Theaflavins(TFs) are the dimers of a couple of epimerized catechins,which are specially formed during black tea fermentation.To explore the differences among four main TF derivatives(theaflavin(TF 1),theaflavin3-galla...Theaflavins(TFs) are the dimers of a couple of epimerized catechins,which are specially formed during black tea fermentation.To explore the differences among four main TF derivatives(theaflavin(TF 1),theaflavin3-gallate(TF 2 A),theaflavin-3'-gallate(TF 2 B),and theaflavin-3,3'-digallate(TF 3)) in scavenging reactive oxygen species(ROS) in vitro,their properties of inhibiting superoxide,singlet oxygen,hydrogen peroxide,and the hydroxyl radical,and their effects on hydroxyl radical-induced DNA oxidative damage were systematically analyzed in the present study.The results show that,compared with()-epigallocatechin gallate(EGCG),TF derivatives were good antioxidants for scavenging ROS and preventing the hydroxyl radical-induced DNA damage in vitro.TF 3 was the most positive in scavenging hydrogen peroxide and hydroxyl radical,and TF 1 suppressed superoxide.Positive antioxidant capacities of TF 2 B on singlet oxygen,hydrogen peroxide,hydroxyl radical,and the hydroxyl radical-induced DNA damage in vitro were found.The differences between the antioxidant capacities of four main TF derivatives in relation to their chemical structures were also discussed.We suggest that these activity differences among TF derivatives would be beneficial to scavenge different ROS with therapeutic potential.展开更多
Objective To investigate oxidative DNA damage in pharmacy technicians preparing antineoplastic drugs at the PIVAS （Pharmacy Intravenous Admixture Service） in two Chinese hospitals. Methods Urinary 8-OHdG served as a...Objective To investigate oxidative DNA damage in pharmacy technicians preparing antineoplastic drugs at the PIVAS （Pharmacy Intravenous Admixture Service） in two Chinese hospitals. Methods Urinary 8-OHdG served as a biomarker. 5-Fluorouracil （5-FU） concentrations in air, masks and gloves were determined. The spill exposure of each PIVAS technician to antineoplastic drugs was investigated. Eighty subjects were divided into exposed group t, II, and control group I, II. Results 5-FU concentration ratios for gloves and masks in exposed group I were significantly higher than those in exposed group II （P〈0.05 or P〈0.01）. The average urinary 8-OHdG concentrations in exposed group I, control group I, exposed group II, and control group II were 24.69＋0.93, 20.68＋1.07, 20.57＋0.55, and 12.96_＋0.73 ng/mg Cr, respectively. Urinary 8-OHdG concentration in exposed group I was significantly higher than that in control group I or that in exposed group 11 （P〈0.02）. There was a significant correlation between urinary 8-OHdG concentrations and spill frequencies per technician （P〈0.01）. Conclusion There was detectable oxidative DNA damage in PIVAS technicians exposed to antineoplastic drugs. This oxidative DNA damage may be associated with their spill exposure experience and contamination of their personal protective equipment.展开更多
Objective:To explore the possible effects of naringin on acrylamide-induced nephrotoxicity in rats.Methods:Sprague-Dawley rats weighing 200-250 g were randomly divided into five groups.The control group was given intr...Objective:To explore the possible effects of naringin on acrylamide-induced nephrotoxicity in rats.Methods:Sprague-Dawley rats weighing 200-250 g were randomly divided into five groups.The control group was given intragastric(i.g.)saline(1 mL)for 10 d.The acrylamide group was given i.g.acrylamide in saline(38.27 mg/kg titrated to 1 mL)for 10 d.The treatment groups were administered with naringin in saline(50 and 100 mg/kg,respectively)for 10 d and given i.g.acrylamide(38.27 mg/kg)1 h after naringin injection.The naringin group was given i.g.naringin(100 mg/kg)alone for 10 d.On day 11,intracardiac blood samples were obtained from the rats when they were under anesthesia,after which they were euthanized.Urea and creatinine concentrations of blood serum samples were analyzed with an autoanalyzer.Enzyme-linked immunosorbent assay was used to quantify malondialdehyde,superoxide dismutase,glutathione,glutathione peroxidase,catalase,tumor necrosis factor-α,nuclear factor-κB,interleukin(IL)-33,IL-6,IL-1β,cyclooxygenase-2,kidney injury molecule-1,mitogen-activated protein kinase-1,and caspase-3 in kidney tissues.Renal tissues were also evaluated by histopathological and immunohistochemical examinations for 8-OHdG and Bcl-2.Results:Naringin attenuated acrylamide-induced nephrotoxicity by significantly decreasing serum urea and creatinine levels.Naringin increased superoxide dismutase,glutathione,glutathione peroxidase,and catalase activities and decreased malondialdehyde levels in kidney tissues.In addition,naringin reduced the levels of inflammatory and apoptotic parameters in kidney tissues.The histopathological assay showed that acrylamide caused histopathological changes and DNA damage,which were ameliorated by naringin.Conclusions:Naringin attenuated inflammation,apoptosis,oxidative stress,and oxidative DNA damage in acrylamide-induced nephrotoxicity in rats.展开更多
BACKGROUND Oxidative damage of DNA and RNA has been associated with mortality of patients with different diseases.However,there is no published data on the potential use of DNA and RNA oxidative damage to predict the ...BACKGROUND Oxidative damage of DNA and RNA has been associated with mortality of patients with different diseases.However,there is no published data on the potential use of DNA and RNA oxidative damage to predict the prognosis of patients with hepatocellular carcinoma(HCC)undergoing liver transplantation(LT).AIM To determine whether patients with increased DNA and RNA oxidative damage prior to LT for HCC have a poor LT prognosis.METHODS Patients with HCC who underwent LT were included in this observational and retrospective study.Serum levels of all three oxidized guanine species(OGS)were measured prior to LT since guanine is the nucleobase that forms DNA and RNA most prone to oxidation.LT mortality at 1 year was the end-point study.RESULTS Surviving patients(n=101)showed lower serum OGS levels(P=0.01)and lower age of the liver donor(P=0.03)than non-surviving patients(n=13).An association between serum OGS levels prior to LT and 1-year LT(odds ratio=2.079;95%confidence interval=1.356-3.189;P=0.001)was found in the logistic regression analysis.CONCLUSION The main new finding was that high serum OGS concentration prior to LT was associated with the mortality 1 year after LT in HCC patients.展开更多
To study the genotoxicity effect of environmental tobacco side-stream smokes (ETSS) on oxidative DNA damage and its molecular mechanism. Methods DNA adduct 8-hydroxydeoxyguanosine (8-OHdG) was used ...To study the genotoxicity effect of environmental tobacco side-stream smokes (ETSS) on oxidative DNA damage and its molecular mechanism. Methods DNA adduct 8-hydroxydeoxyguanosine (8-OHdG) was used as a biomarker of oxidative DNA damage. The level of 8-OHdG in DNA exposed to ETSS was detected by high performance liquid chromatography with electrochemical detection. Organic and inorganic components in ETSS were analyzed by gas chromatography-mass spectrum and atomic absorption spectrum respectively. Results Particle matters (PMs) and volatile organic compounds (VOCs) in ETSS could directly induce oxidative DNA damage and formation of 8-OHdG. There were 123 and 84 kinds of organic components in PMs and VOCs respectively, and 7 kinds of inorganic components in ETSS. Some components, especially quinones and polyphenols in ETSS, could produce free radicals in vitro by auto-oxidation without any biological activity systems, and with the catalytic reaction of metals, the DNA adduct 8-OHdG was produced. Conclusion ETSS have biological oxidative effect on DNA in vitro and in vivo, and expressed direct genotoxicity. 8-OHdG is a valuable biomarker of oxidative DNA damage.展开更多
Studies were performed to determine the extent of nuclear DNA degradation induced by iron, iron-ascorbate, or iron-bleomycin under aerobic conditions in a model system using isolated rat liver nuclei. The effects of f...Studies were performed to determine the extent of nuclear DNA degradation induced by iron, iron-ascorbate, or iron-bleomycin under aerobic conditions in a model system using isolated rat liver nuclei. The effects of five antioxidants (catalase, superoxide dismutase, dimethyl sulfoxide, glutathione and diallyl sulfide) on this oxidative nuclear damage were also investigated. At the 0.05 level for statistical significance, iron induced concentration-dependent DNA degradation, and this effect was enhanced by ascorbate and bleomycin. The antioxidants catalase, dimethyl sulfoxide, and diallyl sulfide significantly reduced the iron-ascorbate-induced DNA damage, whereas superoxide dismutase and dimethyl sulfoxide significantly reduced iron-bleomycin-induced damage. Glutathione significantly increased the iron-bleomycin-induced DNA damage. These results suggest that the reactive oxygen species generated by iron, iron-ascorbate, and iron-bleomycin are responsible for the DNA strand breaks in isolated rat liver nuclei.展开更多
