- Published
- 2019
32. What Are the Major Physicochemical Factors in Determining the Preferential Nuclear Uptake of the DNA 'Light-Switching' Ru(II)-Polypyridyl Complex in Live Cells via Ion-Pairing with Chlorophenolate Counter-Anions?
- Author
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Miao Tang, Chun-Hua Huang, Jie Shao, Rong Huang, Ben-Zhan Zhu, Zhu-Ying Yan, and Xi-Juan Chao
- Subjects
Polymers ,Pyridines ,02 engineering and technology ,010402 general chemistry ,Photochemistry ,01 natural sciences ,Ruthenium ,Metal ,chemistry.chemical_compound ,Coordination Complexes ,Humans ,Molecule ,General Materials Science ,Physical and Theoretical Chemistry ,Ions ,Molecular Structure ,Chemistry, Physical ,Ion pairing ,DNA ,Ion pairs ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,chemistry ,visual_art ,Lipophilicity ,visual_art.visual_art_medium ,0210 nano-technology ,Chlorophenols ,HeLa Cells - Abstract
Delivering potential theranostic metal complexes into preferential cellular targets is becoming of increasing interest. Here we report that nuclear uptake of a cell-impermeable DNA "light-switching" Ru(II)-polypyridyl complex can be significantly facilitated by chlorophenolate counter-anions, which was found, unexpectedly, to be correlated positively with the binding stability but inversely with the lipophilicity of the formed ion pairs.
- Published
- 2019
33. An unusual double radical homolysis mechanism for the unexpected activation of the aldoxime nerve-agent antidotes by polyhalogenated quinoid carcinogens under normal physiological conditions
- Author
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Ben-Zhan Zhu, Jie Shao, Lin-Na Xie, Chun-Hua Huang, Feng Li, Balaraman Kalyanaraman, and Dan Xu
- Subjects
0301 basic medicine ,Pralidoxime ,Free Radicals ,Halogenation ,Chloranil ,Antidotes ,Pyridinium Compounds ,Biochemistry ,Aldehyde ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Nucleophile ,Fragmentation (mass spectrometry) ,Physiology (medical) ,Oximes ,medicine ,Humans ,Chemical Warfare Agents ,Carcinogen ,Nerve agent ,chemistry.chemical_classification ,Pralidoxime Compounds ,Chemistry ,Electron Spin Resonance Spectroscopy ,Models, Theoretical ,Combinatorial chemistry ,Organic Chemistry Phenomena ,Homolysis ,030104 developmental biology ,Carcinogens ,Pyridinium ,Nerve Agents ,030217 neurology & neurosurgery ,medicine.drug - Abstract
We have recently shown that the pyridinium aldoximes, best-known as therapeutic antidotes for chemical warfare nerve-agents, could markedly detoxify the carcinogenic tetrachloro-1,4-benzoquinone (TCBQ) via an unusual double Beckmann fragmentation mechanism. However, it is still not clear why pralidoxime (2-PAM) cannot provide full protection against TCBQ-induced biological damages even when 2-PAM was in excess. Here we show, unexpectedly, that TCBQ can also activate pralidoxime to generate a reactive iminyl radical intermediate in two-consecutive steps, which was detected and unequivocally characterized by the complementary application of ESR spin-trapping, HPLC/MS and nitrogen-15 isotope-labeling studies. The same iminyl radical was observed when TCBQ was substituted by other halogenated quinones. The end product of iminyl radical was isolated and identified as its corresponding reactive and toxic aldehyde. Based on these data, we proposed that the reaction of 2-PAM and TCBQ might be through the following two competing pathways: a nucleophilic attack of 2-PAM on TCBQ forms an unstable transient intermediate, which can decompose not only heterolytically to form 2-CMP via double Beckmann fragmentation, but also homolytically leading to the formation of a reactive iminyl radical in double-steps, which then via H abstraction and further hydrolyzation to form its corresponding more toxic aldehyde. Analogous radical homolysis mechanism was observed with other halogenated quinones and pyridinium aldoximes. This study represents the first detection and identification of reactive iminyl radical intermediates produced under normal physiological conditions, which provides direct experimental evidence to explain only the partial protection by 2-PAM against TCBQ-induced biological damages, and also the potential side-toxic effects induced by 2-PAM and other pyridinium aldoxime nerve-agent antidotes.
