Oxidative RNA Damage Research Articles

Systemic RNA oxidation can be used as a biomarker of infection in challenged with Vibrio parahaemolyticus

More and more evidence support the concept that RNA oxidation plays a substantial role in the progress of multiple diseases; however, only a few studies have reported RNA oxidation caused by microbial pathogens. Urinary 8-oxo-7,8-dihydroguanosine (8-oxo-Gsn) and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dGsn), which are broadly used as indicators of oxidative damage of RNA and DNA, were analyzed in this study to determine which can be used as a biomarker of infection in challenged with Vibrio parahaemolyticus (V. parahaemolyticus). In this work, 24 specific-pathogen-free (SPF) male SD rats were randomly divided into two groups: an infection group and a phosphate-buffered saline (PBS) control group. Our results proved that 8-oxo-Gsn rather than 8-oxo-dGsn was significantly increased after challenged with V. parahaemolyticus in urine and tissue samples of SD rats compared with the PBS control group. Simultaneously, white blood cells (WBCs) counts, intestinal inflammation and inflammatory factors (including CRP, IL-6, IL-1β, TNF-α, IL-10, and IL-17A) were also increased sharply. Which has more clinical value is that the trend of urinary 8-oxo-Gsn was consistent with WBCs, intestinal inflammation and all kinds of inflammatory factors. More importantly is that urinary 8-oxo-Gsn of infection group was positively correlated with WBCs and various inflammatory cytokines. In a word, our results demonstrated that as a systemic RNA oxidation biomarker, we hope 8-oxo-Gsn can be used as a biomarker of the severity of microbial pathogens infection, rather than a specific biomarker of microbial pathogens infection.

Exploring the Links Between Oxidative Stress, RNA Damage and Disease

Exploring the Links Between Oxidative Stress, RNA Damage and Disease

Rapid Manipulation in Irradiance Induces Oxidative Free-Radical Release in a Fast-Ice Algal Community (McMurdo Sound, Antarctica).

Sea ice supports a unique assemblage of microorganisms that underpin Antarctic coastal food-webs, but reduced ice thickness coupled with increased snow cover will modify energy flow and could lead to photodamage in ice-associated microalgae. In this study, microsensors were used to examine the influence of rapid shifts in irradiance on extracellular oxidative free radicals produced by sea-ice algae. Bottom-ice algal communities were exposed to one of three levels of incident light for 10 days: low (0.5 μmol photons m−2 s−1, 30 cm snow cover), mid-range (5 μmol photons m−2 s−1, 10 cm snow), or high light (13 μmol photons m−2 s−1, no snow). After 10 days, the snow cover was reversed (either removed or added), resulting in a rapid change in irradiance at the ice-water interface. In treatments acclimated to low light, the subsequent exposure to high irradiance resulted in a ~400× increase in the production of hydrogen peroxide (H2O2) and a 10× increase in nitric oxide (NO) concentration after 24 h. The observed increase in oxidative free radicals also resulted in significant changes in photosynthetic electron flow, RNA-oxidative damage, and community structural dynamics. In contrast, there was no significant response in sea-ice algae acclimated to high light and then exposed to a significantly lower irradiance at either 24 or 72 h. Our results demonstrate that microsensors can be used to track real-time in-situ stress in sea-ice microbial communities. Extrapolating to ecologically relevant spatiotemporal scales remains a significant challenge, but this approach offers a fundamentally enhanced level of resolution for quantifying the microbial response to global change.

Short-term biological variation and Reference change values of urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine and 8-oxo-7,8-dihydroguanosine.