Background on chemotherapy-induced peripheral neuropathy（CIPN）Incidence,prevalence,and consequences：Up to 90%of cancer patients experience CIPN at some point during or after anticancer treatment（Seretny et al.,201...Background on chemotherapy-induced peripheral neuropathy（CIPN）Incidence,prevalence,and consequences：Up to 90%of cancer patients experience CIPN at some point during or after anticancer treatment（Seretny et al.,2014）.展开更多
We analyze oxidative activity of DNA due to fluorescence of chromosomes inside cells, using flow cytometry method with nanometer spatial resolution. Statistics of fluorescence is presented in histogram as frequency di...We analyze oxidative activity of DNA due to fluorescence of chromosomes inside cells, using flow cytometry method with nanometer spatial resolution. Statistics of fluorescence is presented in histogram as frequency distributions of flashes in the dependence on their intensity and in distributions of Shannon entropy, which was defined on the base of normalized distribution of information in original histogram for frequency of flashes. We show that overall sum of entropy, i.e. total entropy E , for any histogram is invariant and has identical trends of changes all values of E(r) = lnr at reduction of histogram’ rank r. This invariance reflects informational homeostasis of chromosomes activity in multi-scale networks of entropy inside all cells in various samples of blood for DNA inside neutrophils, lymphocytes, inside all leukocytes of human and inside chicken erythrocytes for various dyes, colors and various excitations of fluorescence. Informational homeostasis of oxidative activity of 3D DNA in the full set of chromosomes inside living cells exists for any Shannon-Weaver index of biodiversity of cells, at any state of health different beings. Regulation perturbations in information activity DNA provides informational adaptability and vitality of cells at homeostasis support. Noises of entropy, during regulation of informational homeostasis, depend on the states of health in real time. The main structural reconstructions of chromosomal correlations, corresponding to self-regulation of homeostasis, occur in the most large-scale networks of entropy, for rank r<32. We show that stability of homeostasis is supported by activity of all 46 chromosomes inside cells. Patterns, hidden switching and branching in sequences of averages of H?lder and central moments for noises in regulation of homeostasis define new opportunities in diagnostics of health and immunity. All people and all aerobic beings have one overall homeostatic level for countdown of information activity of DNA inside cells. We noted very bad and dangerous properties of artificial cells with other levels of informational homeostasis for all aerobic beings in foods, medical treatment and in biotechnologies.展开更多
The ubiquitin-editing enzyme A20 is known to regulate inflammation and maintain homeostasis,but its role in self-DNA-mediated inflammation in acute kidney injury(AKI)is not well understood.Here,our study demonstrated ...The ubiquitin-editing enzyme A20 is known to regulate inflammation and maintain homeostasis,but its role in self-DNA-mediated inflammation in acute kidney injury(AKI)is not well understood.Here,our study demonstrated that oxidized self-DNA accumulates in the serum of AKI mice and patients.This oxidized self-DNA exacerbates the progression of AKI by activating the cGAS-STING pathway and NLRP3 inflammasome.While inhibition of the STING pathway only slightly attenuates AKI progression,suppression of NLRP3 inflammasome-mediated pyroptosis significantly alleviates AKI progression and improves the survival of AKI mice.Subsequently,we found that Tnfaip3(encoding A20)is significantly upregulated following oxidized self-DNA treatment.A20 significantly alleviates AKI development by dampening STING signaling pathway and NLRP3-mediated pyroptosis.Moreover,A20-derived peptide(P-II)also significantly alleviates ox-dsDNA-induced pyroptosis and improves the survival and renal injury of AKI mice.Mechanistically,A20 competitively binds with NEK7 and thus inhibiting NLRP3 inflammasome.A20 and P-II interfere with the interaction between NEK7 and NLRP3 through Lys140 of NEK7.Mutation of Lys140 effects on the interaction of NEK7 with A20 and/or NLRP3 complex.Conditional knockout of NEK7 in macrophages or pharmacological inhibition of NEK7 both significantly rescue AKI mouse models.This study reveals a new mechanism by which A20 attenuates oxidized self-DNA-mediated inflammation and provides a new therapeutic strategy for AKI.展开更多
Oxidative stress, the imbalance between the production of reactive oxygen species （ROS） and antioxidant activity is a major culprit of male infertility. Peroxiredoxins （PRDXs） are major antioxidant enzymes of mamm...Oxidative stress, the imbalance between the production of reactive oxygen species （ROS） and antioxidant activity is a major culprit of male infertility. Peroxiredoxins （PRDXs） are major antioxidant enzymes of mammalian spermatozoa and are thiol oxidized and inactivated by ROS in a dose-dependent manner. Their deficiency and/or inactivation have been associated with men infertility. The aim of this study was to elucidate the impact of oxidative stress, generated by the in vivo tert-butyl hydroperoxide （tert-BHP） treatment on rat epididymal spermatozoa during their maturation process. Adult Sprague-Dawley males were treated with 300 -moles tert-BHP/kg or saline （control） per day intraperitoneal for 15 days. Lipid peroxidation （2-thibarbituric acid reactive substances assay）, total amount and thiol oxidation of PRDXs along with the total amount of superoxide dismutase （SOD）, motility and DNA oxidation （8-hydroxy-deoxyguanosine） were determined in epididymal spermatozoa. Total amount of PRDXs and catalase and thiol oxidation of PRDXs were determined in caput and cauda epididymis. While animals were not affected by treatment, their epididymal spermatozoa have decreased motility, increased levels of DNA oxidation and lipid peroxidation along with increased PRDXs （and not SOD） amounts. Moreover, sperm PRDXs were highly thiol oxidized. There was a differential regulation in the expression of PRDX1 and PRDX6 in the epididymis that suggests a segment-specific role for PRDXs. In conclusion, PRDXs are increased in epididymal spermatozoa in an attempt to fight against the oxidative stress generated by tert-BHP in the epididymis. These findings highlight the role of PRDXs in the protection of sperm function and DNA integrity during epididymal maturation.展开更多
It was previously found that the electric charge of water determines its ability to interact with other substances,including biologically significant ones.It is shown here that the electric charge of water can also de...It was previously found that the electric charge of water determines its ability to interact with other substances,including biologically significant ones.It is shown here that the electric charge of water can also determine its ability to penetrate and accumulate in living cells.In particular,it has been shown that the high penetrating ability of positively charged water determines both its active penetration into cells and accumulation in them,which creates favourable conditions for cell proliferation.At the same time,it has been shown that the low penetrating ability of negatively charged water determines its ability to slow down cell proliferation.It also discusses how medics can obtain and use water at different charges.展开更多