- Published
- 2019
34. Molecular mechanism of endocrine-disruptive effects induced by Bisphenol A: The role of transmembrane G-protein estrogen receptor 1 and integrin αvβ3
- Author
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Furong Ren, Cong Wang, Ben-Zhan Zhu, Yu-Xiang Liu, and Zhi-Guo Sheng
- Subjects
endocrine system ,Environmental Engineering ,medicine.drug_class ,G protein ,Population ,Estrogen receptor ,Endocrine Disruptors ,010501 environmental sciences ,Male germ cell proliferation ,01 natural sciences ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,Phenols ,medicine ,Environmental Chemistry ,Endocrine system ,Benzhydryl Compounds ,education ,030304 developmental biology ,0105 earth and related environmental sciences ,General Environmental Science ,0303 health sciences ,education.field_of_study ,urogenital system ,Chemistry ,General Medicine ,Integrin alphaVbeta3 ,Cell biology ,Receptors, Estrogen ,Mechanism of action ,Estrogen ,G-Protein Coupled Estrogen Receptor 1 ,medicine.symptom ,hormones, hormone substitutes, and hormone antagonists - Abstract
Bisphenol A (BPA) is one of the highest volume industrial products worldwide and has been widely used to make various products as the intermediates of polycarbonate plastics and epoxy resins. Inevitably, general population has been widely exposed to BPA due to extensive use of BPA-containing products. BPA has similar chemical structure with the natural estrogen and has been shown to induce a variety of estrogen-like endocrine effects on organism in vivo or in vitro. High doses of BPA tend to act as antagonist of estrogen receptors (ERs) by directly regulating the genomic transcription. However, BPA at environmentally relevant low-dose always disrupt the biological function via a non-genomic manner mediated by membrane receptors, rather than ERs. Although some studies had investigated the non-genomic effects of low-dose BPA, the exact molecular mechanism still remains unclear. Recently, we found that membrane G protein-coupled estrogen receptor 1 and integrin αvβ3 and its relative signal pathways participate in the induction of male germ cell proliferation and thyroid transcription disruption by the low-dose BPA. A profound understanding for the mechanism of action of the environmentally relevant BPA exposure not only contributes to objectively evaluate and predict the potential influence to human health, but also provides theoretical basis and methodological support for assessing health effects trigged by other estrogen-like environmental endocrine disruptors. Based mainly on our recent findings, this review outlines the research progress of molecular mechanism on endocrine disrupting effects of environmental low-dose BPA, existing problems and some consideration for future studies.
- Published
- 2019
35. A new detoxification mechanism for aldoxime therapeutic antidotes for chemical warfare nerve-agents
- Author
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Jie Shao, Lin-Na Xie, Xuan Xiao, Fu-Rong Ren, Chun-Hua Huang, Dan Xu, and Ben-Zhan Zhu
- Subjects
Pralidoxime ,Nitrile ,General Chemical Engineering ,General Chemistry ,Biochemistry ,Combinatorial chemistry ,Hydroxylation ,chemistry.chemical_compound ,Hydroxylamine ,chemistry ,Detoxification ,Materials Chemistry ,medicine ,Nucleophilic substitution ,Pyridinium ,Nerve agent ,medicine.drug - Abstract
Pyridinium aldoximes are best-known as therapeutic antidotes for organophosphorus chemical warfare nerve-agents and pesticides. Polyhalogenated quinones are a class of carcinogenic intermediates and newly identified chlorination disinfection byproducts in drinking water. However, it is not clear what is the exact chemical mechanism underlying such detoxication. Here we showed that pralidoxime, one of the representatives of pyridinium aldoximes, can markedly enhance the dechlorination and hydroxylation of the highly reactive and toxic tetrachloro-1,4-benzoquinone (also called chloranil) in two-consecutive steps to produce the much less toxic 2,5-dichloro-3,6-dihydroxy-1,4-benzoquonine (chloranilic acid), with rate acceleration of up to 180000-times. In contrast, no enhancing effect was observed when the hydroxylamine group was blocked via methylation to form O -methylated pralidoxime. The major reaction product from pralidoxime was characterized as its corresponding nitrile (2-cyano-1-methylpyridinium chloride). Along with oxygen-18 isotope-labeling studies, we proposed that nucleophilic substitution coupled with an unprecedented double Beckmann fragmentation reaction was responsible for this dramatic enhancement of the detoxification reaction. This paper reviewed the unprecedented double Beckmann fragmentation reaction. Our findings may have broad biological and environmental implications for future research on the aldoxime therapeutic agents and carcinogenic polyhalogenated quinones, which are two important classes of compounds of major biomedical and environmental interest.
- Published
- 2018
36. Unexpected reversible and controllable nuclear uptake and efflux of the DNA 'light-switching' Ru(ii)-polypyridyl complex in living cells via ion-pairing with chlorophenolate counter-anions
- Author
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Rong Huang, Zhi-Guo Sheng, Chun-Hua Huang, Zhi-Hui Zhang, Jian-Qiang Zhu, Miao Tang, Sijin Liu, and Ben-Zhan Zhu
- Subjects
Pyridines ,Biomedical Engineering ,Ruthenium ,Metal ,chemistry.chemical_compound ,Coordination Complexes ,medicine ,Humans ,General Materials Science ,Redistribution (chemistry) ,A-DNA ,Cell Nucleus ,Ions ,Transporter ,Biological Transport ,General Chemistry ,General Medicine ,DNA ,medicine.anatomical_structure ,chemistry ,Cytoplasm ,A549 Cells ,visual_art ,visual_art.visual_art_medium ,Biophysics ,ATP-Binding Cassette Transporters ,Efflux ,Nucleus ,Chlorophenols ,HeLa Cells - Abstract
An in-depth understanding of the mechanisms of cellular uptake and efflux would facilitate the design of metal complexes with not only better functionality and targeted theranostic efficiency, but also with controlled toxicity. Here we find, unexpectedly, that the DNA "light-switching" Ru(ii)-polypyridyl complex [Ru(phen)2(dppz)]2+ already delivered to the nucleus via ion-pairing with chlorophenolate counter-anions can gradually efflux to the cytoplasm when the cells were washed and incubated with fresh culture-medium. Interestingly, [Ru(phen)2(dppz)]2+ effluxed to the cytoplasm can be redirected back to the nucleus when the chlorophenolate counter-anions were added again. The efflux of nuclear [Ru(phen)2(dppz)]2+ was found to be mediated mainly via ATP-binding cassette (ABC) transporter proteins. Analogous reversible, but enantio-selective nuclear uptake and efflux were observed with the two pure chiral forms of [Ru(phen)2(dppz)]Cl2. This represents the first report of reversible and controllable nuclear uptake and efflux of a DNA "light-switching" Ru(ii)-complex in living-cells via ion-pairing, which should provide novel insights for future research on using ion-pairing as an effective approach to control the cellular uptake and redistribution of other potential theranostic metal complexes.
