Biomedical subjects

Yao-Zhong Xu

Publications and source records attributed to Yao-Zhong Xu.

7 recordsLinked to original sources

PubMed2006

Novel DNA lesions generated by the interaction between therapeutic thiopurines and UVA light.

The therapeutic effect of the thiopurines, 6-thioguanine (6-TG), 6-mercaptopurine, and its prodrug azathioprine, depends on the incorporation of 6-TG into cellular DNA. Unlike normal DNA bases, 6-TG absorbs UVA radiation, and UVA-mediated photochemical damage of DNA 6-TG has potentially harmful side effects. When free 6-TG is UVA irradiated in solution in the presence of molecular oxygen, reactive oxygen species are generated and 6-TG is oxidized to guanine-6-sulfonate (G(SO3)) and guanine-6-thioguanine in reactions involving singlet oxygen. This conversion is prevented by antioxidants, including the dietary vitamin ascorbate. DNA G(SO3) is also the major photoproduct of 6-TG in DNA and it can be selectively introduced into DNA or oligonucleotides in vitro by mild chemical oxidation. Thermal stability measurements indicate that G(SO3) does not form stable base pairs with any of the normal DNA bases in duplex oligonucleotides and is a powerful block for elongation by Klenow DNA polymerase in primer extension experiments. In cultured human cells, DNA damage produced by 6-TG and UVA treatment is associated with replication inhibition and provokes a p53-dependent DNA damage response.

Antimetabolites, Antineoplastic↗

PubMed2005

Azathioprine and UVA light generate mutagenic oxidative DNA damage.

Oxidative stress and mutagenic DNA lesions formed by reactive oxygen species (ROS) are linked to human malignancy. Clinical treatments inducing chronic oxidative stress may therefore carry a risk of therapy-related cancer. We suggest that immunosuppression by azathioprine (Aza) may be one such treatment. Aza causes the accumulation of 6-thioguanine (6-TG) in patients' DNA. Here we demonstrate that biologically relevant doses of ultraviolet A (UVA) generate ROS in cultured cells with 6-TG-substituted DNA and that 6-TG and UVA are synergistically mutagenic. A replication-blocking DNA 6-TG photoproduct, guanine sulfonate, was bypassed by error-prone, Y-family DNA polymerases in vitro. A preliminary analysis revealed that in five of five cases, Aza treatment was associated with a selective UVA photosensitivity. These findings may partly explain the prevalence of skin cancer in long-term survivors of organ transplantation.

Adenine Phosphoribosyltransferase↗

PubMed2005

Post-synthetic and site-specific modification of endocyclic nitrogen atoms of purines in DNA and its potential for biological and structural studies.

Site-specific modification of the N1-position of purine was explored at the nucleoside and oligomer levels. 2'-deoxyinosine was converted into an N1-2,4-dinitrophenyl derivative 2 that was readily transformed to the desired N1-substituted 2'-deoxyinosine analogues. This approach was used to develop a post-synthetic method for the modification of the endocyclic N1-position of purine at the oligomer level. The phosphoramidite monomer of N1-(2,4-dinitrophenyl)-2'-deoxyinosine 9 was prepared from 2'-deoxyinosine in four steps and incorporated into oligomers using an automated DNA synthesizer. The modified base, N1-(2,4-dinitrophenyl)-hypoxanthine, in synthesized oligomers, upon treatment with respective agents, was converted into corresponding N1-substituted hypoxanthines, including N1-15N-hypoxanthine, N1-methylhypoxanthine and N1-(2-aminoethyl)-hypoxanthine. These modified oligomers can be easily separated and high purity oligomers obtained. Melting curve studies show the oligomer containing N1-methylhypoxanthine or N1-(2-aminoethyl)-hypoxanthine has a reduced thermostability with no particular pairing preference to either cytosine or thymine. The developed method could be adapted for the preparation of oligomers containing mutagenic N1-beta-hydroxyalkyl-hypoxanthines and the availability of the rare base-modified oligomers should offer novel tools for biological and structural studies.

2,4-Dinitrophenol↗

PubMed2005

Evidence for three thymine DNA glycosylases in human cell extracts: substrate specificities of thymine DNA glycosylase activities.