Objective The double transgenic mouse model （APPswe/PSldE9） of Alzheimer＇s disease （AD） has been widely used in experimental studies. β-Amyloid （Aβ） peptide is excessively produced in AD mouse brain, which af...Objective The double transgenic mouse model （APPswe/PSldE9） of Alzheimer＇s disease （AD） has been widely used in experimental studies. β-Amyloid （Aβ） peptide is excessively produced in AD mouse brain, which affects synaptic function and the development of central nervous system. However, little has been reported on characterization of this model. The present study aimed to characterize this mouse AD model and its wild-type counterparts by biochemical and functional approaches. Methods Blood samples were collected from the transgenic and the wild-type mice, and radial arm water maze behavioral test was conducted at the ages of 6 and 12 months. The mice were sacrificed at 12-month age. One hemisphere of the brain was frozen-sectioned for immunohistochemistry and the other hemisphere was dissected into 7 regions. The levels ofAβ1-40, Aβ1-42 and 8-hydroxydeoxyguanosine （8-OHdG） in blood or/and brain samples were analyzed by ELISA. Secretase activities in brain regions were analyzed by in vitro assays. Results The pre-mature death rate of transgenic mice was approximately 35% before 6-month age, and high levels of Aβ1-40 and Aβ1-42 were detected in these dead mice brains with a ratio of 1 ： 1 0. The level of blood-borne Aβ at 6-month age was similar with that at 12-month age. Besides, Aβ1-40 level in the blood was significantly higher than Aβ1-42 level at the ages of 6 and 12 months （ratio 2.37：1）. In contrast, the level of Aβ1-42 in the brain （160.6 ng/mg protein） was higher than that of Aβ1-40 （74 ng/mg protein） （ratio 2.17：1）. In addition, the levels of Aβ1-40 and Aβ1-42 varied markedly among different brain regions. Aβ1-42 level was significantly higher than Aβ1-40 level in cerebellum, frontal and posterior cortex, and hippocampus. Secretase activity assays did not reveal major differences among different brain regions or between wild-type and transgenic mice, suggesting that the transgene PS1 did not lead to higher 7-secretase activity but was more efficient in producing Aβ1-42 peptides. 8-OHdG, the biomarker of DNA oxidative damage, showed a trend of increase in the blood of transgenic mice, but with no significant difference, as compared with the wild-type mice. Behavioral tests showed that transgenic mice had significant memory deficits at 6-month age compared to wild-type controls, and the deficits were exacerbated at 12-month age with more errors. Conclusion These results suggest that this mouse model mimics the early-onset human AD and may represent full-blown disease at as early as 6-month age for experimental studies.展开更多
Objective To investigate the oxidative damage to lung tissue and peripherial blood in PM2.5-treated rats. Methods PM2.5 samples were collected using an auto-sampling instrument in summer and winter. Treated samples we...Objective To investigate the oxidative damage to lung tissue and peripherial blood in PM2.5-treated rats. Methods PM2.5 samples were collected using an auto-sampling instrument in summer and winter. Treated samples were endotracheally instilled into rats. Activity of reduced glutathione peroxidase （GSH-Px） and concentration of malondialdehyde （MDA） were used as oxidative damage biomarkers of lung tissue and peripheral blood detected with the biochemical method. DNA migration length （μm） and rate of tail were used as DNA damage biomarkers of lung tissue and peripheral blood detected with the biochemical method. Results The activity of GSH-Px and the concentration of MDA in lung tissue significantly decreased after exposure to PM2.5 for 7-14 days. In peripheral blood, the concentration of MDA decreased, but the activity of GSH-Px increased 7 and 14 days after experiments. The two indicators had a dose-effect relation and similar changing tendency in lung tissue and peripheral blood. The DNA migration length （μm） and rate of tail in lung tissue and peripheral blood significantly increased 7 and 14 days after exposure to PM2.5. The two indicators had a dose-effect relation and similar changing tendency in lung tissue and peripheral blood. Conclusion PM2.5 has a definite oxidative effect on lung tissue and peripheral blood. The activity of GSH-Px and the concentration of MDA are valuable biomarkers of oxidative lung tissue damage induced by PM2.5. The DNA migration length （μm） and rate of tail are simple and valuable biomarkers of PM2 5-induced DNA damage in lung tissues and peripheral blood. The degree of DNA damage in peripheral blood can predict the degree of DNA damage in lung tissue.展开更多
AIM： To assess whether a correlation exists between oxidative DNA damage occurring in chronic HCV-related hepatitis and expression levels of pro-inflammatory cytokines, TGF-α and c-myc. METHODS： The series included...AIM： To assess whether a correlation exists between oxidative DNA damage occurring in chronic HCV-related hepatitis and expression levels of pro-inflammatory cytokines, TGF-α and c-myc. METHODS： The series included 37 patients with chronic active HCV-related hepatitis and 11 with HCV-related compensated cirrhosis. Eight-hydroxydeoxyguanosine in liver biopsies was quantified using an electrochemical detector. The mRNA expression of TNF-α, IL-1β, TGF-α and c-myc in liver specimens was detected by semiquantitative comparaUve RT-PCR. RESULTS： TNF-α levels were significantly higher in hepatitis patients than in cirrhosis patients （P=0.05）. IL-1β was higher in cirrhosis patients （P=0.05）. A sig- nificant correlation was found between TNF-α and staging （P= 0.05） and between IL-1β levels and grading （P=0.04）. c-myc showed a significantly higher expression in cirrhosis patients （P=0.001）. Eight-hydroxydeoxyguanosine levels were significantly higher in cirrhosis patients （P=0.05） and in HCV genotype 1 （P=0.03）. Considering all patients, 8-hydroxydeoxyguanosine levels were found to be correlated with genotype （P=0.04） and grading （P=0.007）. Also multiple logistic regression analysis demonstrated a significant correlation among the number of DNA adducts, TNF-α expression and HCV genotype （P= 0.02）. CONCLUSION： In chronic HCV-related liver damage, oxidative DNA damage correlates with HCV genotype, grading and TNF-α levels. As HCV-related liver damage progresses, TNF-α levels drop while IL-1β and c-myc levels increase, which may be relevant to liver carcinogenesis.展开更多
Halobenzoquinones（HBQs） are an emerging class of halogenated disinfection byproducts（DBPs） in drinking water, which raised public concerns due to potential carcinogenic effects to human bladder. Our previous work ...Halobenzoquinones（HBQs） are an emerging class of halogenated disinfection byproducts（DBPs） in drinking water, which raised public concerns due to potential carcinogenic effects to human bladder. Our previous work demonstrated that HBQs and hydrogen peroxide（H_2O_2）together generated oxidative DNA damage via a metal-independent and intercalationenhanced oxidation mechanism in vitro. This study further investigated the efficiency of various HBQs to induce oxidative DNA damage in T24 bladder cancer cells. Compared with T24 cells without treatment（3.1 lesions per 10~6 d G）, the level of 8-oxo-7,8-dihydro-2′-deoxyguanosine（8-oxod G） significantly increased by 1.4, 3.2, 8.8, and 9.2 times after treatment with tetrabromo-1,4-benzoquinone（TBBQ）, terachloro-1,4-benzoquinone（TCBQ）,2,6-dichloro-1,4-benzoquinone（2,6-DCBQ） and 2,5-dichloro-1,4-benzoquinone（2,5-DCBQ） for24 hr, respectively. Interestingly, we found that the oxidative potency of HBQs in T24 cells（2,5-DCBQ ≈ 2,6-DCBQ 〉 TCBQ 〉 TBBQ） is inconsistent with that of in vitro ds DNA oxidation（TCBQ 〉 TBBQ 〉 2,5-DCBQ 〉 2,6-DCBQ）, suggesting HBQs induce oxidative lesions in cellular genomic DNA probably involved with a complex mechanism.展开更多
To investigate the accumulation and phytotoxicity of technical hexabromocyclododecane（HBCD）in maize,young seedlings were exposed to solutions of technical HBCD at different concentrations.The uptake kinetics showed ...To investigate the accumulation and phytotoxicity of technical hexabromocyclododecane（HBCD）in maize,young seedlings were exposed to solutions of technical HBCD at different concentrations.The uptake kinetics showed that the HBCD concentration reached an apparent equilibrium within 96 hr,and the accumulation was much higher in roots than in shoots.HBCD accumulation in maize had a positive linear correlation with the exposure concentration.The accumulation of different diastereoisomers followed the orderγ-HBCD〉β-HBCD〉α-HBCD.Compared with their proportions in the technical HBCD exposure solution,the diastereoisomer contribution increased forβ-HBCD and decreased forγ-HBCD in both maize roots and shoots with exposure time,whereas the contribution ofα-HBCD increased in roots and decreased in shoots throughout the experimental period.These results suggest the diastereomer-specific accumulation and translocation of HBCD in maize.Inhibitory effects of HBCD on the early development of maize followed the order of germination rate〉root biomass≥root elongation〉shoot biomass≥shoot elongation.Hydroxyl radical（OH）and histone H2AX phosphorylation（γ-H2AX）were induced in maize by HBCD exposure,indicative of the generation of oxidative stress and DNA double-strand breaks in maize.An OH scavenger inhibited the expression ofγ-H2AX foci in both maize roots and shoots,which suggests the involvement of OH generation in the HBCD-induced DNA damage.The results of this study will offer useful information for a more comprehensive assessment of the environmental behavior and toxicity of technical HBCD.展开更多