- Published
- 2020
37. First Direct and Unequivocal Electron Spin Resonance Spin-Trapping Evidence for pH-Dependent Production of Hydroxyl Radicals from Sulfate Radicals
- Author
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Bo Shao, Jie Shao, Miao Tang, Li Mao, Hui-Ying Gao, Ben-Zhan Zhu, Chun-Hua Huang, and Zhu-Ying Yan
- Subjects
integumentary system ,Spin trapping ,Free Radicals ,Sulfate radical ,Hydroxyl Radical ,Sulfates ,Sulfate radicals ,Radical ,Electron Spin Resonance Spectroscopy ,Ph dependent ,General Chemistry ,010501 environmental sciences ,Hydrogen-Ion Concentration ,equipment and supplies ,Photochemistry ,01 natural sciences ,law.invention ,Cyclic N-Oxides ,law ,Environmental Chemistry ,Spin Labels ,Electron paramagnetic resonance ,0105 earth and related environmental sciences - Abstract
Recently, the sulfate radical (SO4•–) has been found to exhibit broad application prospects in various research fields such as chemical, biomedical, and environmental sciences. It has been suggeste...
- Published
- 2020
38. Potent Oxidation of DNA by Haloquinoid Disinfection Byproducts to the More Mutagenic Imidazolone dIz via an Unprecedented Haloquinone-Enoxy Radical-Mediated Mechanism
- Author
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Li Qin, Na Qu, Bo Shao, Jie Shao, Feng Li, Balaraman Kalyanaraman, Dan Xu, Chun-Hua Huang, Lin-Na Xie, and Ben-Zhan Zhu
- Subjects
Chemistry ,Radical ,Haloquinone ,Imidazoles ,General Chemistry ,DNA ,010501 environmental sciences ,Phenanthrenes ,01 natural sciences ,Decomposition ,Medicinal chemistry ,Quinone ,Disinfection ,chemistry.chemical_compound ,Environmental Chemistry ,Deoxyguanosine ,Nucleoside ,Oxidation-Reduction ,Carcinogen ,0105 earth and related environmental sciences ,Mutagens - Abstract
Halogenated quinones are a class of carcinogenic intermediates and newly identified chlorination disinfection byproducts in drinking water. We found recently that halogenated quinones could enhance the decomposition of hydroperoxides independent of transition-metal ions and formation of the novel quinone enoxy/ketoxy radicals. Here, we show that the major oxidation product was 2-amino-5-[(2-deoxy-β-d-erythro-pentofuranosyl)amino]-4H-imidazol-4-one (dIz) when the nucleoside 2'-deoxyguanosine (dG) was treated with tetrachloro-1,4-benzoquinone (TCBQ) and t-butyl hydroperoxide (t-BuOOH). The formation of dIz was markedly inhibited by typical radical spin-trapping agents. Interestingly and unexpectedly, we found that the generated quinone enoxy radical played a critical role in dIz formation. Using [15N5]-8-oxodG, dIz was found to be produced either directly from dG or through the transient formation of 8-oxodG. Based on these data, we proposed that the production of dIz might be through an unusual haloquinone-enoxy radical-mediated mechanism. Analogous results were observed in the oxidation of ctDNA by TCBQ/t-BuOOH and when t-BuOOH was substituted by the endogenously generated physiologically relevant hydroperoxide 13S-hydroperoxy-9Z,11E-octadecadienoic acid. This is the first report that halogenated quinoid carcinogens and hydroperoxides can induce potent oxidation of dG to the more mutagenic product dIz via an unprecedented quinone-enoxy radical-mediated mechanism, which may partly explain their potential carcinogenicity.