AimThe DNA and RNA oxidative damage products urinary 8‐oxo‐7,8‐dihydro‐2'‐deoxyguanosine (8‐odGsn) and 8‐oxo‐7,8‐dihydroguanosine (8‐oGsn) have potential use in clinical practice. However, biological variation (BV) and reference change values (RCVs) have not been established. The aim of this study was to establish the short‐term between‐subject BV(CVG), within‐subject BV(CVI), and RCVs for urinary 8‐odGsn and 8‐oGsn.MethodsFirst‐morning midstream urine specimens were collected from 20 apparently healthy subjects(ten males and ten females) on five consecutive days. 8‐odGsn and 8‐oGsn were measured using LC‐MS/MS, while urine creatinine (U‐Cr) was also measured to correct their results. A two‐level nested ANOVA was used to estimate the CVI and CVG. ResultsThe values of CVG for 8‐odGsn, 8‐odGsn/U‐Cr, 8‐oGsn, and 8‐oGsn/U‐Cr were 31.2%, 39.6%, 35.3%, and 28.8%, respectively, while CVI for them were 40.5%, 9.0%, 33.5%, and 12.1%, respectively. The RCVs for 8‐odGsn, 8‐odGsn/U‐Cr, 8‐oGsn, and 8‐oGsn/U‐Cr were 112.5%, 26.7%, 93.7%, and 36.5%, respectively.ConclusionBV and RCVs were firstly established for 8‐oxo‐dGsn and 8‐oGsn, and can be used in clinical practice.

Role of RNA Oxidation in Neurodegenerative Diseases.

In the history of nucleic acid research, DNA has always been the main research focus. After the sketch of the human genome was completed in 2000, RNA has been started to gain more attention due to its abundancies in the cell and its essential role in cellular physiology and pathologies. Recent studies have shown that RNAs are susceptible to oxidative damage and oxidized RNA is able to break the RNA strand, and affect the protein synthesis, which can lead to cell degradation and cell death. Studies have shown that RNA oxidation is one of the early events in the formation and development of neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. However, its molecular mechanism, as well as its impact on these diseases, are still unclear. In this article, we review the different types of RNA oxidative damage and the neurodegenerative diseases that are reported to be associated with RNA oxidative damage. In addition, we discuss recent findings on the association between RNA oxidative damage and the development of neurodegenerative diseases, which will have great significance for the development of novel strategies for the prevention and treatment of these diseases.

DES-ROD: Exploring Literature to Develop New Links between RNA Oxidation and Human Diseases.

Normal cellular physiology and biochemical processes require undamaged RNA molecules. However, RNAs are frequently subjected to oxidative damage. Overproduction of reactive oxygen species (ROS) leads to RNA oxidation and disturbs redox (oxidation-reduction reaction) homeostasis. When oxidation damage affects RNA carrying protein-coding information, this may result in the synthesis of aberrant proteins as well as a lower efficiency of translation. Both of these, as well as imbalanced redox homeostasis, may lead to numerous human diseases. The number of studies on the effects of RNA oxidative damage in mammals is increasing by year due to the understanding that this oxidation fundamentally leads to numerous human diseases. To enable researchers in this field to explore information relevant to RNA oxidation and effects on human diseases, we developed DES-ROD, an online knowledgebase that contains processed information from 298,603 relevant documents that consist of PubMed abstracts and PubMed Central full-text articles. The system utilizes concepts/terms from 38 curated thematic dictionaries mapped to the analyzed documents. Researchers can explore enriched concepts, as well as enriched pairs of putatively associated concepts. In this way, one can explore mutual relationships between any combinations of two concepts from used dictionaries. Dictionaries cover a wide range of biomedical topics, such as human genes and proteins, pathways, Gene Ontology categories, mutations, noncoding RNAs, enzymes, toxins, metabolites, and diseases. This makes insights into different facets of the effects of RNA oxidation and the control of this process possible. The usefulness of the DES-ROD system is demonstrated by case studies on some known information, as well as potentially novel information involving RNA oxidation and diseases. DES-ROD is the first knowledgebase based on text and data mining that focused on the exploration of RNA oxidation and human diseases.