We have studied the genotoxic and apoptotic potential of ferric oxide nanoparticles（Fe_2O_3-NPs） in Raphanus sativus（radish）.Fe_2O_3-NPs retarded the root length and seed germination in radish.Ultrathin sections o...We have studied the genotoxic and apoptotic potential of ferric oxide nanoparticles（Fe_2O_3-NPs） in Raphanus sativus（radish）.Fe_2O_3-NPs retarded the root length and seed germination in radish.Ultrathin sections of treated roots showed subcellular localization of Fe_2O_3-NPs,along with the appearance of damaged mitochondria and excessive vacuolization.Flow cytometric analysis of Fe_2O_3-NPs（1.0 mg/m L） treated groups exhibited 219.5%,161%,120.4% and 161.4% increase in intracellular reactive oxygen species（ROS）,mitochondrial membrane potential（ΔΨm）,nitric oxide（NO） and Ca2＋influx in radish protoplasts.A concentration dependent increase in the antioxidative enzymes glutathione（GSH）,catalase（CAT）,superoxide dismutase（SOD） and lipid peroxidation（LPO） has been recorded.Comet assay showed a concentration dependent increase in deoxyribonucleic acid（DNA） strand breaks in Fe_2O_3-NPs treated groups.Cell cycle analysis revealed 88.4% of cells in sub-G1 apoptotic phase,suggesting cell death in Fe_2O_3-NPs（2.0 mg/m L） treated group.Taking together,the genotoxicity induced by Fe_2O_3-NPs highlights the importance of environmental risk associated with improper disposal of nanoparticles（NPs） and radish can serve as a good indicator for measuring the phytotoxicity of NPs grown in NP-polluted environment.展开更多
Haloacetamides（HAMs） are cytotoxic, genotoxic, and mutagenic byproducts of drinking water disinfection. They are soft electrophilic compounds that form covalent bonds with the free thiol/thiolate in cysteine residue...Haloacetamides（HAMs） are cytotoxic, genotoxic, and mutagenic byproducts of drinking water disinfection. They are soft electrophilic compounds that form covalent bonds with the free thiol/thiolate in cysteine residues through an S_N2 reaction mechanism.Toxicity of the monohalogenated HAMs（iodoacetamide, IAM; bromoacetamide, BAM;or chloroacetamide, CAM） varied depending on the halogen substituent. The aim of this research was to investigate how the halogen atom affects the reactivity and toxicological properties of HAMs, measured as induction of oxidative/electrophilic stress response and genotoxicity. Additionally, we wanted to determine how well in silico estimates of electrophilic softness matched thiol/thiolate reactivity and in vitro toxicological endpoints.Each of the HAMs significantly induced nuclear Rad51 accumulation and ARE signaling activity compared to a negative control. The rank order of effect was IAM 〉 BAM 〉 CAM for Rad51, and BAM ≈ IAM 〉 CAM for ARE. In general, electrophilic softness and in chemico thiol/thiolate reactivity provided a qualitative indicator of toxicity, as the softer electrophiles IAM and BAM were more thiol/thiolate reactive and were more toxic than CAM.展开更多
Background:Radiotherapy(RT)is a key treatment modality in cancer therapy,utilizing high-energy radiation to directly kill tumor cells.Recent research has increasingly highlighted RT’s potential to indirectly enhance ...Background:Radiotherapy(RT)is a key treatment modality in cancer therapy,utilizing high-energy radiation to directly kill tumor cells.Recent research has increasingly highlighted RT’s potential to indirectly enhance antitumor immunity.However,this immune activation alone often fails to generate sustained systemic antitumor responses.In this study,we aimed to investigate the antitumor effects of combining cholesterolized toll-like receptor 7(TLR7)agonist liposomes,specifically 1V209-Cho-Lip,with RT.Methods:Mouse tumor models were used to assess the impact of combining 1V209-Cho-Lip with RT on tumor progression and modification of the tumor microenvironment.In vitro,primary mouse bone marrow-derived dendritic cells(BMDCs)were utilized to investigate changes in function and the activated pathways through RNA sequencing.Additionally,we explored the role of oxidized mitochondrial DNA(ox-mtDNA)released from irradiated tumor cells as a damage-associated molecular pattern in modulating immune responses.The involvement of interleukin-1β(IL-1β)and the inflammasome pathway in the antitumor efficacy of the combined treatment was evaluated using Il-1β^(−/−)and cysteinyl aspartate specific proteinase 1 knockout(Casp1^(−/−))mouse models.Results:The combination of 1V209-Cho-Lip and RT significantly inhibited tumor growth and induced antitumor immunity in tumor models.This combination therapy enhanced maturation,antigen presentation and IL-1βsecretion of dendritic cells(DCs)in vitro.Ox-mtDNA released from irradiated tumor cells synergized with 1V209-Cho-Lip to activate the inflammasome pathway in DCs.The antitumor effect of the combined therapy was significantly reduced in Il-1β^(−/−)and Casp1^(−/−)mice.Conclusions:This study suggests that the combination of 1V209-Cho-Lip with RT might be a promising antitumor strategy and further studies are warranted to explore the clinical relevance of this combination therapy.展开更多
Exposure to ionizing radiation,a physical treatment that inactivates live tumor cells,has been extensively applied to enhance the antitumor responses induced by cancer cell vaccines in both animal research and human c...Exposure to ionizing radiation,a physical treatment that inactivates live tumor cells,has been extensively applied to enhance the antitumor responses induced by cancer cell vaccines in both animal research and human clinical trials.However,the mechanisms by which irradiated cells function as immunogenic tumor vaccines and induce effective antitumor responses have not been fully explored.Here,we demonstrate that oxidized mitochondrial DNA(mtDNA)and stimulator of interferon genes(STING)signaling play a key roles in the enhanced antitumor effect achieved with an irradiated tumor cell vaccine.Elevations in ROS and oxidized mtDNA 8-OHG content could be induced in irradiated tumor cells.Oxidized mtDNA derived from irradiated tumor cells gained access to the cytosol of dendritic cells(DCs).Oxidized mtDNA,as a DAMP or adjuvant,activated the STING-TBK1-IRF3-IFN-β pathway in DCs,which subsequently cross-presented irradiated tumor cell-derived antigens to CD8^(+)T cells and elicited antitumor immunity.The results of our study provide insight into the mechanism by which an irradiated cell vaccine mediates antitumor immunity,which may have implications for new strategies to improve the efficacy of irradiated vaccines.展开更多
基金Project supported by the National Natural Science Foundation of China (No. 30901002)the Fundamental Research Funds for the Central Universitiesthe China Postdoctoral Science Foundation Funded Project (No. 20070421210)
文摘Theaflavins(TFs) are the dimers of a couple of epimerized catechins,which are specially formed during black tea fermentation.To explore the differences among four main TF derivatives(theaflavin(TF 1),theaflavin3-gallate(TF 2 A),theaflavin-3'-gallate(TF 2 B),and theaflavin-3,3'-digallate(TF 3)) in scavenging reactive oxygen species(ROS) in vitro,their properties of inhibiting superoxide,singlet oxygen,hydrogen peroxide,and the hydroxyl radical,and their effects on hydroxyl radical-induced DNA oxidative damage were systematically analyzed in the present study.The results show that,compared with()-epigallocatechin gallate(EGCG),TF derivatives were good antioxidants for scavenging ROS and preventing the hydroxyl radical-induced DNA damage in vitro.TF 3 was the most positive in scavenging hydrogen peroxide and hydroxyl radical,and TF 1 suppressed superoxide.Positive antioxidant capacities of TF 2 B on singlet oxygen,hydrogen peroxide,hydroxyl radical,and the hydroxyl radical-induced DNA damage in vitro were found.The differences between the antioxidant capacities of four main TF derivatives in relation to their chemical structures were also discussed.We suggest that these activity differences among TF derivatives would be beneficial to scavenge different ROS with therapeutic potential.