- Published
- 2020
39. First unequivocal identification of the critical acyl radicals from the anti-tuberculosis drug isoniazid and its hydrazide analogs by complementary applications of ESR spin-trapping and HPLC/MS methods
- Author
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Li Qin, Bo Shao, Li Mao, Ben-Zhan Zhu, and Chun-Hua Huang
- Subjects
0301 basic medicine ,Free Radicals ,Stereochemistry ,Radical ,Antitubercular Agents ,Hydrazide ,Biochemistry ,High-performance liquid chromatography ,Adduct ,Mycobacterium tuberculosis ,Cyclic N-Oxides ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Physiology (medical) ,medicine ,Isoniazid ,Chromatography, High Pressure Liquid ,biology ,Spin trapping ,Electron Spin Resonance Spectroscopy ,biology.organism_classification ,030104 developmental biology ,chemistry ,Nitrogen Oxides ,Spin Labels ,NAD+ kinase ,Spin Trapping ,030217 neurology & neurosurgery ,medicine.drug - Abstract
The carbon-centered isonicotinic acyl radical of isoniazid (INH), a widely-used frontline anti-tuberculosis drug, has been considered to play a critical role in inhibiting Mycobacterium tuberculosis, but not fully identified. Here we show that this radical intermediate can be unequivocally characterized by complementary applications of ESR spin-trapping and HPLC/MS methods by employing N-tert-butyl-α-phenylnitrone (PBN) as the suitable spin-trapping agent, which can form the most stable radical adduct. More importantly, for the first time, analogous carbon-centered acyl radicals and their respective NAD+ adducts have also been detected and identified from its two isomers (nicotinic acid hydrazide and 2-pyridinecarbohydrazide) and benzhydrazide which are structurally-related to INH, but not by 2-chloroisonicotinohydrazide. This study represents the first unequivocal identification of the carbon-centered acyl radicals of INH and other hydrazide analogs by both ESR spin-trapping and HPLC/MS methods, which may have broad biomedical and toxicological significance for future research for more efficient hydrazide anti-tuberculosis drugs.
- Published
- 2020
40. Diethyldithiocarbamate-copper nanocomplex reinforces disulfiram chemotherapeutic efficacy through light-triggered nuclear targeting
- Author
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Wenya Feng, Liting Ren, Nanfeng Zheng, Sijin Liu, Juan Ma, Ben-Zhan Zhu, Jie Shao, and Ming Xu
- Subjects
Drug ,DSF-Cu nanocomplex ,media_common.quotation_subject ,epithelial-mesenchymal transition ,Medicine (miscellaneous) ,Antineoplastic Agents ,Breast Neoplasms ,Theranostic Nanomedicine ,Metastasis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Drug Delivery Systems ,In vivo ,Cell Line, Tumor ,Neoplasms ,Disulfiram ,medicine ,Animals ,Humans ,metastasis ,Epithelial–mesenchymal transition ,Low-Level Light Therapy ,Neoplasm Metastasis ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,diethyldithiocarbamate ,030304 developmental biology ,media_common ,Cell Nucleus ,0303 health sciences ,business.industry ,In vitro toxicology ,Drug Repositioning ,Cancer ,Photothermal therapy ,medicine.disease ,light-triggered nuclear targeting ,Drug Liberation ,Nanomedicine ,030220 oncology & carcinogenesis ,Cancer research ,Nanoparticles ,Female ,business ,Ditiocarb ,Copper ,medicine.drug ,Research Paper - Abstract
To circumvent the huge cost, long R&D time and the difficulty to identify the targets of new drugs, repurposing the ones that have been clinically approved has been considered as a viable strategy to treat different diseases. In the current study, we outlined the rationale for repurposing disulfiram (DSF, an old alcohol-aversion drug) to treat primary breast cancer and its metastases. Methods: To overcome a few shortcomings of the individual administration of DSF, such as the dependence on copper ions (Cu2+) and limited capability in selective targeting, we here artificially synthesized the active form of DSF, diethyldithiocarbamate (DTC)-Cu complex (CuET) for cancer therapeutics. To achieve a greater efficacy in vivo, smart nanomedicines were devised through a one-step self-assembly of three functional components including a chemically stable and biocompatible phase-change material (PCM), the robust anticancer drug (CuET) and a near-infrared (NIR) dye (DIR), namely CuET/DIR NPs. A number of in vitro assays were performed including the photothermal efficacy, light-triggered drug release behavior, nuclear localization, DNA damage and induction of apoptosis of CuET/DIR NPs and molecular mechanisms underlying CuET-induced repression on cancer metastatic behaviors. Meanwhile, the mice bearing 4T1-LG12-drived orthotopic tumors were employed to evaluate in vivo biodistribution and anti-tumor effect of CuET/DIR NPs. The intravenous injection model was employed to reflect the changes of the intrinsic metastatic propensity of 4T1-LG12 cells responding to CuET/DIR NPs. Results: The rationally designed nanomedicines have self-traceability for bioimaging, long blood circulation time for enhanced drug accumulation in the tumor site and photo-responsive release of the anticancer drugs. Moreover, our data unearthed that CuET/DIR nanomedicines behave like "Trojan horse" to transport CuET into the cytoplasm, realizing substantial intracellular accumulation. Upon NIR laser irradiation, massive CuET would be triggered to release from the nanomedicines and reach a high local concentration towards the nucleus, where the pro-apoptotic effects were conducted. Importantly, our CuET/DIR nanomedicines revealed a pronounced capability to leash breast cancer metastases through inhibition on EMT. Additionally, these nanomedicines showed great biocompatibility in animals. Conclusion: These combined data unearthed a remarkably enhanced tumor-killing efficacy of our CuET nanomedicines through nuclear targeting. This work may open a new research area of repurposing DSF as innovative therapeutic agents to treat breast cancer and its metastases.