BACKGROUND: Purified human thymine DNA glycosylase (TDG) recognizes a G: T mispair in a CpG sequence context more strongly than in any other, in addition to its inactivity toward 2-aminopurine: T or 2,6 diaminopurine: T pairs. We investigated the multiplicity of TDG to establish a better relationship between in vitro G: T mismatch incision and in vivo repair of a G: T to a G: C pair. MATERIAL/METHODS: Cell-free extract was prepared from A1235-MR4 human glioma cells grown in tissue culture. Fractions containing TDG activities were separated on a strong anion-exchange column. 45-bp DNA containing a single G: T or altered G: T mispair was prepared for measuring mismatch-specific strand-incision. RESULTS: The extract yielded three fractions containing TDG activities. Each was further purified on a sizing column to exclude a relationship between a small fragment and TDG activity. While the substrate activity range of fraction III, eluting at the highest salt concentration, was the same as the known TDG, fractions eluted at medium and low concentrations were distinct: fractions I and II reacted with substrates of known TDG and DNA containing or 2-aminopurine: T (2,6-diaminopurine: T) base pairs. Modified m4T mispaired with G in DNA was acted on by fraction I and not II or III, suggesting fraction I activity is distinct. Each fraction showed strong activity on DNA with G: U and G: T mispairs in the CpG sequence context. CONCLUSIONS: The unique range of each TDG activity corresponding to the three fractions indicates that human cells possibly express three distinct TDGs.

Base Pairing↗

PubMed2004

4-Thio-5-bromo-2'-deoxyuridine: chemical synthesis and therapeutic potential of UVA-induced DNA damage.

4-Thio-5-bromo-2'-deoxyuridine (3a) is prepared from 5-bromo-2'-deoxyuridine (BrdU) and its key properties are explored. The thionucleoside (3a) can react readily with monobromobimane and produces high fluorescence. 3a has UV maximum absorption at 340 nm and can be incorporated into cellular DNA. The cells containing 3a become sensitive to UVA light, offering therapeutic potential for UVA-induced cell killing.

Antineoplastic Agents↗

PubMed2003

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Anatomy↗

PubMed2002

Lack of effects of vitamin E on aluminium-induced deficit of synaptic plasticity in rat dentate gyrus in vivo.

Aluminium (Al), has the potential to be neurotoxic in humans and animals, and is present in many manufactured foods and medicines and is also added to drinking water for purification purposes. Our previous study demonstrated that chronic Al exposure induced deficits of both long-term potentiation (LTP) and long-term depression (LTD) of excitatory postsynaptic potential (EPSP) and population spike (PS) in rat dentate gyrus (DG) of hippocampus in vivo (Wang et al., 2001). The purpose of the present study was to investigate whether the Al-induced impairment of synaptic plasticity could be reversed by dietary supplementation with vitamin E (Vit E; alpha-tocopherol). Neonatal Wistar rats were exposed to Al from parturition throughout life by drinking 0.3% aluminium chloride (AlCl3) solution or a diet supplemented with Vit E at 500 microg/g/day with 0.3% AlCl3. The input/output (I/O) function, EPSP and PS were measured in DG area of adult rats (80-100 days of age) in response to stimulation applied to the lateral perforant path. The results showed that: (1) chronic Al exposure reduced the amplitudes of both EPSP LTP (control: 130.4+/-3%, n=7; Al-exposed: 110+/-2%, n=9, P<0.001) and PS LTP (control: 241+/-19%, n=7; Al-exposed: 130+/-7%, n=9, P<0.001) significantly. Vit E had no significant effects on the Al-induced deficits of EPSP LTP (Al-exposed: 110+/-2%, n=9; Al-exposed+Vit E: 112+/-2%, n=8, P>0.05) and PS LTP (Al-exposed: 130+/-7%, n=9; Al-exposed+Vit E: 129+/-4%, n=8; P>0.05); (2) the amplitudes of EPSP LTD (control: 84+/-4%, n=7; Al-exposed: 92+/-7%, n=9, P<0.01) and PS LTD (control: 81+/-4%, n=7; Al-exposed: 98+/-5%, n=9, P<0.001) were also decreased by Al treatment. The impaired EPSP LTD (Al-exposed: 92+/-7%, n=9; Al-exposed+Vit E: 93+/-4%, n=8, P>0.05) and PS LTD (Al-exposed: 98+/-5%, n=9; Al-exposed+Vit E: 94+/-6%, n=8, P>0.05) were also not significantly affected by Vit E treatment. It was suggested that dietary supplementation with Vit E did not reverse the impairment of synaptic plasticity induced by Al in DG in vivo.

Aluminum↗