基金supported by the Scientific Research Fund of Health Bureau in Zhejiang Province (2009A089)Scientific Research Fund of Education Bureau in Zhejiang Province (Y200804934)
文摘Objective To investigate oxidative DNA damage in pharmacy technicians preparing antineoplastic drugs at the PIVAS （Pharmacy Intravenous Admixture Service） in two Chinese hospitals. Methods Urinary 8-OHdG served as a biomarker. 5-Fluorouracil （5-FU） concentrations in air, masks and gloves were determined. The spill exposure of each PIVAS technician to antineoplastic drugs was investigated. Eighty subjects were divided into exposed group t, II, and control group I, II. Results 5-FU concentration ratios for gloves and masks in exposed group I were significantly higher than those in exposed group II （P〈0.05 or P〈0.01）. The average urinary 8-OHdG concentrations in exposed group I, control group I, exposed group II, and control group II were 24.69＋0.93, 20.68＋1.07, 20.57＋0.55, and 12.96_＋0.73 ng/mg Cr, respectively. Urinary 8-OHdG concentration in exposed group I was significantly higher than that in control group I or that in exposed group 11 （P〈0.02）. There was a significant correlation between urinary 8-OHdG concentrations and spill frequencies per technician （P〈0.01）. Conclusion There was detectable oxidative DNA damage in PIVAS technicians exposed to antineoplastic drugs. This oxidative DNA damage may be associated with their spill exposure experience and contamination of their personal protective equipment.
文摘Objective:To explore the possible effects of naringin on acrylamide-induced nephrotoxicity in rats.Methods:Sprague-Dawley rats weighing 200-250 g were randomly divided into five groups.The control group was given intragastric(i.g.)saline(1 mL)for 10 d.The acrylamide group was given i.g.acrylamide in saline(38.27 mg/kg titrated to 1 mL)for 10 d.The treatment groups were administered with naringin in saline(50 and 100 mg/kg,respectively)for 10 d and given i.g.acrylamide(38.27 mg/kg)1 h after naringin injection.The naringin group was given i.g.naringin(100 mg/kg)alone for 10 d.On day 11,intracardiac blood samples were obtained from the rats when they were under anesthesia,after which they were euthanized.Urea and creatinine concentrations of blood serum samples were analyzed with an autoanalyzer.Enzyme-linked immunosorbent assay was used to quantify malondialdehyde,superoxide dismutase,glutathione,glutathione peroxidase,catalase,tumor necrosis factor-α,nuclear factor-κB,interleukin(IL)-33,IL-6,IL-1β,cyclooxygenase-2,kidney injury molecule-1,mitogen-activated protein kinase-1,and caspase-3 in kidney tissues.Renal tissues were also evaluated by histopathological and immunohistochemical examinations for 8-OHdG and Bcl-2.Results:Naringin attenuated acrylamide-induced nephrotoxicity by significantly decreasing serum urea and creatinine levels.Naringin increased superoxide dismutase,glutathione,glutathione peroxidase,and catalase activities and decreased malondialdehyde levels in kidney tissues.In addition,naringin reduced the levels of inflammatory and apoptotic parameters in kidney tissues.The histopathological assay showed that acrylamide caused histopathological changes and DNA damage,which were ameliorated by naringin.Conclusions:Naringin attenuated inflammation,apoptosis,oxidative stress,and oxidative DNA damage in acrylamide-induced nephrotoxicity in rats.
文摘BACKGROUND Oxidative damage of DNA and RNA has been associated with mortality of patients with different diseases.However,there is no published data on the potential use of DNA and RNA oxidative damage to predict the prognosis of patients with hepatocellular carcinoma(HCC)undergoing liver transplantation(LT).AIM To determine whether patients with increased DNA and RNA oxidative damage prior to LT for HCC have a poor LT prognosis.METHODS Patients with HCC who underwent LT were included in this observational and retrospective study.Serum levels of all three oxidized guanine species(OGS)were measured prior to LT since guanine is the nucleobase that forms DNA and RNA most prone to oxidation.LT mortality at 1 year was the end-point study.RESULTS Surviving patients(n=101)showed lower serum OGS levels(P=0.01)and lower age of the liver donor(P=0.03)than non-surviving patients(n=13).An association between serum OGS levels prior to LT and 1-year LT(odds ratio=2.079;95%confidence interval=1.356-3.189;P=0.001)was found in the logistic regression analysis.CONCLUSION The main new finding was that high serum OGS concentration prior to LT was associated with the mortality 1 year after LT in HCC patients.
基金The research was supported and financed by brainstorm project and public good fund from the Ministry of Science and TechnologyChina (2001BA704B01& 2001DIA10001).
文摘To study the genotoxicity effect of environmental tobacco side-stream smokes (ETSS) on oxidative DNA damage and its molecular mechanism. Methods DNA adduct 8-hydroxydeoxyguanosine (8-OHdG) was used as a biomarker of oxidative DNA damage. The level of 8-OHdG in DNA exposed to ETSS was detected by high performance liquid chromatography with electrochemical detection. Organic and inorganic components in ETSS were analyzed by gas chromatography-mass spectrum and atomic absorption spectrum respectively. Results Particle matters (PMs) and volatile organic compounds (VOCs) in ETSS could directly induce oxidative DNA damage and formation of 8-OHdG. There were 123 and 84 kinds of organic components in PMs and VOCs respectively, and 7 kinds of inorganic components in ETSS. Some components, especially quinones and polyphenols in ETSS, could produce free radicals in vitro by auto-oxidation without any biological activity systems, and with the catalytic reaction of metals, the DNA adduct 8-OHdG was produced. Conclusion ETSS have biological oxidative effect on DNA in vitro and in vivo, and expressed direct genotoxicity. 8-OHdG is a valuable biomarker of oxidative DNA damage.