- Published
- 2020
41. Chiral Os(II) Polypyridyl Complexes as Enantioselective Nuclear DNA Imaging Agents Especially Suitable for Correlative High-Resolution Light and Electron Microscopy Studies
- Author
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Ben-Zhan Zhu, Tao Xu, Li Qin, Bo Shao, Yanhong Xue, Rong Huang, Fengping Feng, Miao Tang, Chun-Hua Huang, Li Mao, and Zhu-Ying Yan
- Subjects
Materials science ,Osmium Tetroxide ,Mitosis ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,law.invention ,chemistry.chemical_compound ,Microscopy, Electron, Transmission ,law ,Cell Line, Tumor ,Animals ,Humans ,General Materials Science ,Cell Nucleus ,Microscopy ,Enantioselective synthesis ,Cationic polymerization ,Stereoisomerism ,DNA ,021001 nanoscience & nanotechnology ,Combinatorial chemistry ,0104 chemical sciences ,Nuclear DNA ,chemistry ,Transmission electron microscopy ,Reagent ,Electron microscope ,0210 nano-technology ,Phenanthrolines - Abstract
The high-resolution technique transmission electron microscopy (TEM), with OsO4 as the traditional fixative, is an essential tool for cell biology and medicine. Although OsO4 has been extensively used, it is far from perfect because of its high volatility and toxicity. Os(II) polypyridyl complexes like [Os(phen)2(dppz)]2+ (phen = 1,10-phenanthroline; dppz = dipyridophenazine) are not only the well-known molecular DNA “light-switches” but also the potential ideal candidates for TEM studies. Here, we report that the cell-impermeable cationic [Os(phen)2(dppz)]2+ can be preferentially delivered into the live-cell nucleus through ion-pairing with chlorophenolate counter-anions, where it functions as an unparalleled enantioselective nuclear DNA imaging reagent especially suitable for correlative light and electron microscopy (CLEM) studies in both living and fixed cells, which can clearly visualize chromosome aggregation and decondensation during mitosis simultaneously. We propose that the chiral Os(II) polypyr...
- Published
- 2020
42. An unexpected antioxidant and redox activity for the classic copper-chelating drug penicillamine
- Author
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Bo Shao, Li Qin, Li Mao, Chun-Hua Huang, Ben-Zhan Zhu, Jie Shao, and Dan Xu
- Subjects
Antioxidant ,Autoxidation ,Metabolite ,medicine.medical_treatment ,Penicillamine ,Pharmacology ,Biochemistry ,Redox ,Antioxidants ,Hydroquinones ,chemistry.chemical_compound ,chemistry ,Pharmaceutical Preparations ,Physiology (medical) ,Toxicity ,medicine ,Chelation ,Cytotoxicity ,Oxidation-Reduction ,Copper ,medicine.drug ,Chelating Agents - Abstract
Penicillamine has been widely-used clinically as a copper-chelating drug for the treatment of copper-overload in Wilson's disease. In this study, we found that penicillamine provided marked protection against cytotoxicity induced by tetrachlorohydroquinone (TCHQ), a major toxic metabolite of the well-known wood preservative pentachlorophenol, while other classic copper-chelating agents do not. We found, unexpectedly, that both TCHQ autooxidation and tetrachlorosemiquinone radical (TCSQ•-) formation were remarkably delayed by penicillamine. Further investigation showed that TCSQ•- was reduced back to TCHQ by penicillamine, with the concurrent formation of its corresponding disulfide. These data demonstrated that the protection by penicillamine against TCHQ-induced toxicity was not due to its classic Cu-chelating property, but rather to its reduction of the reactive TCSQ•- to the much less-reactive TCHQ. This is the first report of an unexpected antioxidant and redox activity for penicillamine, which might prove highly relevant to its biological activities.
- Published
- 2019
43. Intrinsic chemiluminescence production from the degradation of haloaromatic pollutants during environmentally-friendly advanced oxidation processes: Mechanism, structure–activity relationship and potential applications
- Author
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Hui-Ying Gao, Ben-Zhan Zhu, Chen Shen, Liya Zhu, Jie Shao, and Li Mao
- Subjects
Luminescence ,Pentachlorophenol ,Environmental Engineering ,Semiquinone ,Metabolite ,Radical ,010501 environmental sciences ,010402 general chemistry ,01 natural sciences ,Structure-Activity Relationship ,chemistry.chemical_compound ,Benzoquinones ,Environmental Chemistry ,Organic chemistry ,Hydrogen peroxide ,0105 earth and related environmental sciences ,General Environmental Science ,Pollutant ,Hydrocarbons, Halogenated ,Hydroxyl Radical ,Hydrogen Peroxide ,General Medicine ,0104 chemical sciences ,Models, Chemical ,chemistry ,Environmental chemistry ,Degradation (geology) ,Hydroxyl radical ,Oxidation-Reduction - Abstract
The ubiquitous distribution of halogenated aromatic compounds (XAr) coupled with their carcinogenicity has raised public concerns on their potential risks to both human health and the ecosystem. Recently, advanced oxidation processes (AOPs) have been considered as an "environmentally-friendly" technology for the remediation and destruction of such recalcitrant and highly toxic XAr. During our study on the mechanism of metal-independent production of hydroxyl radicals (OH) by halogenated quinones and H2O2, we found, unexpectedly, that an unprecedented OH-dependent two-step intrinsic chemiluminescene (CL) can be produced by H2O2 and tetrachloro-p-benzoquinone, the major carcinogenic metabolite of the widely used wood preservative pentachlorophenol. Further investigations showed that, in all OH-generating systems, CL can also be produced not only by pentachlorophenol and all other halogenated phenols, but also by all XAr tested. A systematic structure-activity relationship study for all 19 chlorophenolic congeners showed that the CL increased with an increasing number of Cl-substitution in general. More importantly, a relatively good correlation was observed between the formation of quinoid/semiquinone radical intermediates and CL generation. Based on these results, we propose that OH-dependent formation of quinoid intermediates and electronically excited carbonyl species is responsible for this unusual CL production; and a rapid, sensitive, simple, and effective CL method was developed not only to detect and quantify trace amount of XAr, but also to provide useful information for predicting the toxicity or monitoring real-time degradation kinetics of XAr. These findings may have broad chemical, environmental and biological implications for future studies on halogenated aromatic persistent organic pollutants.
- Published
- 2017
44. Unusual Double Beckmann Fragmentation Reaction under Physiological Conditions
- Author
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Jun-Ge Zhu, Dan Xu, Lin-Na Xie, Balaraman Kalyanaraman, Bo Shao, Hui-Ying Gao, Ben-Zhan Zhu, Chun-Hua Huang, Feng Li, and Chen Shen
- Subjects
0301 basic medicine ,Reaction mechanism ,Pralidoxime Compounds ,Pralidoxime ,Molecular Structure ,Nitrile ,Organic Chemistry ,Chloride ,Hydroxylation ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,chemistry ,medicine ,Nucleophilic substitution ,Organic chemistry ,Metabolic Detoxication, Phase I ,Pyridinium ,Carcinogen ,medicine.drug - Abstract
Pyridinium aldoximes, which are best-known as therapeutic antidotes for organophosphorus chemical warfare nerve-agents and pesticides, have been found to markedly detoxify polyhalogenated quinones, which are a class of carcinogenic intermediates and recently identified disinfection byproducts in drinking water. However, the exact chemical mechanism underlying this detoxication remains unclear. Here we demonstrate that pralidoxime can remarkably facilitate the dechlorination/hydroxylation of the highly toxic tetrachloro-1,4-benzoquinone in two-consecutive steps to generate the much less toxic 2,5-dichloro-3,6-dihydroxy-1,4-benzoquonine, with rate enhancements of up to 180 000-times. On the contrary, no accelerating effect was noticed with O-methylated pralidoxime. The major reaction product from pralidoxime was identified as its corresponding nitrile (2-cyano-1-methylpyridinium chloride). Along with oxygen-18 isotope-labeling studies, a reaction mechanism was proposed in which nucleophilic substitution coupled with an unprecedented double Beckmann fragmentation reaction was responsible for the dramatic enhancement in the detoxification process. This represents the first report of an unusually mild and facile Beckmann-type fragmentation that can occur under normal physiological conditions in two-consecutive steps. The study may have broad biomedical and environmental significance for future investigations of aldoxime therapeutic agents and carcinogenic polyhalogenated quinones.
- Published
- 2017
45. Free-Radical-Mediated Photoinduced Electron Transfer between 6-Thioguanine and Tryptophan Leading to DNA-Protein-Like Cross-Link.
- Author
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Dong, Junjie, Chunhua Huang, Shaoshi Guo, Ye Xia, Yue Hou, Chunfan Yang, Xianwang Zhang, Jialong Jie, Ben-Zhan Zhu, and Hongmei Su
- Published
- 2022
- Full Text
- View/download PDF
46. Mechanism of unprecedented hydroxyl radical production and site-specific oxidative DNA damage by photoactivation of the classic arylhydroxamic acid carcinogens
- Author
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Dan Xu, Jie Shao, Bo Shao, Balaraman Kalyanaraman, Ben-Zhan Zhu, Lin-Na Xie, Li Mao, and Chun-Hua Huang
- Subjects
0301 basic medicine ,Cancer Research ,Spin trapping ,DNA damage ,Guanine ,Radical ,General Medicine ,Photochemistry ,Thymine ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,Hydroxyl radical ,Cytosine ,DNA - Abstract
The carcinogenicity of N-hydroxy-2-acetamidofluorene (N-OHAAF), the major genotoxic metabolite of the classic model aromatic amine (AA) carcinogen 2-acetylaminofluorene, has been attributed mainly to the formation of DNA adducts via arylnitrenium upon enzymatic activation. Here, we show, unexpectedly, that exposure of N-OHAAF to UV or sunlight irradiation can not only induce the formation of the well-known covalent DNA adducts, but, more interestingly, simultaneous generation of oxidative DNA damage was also observed as measured by the formation of DNA single-/double-strand breaks (SSBs/DSBs) and 8-oxo-2'-deoxyguanosine (8-oxodG), which were partly inhibited by the typical hydroxyl radical (•OH) scavengers. Electron spin resonance spin-trapping and fluorescent studies unequivocally confirmed that the highly reactive •OH was generated from photolysis of N-OHAAF. Further DNA sequencing investigations suggest that photoactivation of N-OHAAF caused preferential cleavage at guanine, thymine and cytosine sites. More importantly, the formation of 8-oxodG and DSBs were also observed when fibroblast Balb/c-3T3 cells were co-exposed to N-OHAAF/UV irradiation as measured by double immunofluorescence staining. Taken together, we propose that both •OH and amidyl radicals can be readily produced via N-OH homolysis in N-OHAAF by photoirradiation, which can induce both oxidative and covalent DNA damage. This represents the first report of •OH production and site-specific DNA damage via photoactivation of the genotoxic hydroxamic acid intermediate, which provides a new free radical perspective to better understand the molecular mechanism for the carcinogenicity of AAs.