文摘Studies were performed to determine the extent of nuclear DNA degradation induced by iron, iron-ascorbate, or iron-bleomycin under aerobic conditions in a model system using isolated rat liver nuclei. The effects of five antioxidants (catalase, superoxide dismutase, dimethyl sulfoxide, glutathione and diallyl sulfide) on this oxidative nuclear damage were also investigated. At the 0.05 level for statistical significance, iron induced concentration-dependent DNA degradation, and this effect was enhanced by ascorbate and bleomycin. The antioxidants catalase, dimethyl sulfoxide, and diallyl sulfide significantly reduced the iron-ascorbate-induced DNA damage, whereas superoxide dismutase and dimethyl sulfoxide significantly reduced iron-bleomycin-induced damage. Glutathione significantly increased the iron-bleomycin-induced DNA damage. These results suggest that the reactive oxygen species generated by iron, iron-ascorbate, and iron-bleomycin are responsible for the DNA strand breaks in isolated rat liver nuclei.
基金the National Cancer Institute[CA122298(MRK)]the National Institutes of Health,[R21NS091667(MRK and JCF)]+2 种基金the Earl and Betty Herr Professor in Pediatric Oncology Research,Jeff Gordon Children’s Foundationthe Riley Children’s Foundation(MRK)IU Simon Cancer Center Neurotoxicity Working Group(MRK and JCF)
文摘Background on chemotherapy-induced peripheral neuropathy（CIPN）Incidence,prevalence,and consequences：Up to 90%of cancer patients experience CIPN at some point during or after anticancer treatment（Seretny et al.,2014）.
文摘We analyze oxidative activity of DNA due to fluorescence of chromosomes inside cells, using flow cytometry method with nanometer spatial resolution. Statistics of fluorescence is presented in histogram as frequency distributions of flashes in the dependence on their intensity and in distributions of Shannon entropy, which was defined on the base of normalized distribution of information in original histogram for frequency of flashes. We show that overall sum of entropy, i.e. total entropy E , for any histogram is invariant and has identical trends of changes all values of E(r) = lnr at reduction of histogram’ rank r. This invariance reflects informational homeostasis of chromosomes activity in multi-scale networks of entropy inside all cells in various samples of blood for DNA inside neutrophils, lymphocytes, inside all leukocytes of human and inside chicken erythrocytes for various dyes, colors and various excitations of fluorescence. Informational homeostasis of oxidative activity of 3D DNA in the full set of chromosomes inside living cells exists for any Shannon-Weaver index of biodiversity of cells, at any state of health different beings. Regulation perturbations in information activity DNA provides informational adaptability and vitality of cells at homeostasis support. Noises of entropy, during regulation of informational homeostasis, depend on the states of health in real time. The main structural reconstructions of chromosomal correlations, corresponding to self-regulation of homeostasis, occur in the most large-scale networks of entropy, for rank r<32. We show that stability of homeostasis is supported by activity of all 46 chromosomes inside cells. Patterns, hidden switching and branching in sequences of averages of H?lder and central moments for noises in regulation of homeostasis define new opportunities in diagnostics of health and immunity. All people and all aerobic beings have one overall homeostatic level for countdown of information activity of DNA inside cells. We noted very bad and dangerous properties of artificial cells with other levels of informational homeostasis for all aerobic beings in foods, medical treatment and in biotechnologies.
基金funded by the National Natural Science Foundation of China(Nos.8197219382171003).
文摘The ubiquitin-editing enzyme A20 is known to regulate inflammation and maintain homeostasis,but its role in self-DNA-mediated inflammation in acute kidney injury(AKI)is not well understood.Here,our study demonstrated that oxidized self-DNA accumulates in the serum of AKI mice and patients.This oxidized self-DNA exacerbates the progression of AKI by activating the cGAS-STING pathway and NLRP3 inflammasome.While inhibition of the STING pathway only slightly attenuates AKI progression,suppression of NLRP3 inflammasome-mediated pyroptosis significantly alleviates AKI progression and improves the survival of AKI mice.Subsequently,we found that Tnfaip3(encoding A20)is significantly upregulated following oxidized self-DNA treatment.A20 significantly alleviates AKI development by dampening STING signaling pathway and NLRP3-mediated pyroptosis.Moreover,A20-derived peptide(P-II)also significantly alleviates ox-dsDNA-induced pyroptosis and improves the survival and renal injury of AKI mice.Mechanistically,A20 competitively binds with NEK7 and thus inhibiting NLRP3 inflammasome.A20 and P-II interfere with the interaction between NEK7 and NLRP3 through Lys140 of NEK7.Mutation of Lys140 effects on the interaction of NEK7 with A20 and/or NLRP3 complex.Conditional knockout of NEK7 in macrophages or pharmacological inhibition of NEK7 both significantly rescue AKI mouse models.This study reveals a new mechanism by which A20 attenuates oxidized self-DNA-mediated inflammation and provides a new therapeutic strategy for AKI.
文摘Oxidative stress, the imbalance between the production of reactive oxygen species （ROS） and antioxidant activity is a major culprit of male infertility. Peroxiredoxins （PRDXs） are major antioxidant enzymes of mammalian spermatozoa and are thiol oxidized and inactivated by ROS in a dose-dependent manner. Their deficiency and/or inactivation have been associated with men infertility. The aim of this study was to elucidate the impact of oxidative stress, generated by the in vivo tert-butyl hydroperoxide （tert-BHP） treatment on rat epididymal spermatozoa during their maturation process. Adult Sprague-Dawley males were treated with 300 -moles tert-BHP/kg or saline （control） per day intraperitoneal for 15 days. Lipid peroxidation （2-thibarbituric acid reactive substances assay）, total amount and thiol oxidation of PRDXs along with the total amount of superoxide dismutase （SOD）, motility and DNA oxidation （8-hydroxy-deoxyguanosine） were determined in epididymal spermatozoa. Total amount of PRDXs and catalase and thiol oxidation of PRDXs were determined in caput and cauda epididymis. While animals were not affected by treatment, their epididymal spermatozoa have decreased motility, increased levels of DNA oxidation and lipid peroxidation along with increased PRDXs （and not SOD） amounts. Moreover, sperm PRDXs were highly thiol oxidized. There was a differential regulation in the expression of PRDX1 and PRDX6 in the epididymis that suggests a segment-specific role for PRDXs. In conclusion, PRDXs are increased in epididymal spermatozoa in an attempt to fight against the oxidative stress generated by tert-BHP in the epididymis. These findings highlight the role of PRDXs in the protection of sperm function and DNA integrity during epididymal maturation.
文摘It was previously found that the electric charge of water determines its ability to interact with other substances,including biologically significant ones.It is shown here that the electric charge of water can also determine its ability to penetrate and accumulate in living cells.In particular,it has been shown that the high penetrating ability of positively charged water determines both its active penetration into cells and accumulation in them,which creates favourable conditions for cell proliferation.At the same time,it has been shown that the low penetrating ability of negatively charged water determines its ability to slow down cell proliferation.It also discusses how medics can obtain and use water at different charges.