- Published
- 2019
47. The Critical Role of X Chromosome-Linked Inhibitor of Apoptosis (XIAP) in Differential Synergism Induced by Pentachlorophenol and Copper-1,10-Phenanthroline Complex in Normal and Cancer Liver Cells
- Author
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Ben-Zhan Zhu, Xi-Juan Chao, Zhi-Guo Sheng, Rui-Mei Fan, Yu-Xiang Liu, and Chen Shen
- Subjects
0301 basic medicine ,Pentachlorophenol ,Apoptosis Inhibitor ,Cell Survival ,Population ,Caspase 3 ,Apoptosis ,X-Linked Inhibitor of Apoptosis Protein ,Toxicology ,Inhibitor of apoptosis ,03 medical and health sciences ,0302 clinical medicine ,Organometallic Compounds ,Humans ,education ,chemistry.chemical_classification ,Membrane Potential, Mitochondrial ,education.field_of_study ,Reactive oxygen species ,Chemistry ,Drug Synergism ,Hep G2 Cells ,Molecular biology ,XIAP ,030104 developmental biology ,Cancer cell ,Hepatocytes ,Reactive Oxygen Species ,Transcriptome ,030217 neurology & neurosurgery ,Copper ,Phenanthrolines - Abstract
Chemical pollutants often co-occur and can interact to cause unexpected combined toxic effects. Both pentachlorophenol (PCP) and copper-1,10-phenanthroline [Cu(OP)2], used as wood preservatives, coexist in fluids and tissues of ordinary population. Our previous studies demonstrate that a combination of subtoxic PCP and Cu(OP)2 causes synergistic toxicity on Escherichia coli and hepatocarcinoma cells. However, it is not clear whether this effect also occurs in normal hepatocytes; and if so, what are the differences as compared with the hepatocarcinoma cells. We demonstrate that the combination of low-toxic PCP and Cu(OP)2 (0-1.6 µM; PCP/Cu(OP)2 molar ratio: 2:1) induces a concentration-dependent intracellular copper accumulation, apoptosis, caspase-3/9 activation, depolarization of mitochondrial membrane potential, and oxidative stress (reactive oxygen species increasing and glutathione/oxidized glutathione ratio decreasing) in both normal hepatocytes HL-7702 and hepatocarcinoma HepG2 cells. However, HepG2 cells are more susceptible to the above molecular events as compared with HL-7702 cells. Further data reveal that PCP/Cu(OP)2 markedly decreases X chromosome-linked inhibitor of apoptosis (XIAP), p-ERK-1/2, and p-JNK protein expression in HepG2, but not HL-7702. Overexpression of XIAP gene in HepG2 significantly blocks PCP/Cu(OP)2-induced cytotoxicity, caspase activity, apoptosis, ROS accumulation, and antioxidant genes expression. These results suggest that the combination of low-toxic PCP and Cu(OP)2 preferentially induce synergistic cytotoxicity in human hepatocarcinoma cells by XIAP-ROS-apoptosis pathway, compared with the normal hepatocytes. The present data not only confirm the synergistic toxicity of PCP/Cu(OP)2 combination in normal liver cells, but also suggest a possible opportunity in developing new therapeutic approaches for liver cancer by sensitizing cancer cells to chemotherapy.
- Published
- 2018
48. Delivering the cell-impermeable DNA ‘light-switching’ Ru(<scp>ii</scp>) complexes preferentially into live-cell nucleus via an unprecedented ion-pairing method
- Author
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Chun-Hua Huang, Ben-Zhan Zhu, Yan Li, and Xi-Juan Chao
- Subjects
010405 organic chemistry ,Enantioselective synthesis ,Cationic polymerization ,chemistry.chemical_element ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,Ruthenium ,Nuclear DNA ,Metal ,chemistry.chemical_compound ,medicine.anatomical_structure ,Tolfenamic acid ,chemistry ,visual_art ,visual_art.visual_art_medium ,medicine ,Organic chemistry ,Nucleus ,DNA ,medicine.drug - Abstract
The dipyridophenazine (dppz) based ruthenium polypyridyl complexes are known as molecular ‘light-switches’ for DNA. This property is poised to serve in diagnostic and therapeutic applications, but the poor cellular uptake restricts their use in live cells. Herein, we show that the cellular uptake, and more interestingly and surprisingly, the nuclear uptake of cell-impermeable Ru(II)–polypyridyl cationic complexes such as [Ru(bpy)2(dppz)]2+ were remarkably enhanced by three structurally unrelated biochemical agents (pentachlorophenol, carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone and tolfenamic acid), by forming lipophilic and relatively stable ion-pair complexes, via a passive diffusion mechanism. Enantioselective imaging of live-cell nuclear DNA was observed between the two chiral forms of Ru(II) complexes. This represents the first report of an unprecedented new method for delivering the DNA ‘light-switching’ Ru(II) complexes into the nucleus of living cells via ion-pairing, which could serve as a promising general live-cell delivery method for other potentially bio-medically important but cell-impermeable metal complexes.
- Published
- 2016
49. Different modes of synergistic toxicities between metam/copper (II) and metam/zinc (II) in HepG2 cells: apoptosis vs. necrosis
- Author
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Zhi-Guo Sheng, Mingxin Li, Ben-Zhan Zhu, Li Mao, Chin-pao Huang, and Rui-Mei Fan
- Subjects
0301 basic medicine ,Programmed cell death ,biology ,Health, Toxicology and Mutagenesis ,Cytochrome c ,chemistry.chemical_element ,General Medicine ,Zinc ,Phosphatidylserine ,Management, Monitoring, Policy and Law ,Toxicology ,Copper ,Metam sodium ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,chemistry ,Apoptosis ,Toxicity ,biology.protein ,Nuclear chemistry - Abstract
Both metam sodium and copper/zinc-containing compounds are widely used as fungicides. They therefore may co-occur in the biosphere. Despite certain studies of individual toxicity for either metam or copper (II)/zinc (II), their synergistic toxicity has not been examined. In this paper, a remarkable synergistic toxicity was observed in HepG2 cells when metam and copper (II)/zinc (II) at non-toxic and sub-toxic levels were combined. Unexpectedly, cell death modes between metam/copper (II) and metam/zinc (II) were different: For metam/copper (II), apoptosis was evident from morphological characteristics including cytoplasm-chromatin condensation, phosphatidylserine (PS) exposure, SubG0 /G1 DNA fragmentation, mitochondrial membrane potential decrease, pro/anti-apoptotic protein activation, and cytochrome c release; for metam/zinc (II), necrosis was evident from organelle swelling and uncontrolled collapse. To our knowledge, this work first not only demonstrates the synergistic toxicities of metam and both copper (II)/zinc (II), but also verifies the different modes of apoptosis/necrosis between metam/copper (II) and metam/zinc (II). © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1964-1973, 2016.
- Published
- 2015
50. Unprecedented strong intrinsic chemiluminescence generation from degradation of halogenated hydroxy-quinoid pollutants by Co(II)-mediated advanced oxidation processes: The critical role of site-specific production of hydroxyl radicals
- Author
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Hui-Ying Gao, Ben-Zhan Zhu, Li Mao, Bo Shao, Chun-Hua Huang, Rong Huang, Li Qin, and Jie Shao
- Subjects
inorganic chemicals ,chemistry.chemical_classification ,Reactive oxygen species ,General Chemical Engineering ,Radical ,Advanced oxidation process ,02 engineering and technology ,General Chemistry ,010402 general chemistry ,021001 nanoscience & nanotechnology ,Photochemistry ,01 natural sciences ,Industrial and Manufacturing Engineering ,0104 chemical sciences ,law.invention ,chemistry.chemical_compound ,chemistry ,Chloranilic acid ,Dihydroxylation ,law ,Environmental Chemistry ,Degradation (geology) ,Hydroxyl radical ,0210 nano-technology ,Chemiluminescence - Abstract
We found previously that an unusual two-step hydroxyl radical ( OH)–dependent chemiluminescence (CL) can be produced by the carcinogenic tetrachloro-1,4-benzoquinone (TCBQ, also known as p-chloranil) and H2O2. However, neither OH generation nor CL emission could be observed between H2O2 and chloranilic acid (CA), the dihydroxylation product of TCBQ. Here we found, unexpectedly, that distinct CL could be produced from CA/H2O2 in the presence of a variety of transition metal ions, among them Co(II) was found to be the most effective. Interestingly, the kinetic profiles of CL production, CA degradation, and reactive oxygen species (ROS) generation were found to be markedly changed with the molar ratios of Co(II):CA. When compared with the classic Fe(II)-mediated Fenton system, we found that the much stronger CL emission and more effective degradation of CA induced by Co(II)-mediated Fenton-like system is mainly due to the highly reactive OH generated site-specifically by Co(II)/H2O2, although other ROS such as O2 − and 1O2 were also detected. More interestingly, not only CA, other halogenated anilic acids and catechols could also produce significant CL by Co(II)-mediated Fenton-like system. This is the first report on the distinct CL emission from degradation of halogenated hydroxyl-quinones by Co(II)-mediated Fenton-like advanced oxidation process, which is dependent on the site-specifically produced OH. These findings may have potential applications in measuring halogenated hydroxyl-quinones, and developing more effective techniques to degrade these types of important environmental pollutants.
- Published
- 2020
Catalog
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