基金supported by ApoPharma Inc.through a collaborative research project between NRC-IBS and ApoPharma Inc
文摘Objective The double transgenic mouse model （APPswe/PSldE9） of Alzheimer＇s disease （AD） has been widely used in experimental studies. β-Amyloid （Aβ） peptide is excessively produced in AD mouse brain, which affects synaptic function and the development of central nervous system. However, little has been reported on characterization of this model. The present study aimed to characterize this mouse AD model and its wild-type counterparts by biochemical and functional approaches. Methods Blood samples were collected from the transgenic and the wild-type mice, and radial arm water maze behavioral test was conducted at the ages of 6 and 12 months. The mice were sacrificed at 12-month age. One hemisphere of the brain was frozen-sectioned for immunohistochemistry and the other hemisphere was dissected into 7 regions. The levels ofAβ1-40, Aβ1-42 and 8-hydroxydeoxyguanosine （8-OHdG） in blood or/and brain samples were analyzed by ELISA. Secretase activities in brain regions were analyzed by in vitro assays. Results The pre-mature death rate of transgenic mice was approximately 35% before 6-month age, and high levels of Aβ1-40 and Aβ1-42 were detected in these dead mice brains with a ratio of 1 ： 1 0. The level of blood-borne Aβ at 6-month age was similar with that at 12-month age. Besides, Aβ1-40 level in the blood was significantly higher than Aβ1-42 level at the ages of 6 and 12 months （ratio 2.37：1）. In contrast, the level of Aβ1-42 in the brain （160.6 ng/mg protein） was higher than that of Aβ1-40 （74 ng/mg protein） （ratio 2.17：1）. In addition, the levels of Aβ1-40 and Aβ1-42 varied markedly among different brain regions. Aβ1-42 level was significantly higher than Aβ1-40 level in cerebellum, frontal and posterior cortex, and hippocampus. Secretase activity assays did not reveal major differences among different brain regions or between wild-type and transgenic mice, suggesting that the transgene PS1 did not lead to higher 7-secretase activity but was more efficient in producing Aβ1-42 peptides. 8-OHdG, the biomarker of DNA oxidative damage, showed a trend of increase in the blood of transgenic mice, but with no significant difference, as compared with the wild-type mice. Behavioral tests showed that transgenic mice had significant memory deficits at 6-month age compared to wild-type controls, and the deficits were exacerbated at 12-month age with more errors. Conclusion These results suggest that this mouse model mimics the early-onset human AD and may represent full-blown disease at as early as 6-month age for experimental studies.
基金supported by National Natural Scientific Foundation (No. 90406024)the Natural Science Fund of Tianjin (No. 023606611)
文摘Objective To investigate the oxidative damage to lung tissue and peripherial blood in PM2.5-treated rats. Methods PM2.5 samples were collected using an auto-sampling instrument in summer and winter. Treated samples were endotracheally instilled into rats. Activity of reduced glutathione peroxidase （GSH-Px） and concentration of malondialdehyde （MDA） were used as oxidative damage biomarkers of lung tissue and peripheral blood detected with the biochemical method. DNA migration length （μm） and rate of tail were used as DNA damage biomarkers of lung tissue and peripheral blood detected with the biochemical method. Results The activity of GSH-Px and the concentration of MDA in lung tissue significantly decreased after exposure to PM2.5 for 7-14 days. In peripheral blood, the concentration of MDA decreased, but the activity of GSH-Px increased 7 and 14 days after experiments. The two indicators had a dose-effect relation and similar changing tendency in lung tissue and peripheral blood. The DNA migration length （μm） and rate of tail in lung tissue and peripheral blood significantly increased 7 and 14 days after exposure to PM2.5. The two indicators had a dose-effect relation and similar changing tendency in lung tissue and peripheral blood. Conclusion PM2.5 has a definite oxidative effect on lung tissue and peripheral blood. The activity of GSH-Px and the concentration of MDA are valuable biomarkers of oxidative lung tissue damage induced by PM2.5. The DNA migration length （μm） and rate of tail are simple and valuable biomarkers of PM2 5-induced DNA damage in lung tissues and peripheral blood. The degree of DNA damage in peripheral blood can predict the degree of DNA damage in lung tissue.
基金Supported by PRIN grants from the Italian Ministry of Science and Technology, No. 2003063143-006
文摘AIM： To assess whether a correlation exists between oxidative DNA damage occurring in chronic HCV-related hepatitis and expression levels of pro-inflammatory cytokines, TGF-α and c-myc. METHODS： The series included 37 patients with chronic active HCV-related hepatitis and 11 with HCV-related compensated cirrhosis. Eight-hydroxydeoxyguanosine in liver biopsies was quantified using an electrochemical detector. The mRNA expression of TNF-α, IL-1β, TGF-α and c-myc in liver specimens was detected by semiquantitative comparaUve RT-PCR. RESULTS： TNF-α levels were significantly higher in hepatitis patients than in cirrhosis patients （P=0.05）. IL-1β was higher in cirrhosis patients （P=0.05）. A sig- nificant correlation was found between TNF-α and staging （P= 0.05） and between IL-1β levels and grading （P=0.04）. c-myc showed a significantly higher expression in cirrhosis patients （P=0.001）. Eight-hydroxydeoxyguanosine levels were significantly higher in cirrhosis patients （P=0.05） and in HCV genotype 1 （P=0.03）. Considering all patients, 8-hydroxydeoxyguanosine levels were found to be correlated with genotype （P=0.04） and grading （P=0.007）. Also multiple logistic regression analysis demonstrated a significant correlation among the number of DNA adducts, TNF-α expression and HCV genotype （P= 0.02）. CONCLUSION： In chronic HCV-related liver damage, oxidative DNA damage correlates with HCV genotype, grading and TNF-α levels. As HCV-related liver damage progresses, TNF-α levels drop while IL-1β and c-myc levels increase, which may be relevant to liver carcinogenesis.
基金supported by the Ministry of Science and Technology of China(Nos.2016YFA0203102,2016YFC0900301 and 2014CB932003)the National Natural Science Foundation of China(Nos.21375142,21321004,and 21435008)the Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDB14030000)
文摘Halobenzoquinones（HBQs） are an emerging class of halogenated disinfection byproducts（DBPs） in drinking water, which raised public concerns due to potential carcinogenic effects to human bladder. Our previous work demonstrated that HBQs and hydrogen peroxide（H_2O_2）together generated oxidative DNA damage via a metal-independent and intercalationenhanced oxidation mechanism in vitro. This study further investigated the efficiency of various HBQs to induce oxidative DNA damage in T24 bladder cancer cells. Compared with T24 cells without treatment（3.1 lesions per 10~6 d G）, the level of 8-oxo-7,8-dihydro-2′-deoxyguanosine（8-oxod G） significantly increased by 1.4, 3.2, 8.8, and 9.2 times after treatment with tetrabromo-1,4-benzoquinone（TBBQ）, terachloro-1,4-benzoquinone（TCBQ）,2,6-dichloro-1,4-benzoquinone（2,6-DCBQ） and 2,5-dichloro-1,4-benzoquinone（2,5-DCBQ） for24 hr, respectively. Interestingly, we found that the oxidative potency of HBQs in T24 cells（2,5-DCBQ ≈ 2,6-DCBQ 〉 TCBQ 〉 TBBQ） is inconsistent with that of in vitro ds DNA oxidation（TCBQ 〉 TBBQ 〉 2,5-DCBQ 〉 2,6-DCBQ）, suggesting HBQs induce oxidative lesions in cellular genomic DNA probably involved with a complex mechanism.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDB14020202)the National Natural Science Foundation of China(Nos.21321004 and 21407041)
文摘To investigate the accumulation and phytotoxicity of technical hexabromocyclododecane（HBCD）in maize,young seedlings were exposed to solutions of technical HBCD at different concentrations.The uptake kinetics showed that the HBCD concentration reached an apparent equilibrium within 96 hr,and the accumulation was much higher in roots than in shoots.HBCD accumulation in maize had a positive linear correlation with the exposure concentration.The accumulation of different diastereoisomers followed the orderγ-HBCD〉β-HBCD〉α-HBCD.Compared with their proportions in the technical HBCD exposure solution,the diastereoisomer contribution increased forβ-HBCD and decreased forγ-HBCD in both maize roots and shoots with exposure time,whereas the contribution ofα-HBCD increased in roots and decreased in shoots throughout the experimental period.These results suggest the diastereomer-specific accumulation and translocation of HBCD in maize.Inhibitory effects of HBCD on the early development of maize followed the order of germination rate〉root biomass≥root elongation〉shoot biomass≥shoot elongation.Hydroxyl radical（OH）and histone H2AX phosphorylation（γ-H2AX）were induced in maize by HBCD exposure,indicative of the generation of oxidative stress and DNA double-strand breaks in maize.An OH scavenger inhibited the expression ofγ-H2AX foci in both maize roots and shoots,which suggests the involvement of OH generation in the HBCD-induced DNA damage.The results of this study will offer useful information for a more comprehensive assessment of the environmental behavior and toxicity of technical HBCD.
基金funded by the National Plan for Science,Technology and Innovation(MAARIFAH)King Abdul Aziz City for Science and Technology,Kingdom of Saudi Arabia,award number 12-BIO2919-02
文摘We have studied the genotoxic and apoptotic potential of ferric oxide nanoparticles（Fe_2O_3-NPs） in Raphanus sativus（radish）.Fe_2O_3-NPs retarded the root length and seed germination in radish.Ultrathin sections of treated roots showed subcellular localization of Fe_2O_3-NPs,along with the appearance of damaged mitochondria and excessive vacuolization.Flow cytometric analysis of Fe_2O_3-NPs（1.0 mg/m L） treated groups exhibited 219.5%,161%,120.4% and 161.4% increase in intracellular reactive oxygen species（ROS）,mitochondrial membrane potential（ΔΨm）,nitric oxide（NO） and Ca2＋influx in radish protoplasts.A concentration dependent increase in the antioxidative enzymes glutathione（GSH）,catalase（CAT）,superoxide dismutase（SOD） and lipid peroxidation（LPO） has been recorded.Comet assay showed a concentration dependent increase in deoxyribonucleic acid（DNA） strand breaks in Fe_2O_3-NPs treated groups.Cell cycle analysis revealed 88.4% of cells in sub-G1 apoptotic phase,suggesting cell death in Fe_2O_3-NPs（2.0 mg/m L） treated group.Taking together,the genotoxicity induced by Fe_2O_3-NPs highlights the importance of environmental risk associated with improper disposal of nanoparticles（NPs） and radish can serve as a good indicator for measuring the phytotoxicity of NPs grown in NP-polluted environment.
基金partial support from the U.S.Army Engineer Research and Development Center and the Army Environmental Quality Technology program, CESU W9132T-16-2-0005 (MJP)partly supported by the interagency agreement IAG #NTR 12003 from the National Institute of Environmental Health Sciences/Division of the National Toxicology Program to the National Center for Advancing Translational Sciences, National Institutes of Health
文摘Haloacetamides（HAMs） are cytotoxic, genotoxic, and mutagenic byproducts of drinking water disinfection. They are soft electrophilic compounds that form covalent bonds with the free thiol/thiolate in cysteine residues through an S_N2 reaction mechanism.Toxicity of the monohalogenated HAMs（iodoacetamide, IAM; bromoacetamide, BAM;or chloroacetamide, CAM） varied depending on the halogen substituent. The aim of this research was to investigate how the halogen atom affects the reactivity and toxicological properties of HAMs, measured as induction of oxidative/electrophilic stress response and genotoxicity. Additionally, we wanted to determine how well in silico estimates of electrophilic softness matched thiol/thiolate reactivity and in vitro toxicological endpoints.Each of the HAMs significantly induced nuclear Rad51 accumulation and ARE signaling activity compared to a negative control. The rank order of effect was IAM 〉 BAM 〉 CAM for Rad51, and BAM ≈ IAM 〉 CAM for ARE. In general, electrophilic softness and in chemico thiol/thiolate reactivity provided a qualitative indicator of toxicity, as the softer electrophiles IAM and BAM were more thiol/thiolate reactive and were more toxic than CAM.
基金supported by the National Science Foundation for Excellent Young Scholars(32122052)National Natural Science Foundation Regional Innovation and Development(No.U19A2003)+3 种基金National Natural Science Foundation of China(82102896)China Postdoctoral Science Foundation(2024M762248)Natural Science Foundation of Sichuan Province(2024NSFSC1883)Postdoctor Research Fund of West China Hospital,Sichuan University(2024HXBH055).
文摘Background:Radiotherapy(RT)is a key treatment modality in cancer therapy,utilizing high-energy radiation to directly kill tumor cells.Recent research has increasingly highlighted RT’s potential to indirectly enhance antitumor immunity.However,this immune activation alone often fails to generate sustained systemic antitumor responses.In this study,we aimed to investigate the antitumor effects of combining cholesterolized toll-like receptor 7(TLR7)agonist liposomes,specifically 1V209-Cho-Lip,with RT.Methods:Mouse tumor models were used to assess the impact of combining 1V209-Cho-Lip with RT on tumor progression and modification of the tumor microenvironment.In vitro,primary mouse bone marrow-derived dendritic cells(BMDCs)were utilized to investigate changes in function and the activated pathways through RNA sequencing.Additionally,we explored the role of oxidized mitochondrial DNA(ox-mtDNA)released from irradiated tumor cells as a damage-associated molecular pattern in modulating immune responses.The involvement of interleukin-1β(IL-1β)and the inflammasome pathway in the antitumor efficacy of the combined treatment was evaluated using Il-1β^(−/−)and cysteinyl aspartate specific proteinase 1 knockout(Casp1^(−/−))mouse models.Results:The combination of 1V209-Cho-Lip and RT significantly inhibited tumor growth and induced antitumor immunity in tumor models.This combination therapy enhanced maturation,antigen presentation and IL-1βsecretion of dendritic cells(DCs)in vitro.Ox-mtDNA released from irradiated tumor cells synergized with 1V209-Cho-Lip to activate the inflammasome pathway in DCs.The antitumor effect of the combined therapy was significantly reduced in Il-1β^(−/−)and Casp1^(−/−)mice.Conclusions:This study suggests that the combination of 1V209-Cho-Lip with RT might be a promising antitumor strategy and further studies are warranted to explore the clinical relevance of this combination therapy.
基金This work was supported by the National Natural Science Foundation Regional Innovation and Development(No.U19A2003)National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2018ZX09733001)+1 种基金Excellent Youth Foundation of the Sichuan Scientific Committee Grant in China(No.2019JDJQ008)Development Program of China(No.2016YFA0201402).
文摘Exposure to ionizing radiation,a physical treatment that inactivates live tumor cells,has been extensively applied to enhance the antitumor responses induced by cancer cell vaccines in both animal research and human clinical trials.However,the mechanisms by which irradiated cells function as immunogenic tumor vaccines and induce effective antitumor responses have not been fully explored.Here,we demonstrate that oxidized mitochondrial DNA(mtDNA)and stimulator of interferon genes(STING)signaling play a key roles in the enhanced antitumor effect achieved with an irradiated tumor cell vaccine.Elevations in ROS and oxidized mtDNA 8-OHG content could be induced in irradiated tumor cells.Oxidized mtDNA derived from irradiated tumor cells gained access to the cytosol of dendritic cells(DCs).Oxidized mtDNA,as a DAMP or adjuvant,activated the STING-TBK1-IRF3-IFN-β pathway in DCs,which subsequently cross-presented irradiated tumor cell-derived antigens to CD8^(+)T cells and elicited antitumor immunity.The results of our study provide insight into the mechanism by which an irradiated cell vaccine mediates antitumor immunity,which may have implications for new strategies to improve the efficacy of irradiated vaccines.