A potential urinary biomarker to determine frailty status among older adults

BackgroundAssociation of oxidative stress biomarkers with aging and several age-related diseases is well documented. However, the possible role of these factors on frailty status in older adults has not been extensively studied. ObjectiveTo evaluate whether urinary 8-oxo-7,8-dihydroguanosine (8-oxo-Gsn), a biomarker of RNA oxidative damage, was independently associated with frailty. MethodsIn this cross-sectional analysis, frailty phenotype was assessed among 230 participants living in a senior community. Participants received a comprehensive geriatric assessment. Serum high-sensitivity C-reactive protein (hsCRP), white blood cell count (WBC), urinary 8-oxo-7,8-dihydro-2′-deoxyguanosine, and 8-oxo-Gsn were measured. ResultsParticipants’ mean age was 83.9 ± 4.4 years. In total, 33 % were frail, 45 % were pre-frail, and 22 % were non-frail. Urinary 8-oxo-Gsn, serum hsCRP, and WBC were significantly higher in the frail group than in the non-frail and pre-frail groups (p-values < 0.05). Adjusting for age, sex, and Charlson comorbidity index, statistically significant positive associations with frailty were observed for urinary 8-oxo-Gsn (odds ratio [OR]: 1.70, 95 % confidence interval [CI]: 0.264–0.732) and hsCRP (OR: 1.337, 95 % CI: 0.089–0.412). Urinary 8-oxo-Gsn of 3.175 μmol/mol had the optimal predictive value for frailty, with an area under the receiver operating characteristic curve (AUC) of 0.72 (95 % CI: 0.649–0.788). The prediction probability combining urinary 8-oxo-Gsn and a simple question evaluating exhaustion had the optimal predictive value for frailty, with an AUC of 0.90 (p < 0.001, 95 % CI: 0.85–0.95). ConclusionUrinary 8-oxo-Gsn level was independently associated with frailty. This urinary biomarker may be a promising indicator of frailty.

The Significance of 8-oxoGsn in Aging-Related Diseases.

Aging is a common risk factor for the occurrence and development of many diseases, such as Parkinson’s disease, Alzheimer’s disease, diabetes, hypertension, atherosclerosis and coronary heart disease, and cancer, among others, and is a key problem threatening the health and life expectancy of the elderly. Oxidative damage is an important mechanism involved in aging. The latest discovery pertaining to oxidative damage is that 8-oxoGsn (8-oxo-7,8-dihydroguanosine), an oxidative damage product of RNA, can represent the level of oxidative stress. The significance of RNA oxidative damage to aging has not been fully explained, but the relationship between the accumulation of 8-oxoGsn, a marker of RNA oxidative damage, and the occurrence of diseases has been confirmed in many aging-related diseases. Studying the aging mechanism, monitoring the aging level of the body and exploring the corresponding countermeasures are of great significance for achieving healthy aging and promoting public health and social development. This article reviews the progress of research on 8-oxoGsn in aging-related diseases.

8-Hydroxyguanosine as a possible RNA oxidative modification marker in urine from colorectal cancer patients: Evaluation by ultra performance liquid chromatography-tandem mass spectrometry

Oxidative RNA damage has been found to be associated with a variety of diseases, and 8-hydroxyguanosine (8-OHG) is a typical marker of oxidative modification of RNA. This guanosine modification is an emerging biomarker for disease detection and determination of 8-OHG in human urine is favored because it is noninvasive to patients. However, due to its poor ionization efficiency in mass spectrometry and trace amount in urine, accurate quantification of this modified nucleoside is still challenging. Herein, a rapid, accurate, sensitive and robust method using solid-phase extraction (SPE) combined with isotope dilution ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed for detection of this oxidative RNA modification in human urine. The limit of detection can reach 1.5 fmol and the method exhibits good precision on intra-day (1.8–3.3%) and inter-day (0.6–1.2%) analyses. Satisfactory recovery (87.5–107.2%) at three spiked levels was achieved by using HLB cartridge for urine pretreatment. Using this method, we quantified 8-OHG in urine from 65 colorectal cancer (CRC) patients and 76 healthy volunteers. The measured level of urinary 8-OHG for CRC patients and healthy controls is 1.91 ± 0.63 nmol/mmol creatinine and 1.33 ± 0.35 nmol/mmol creatinine, respectively. We found the content of 8-OHG in urine was raised in CRC patients patients, implying this oxidative RNA modification marker could act as a potential noninvasive indicator for early screening of CRC. In addition, this study will make contributions to the investigations of the influences of oxidative stress on the formation and development of CRC.

Oxidative damage in mitochondrial fatty acids oxidation disorders patients and the in vitro effect of l-carnitine on DNA damage induced by the accumulated metabolites

BackgroundThe mitochondrial fatty acids oxidation disorders (FAOD) are inherited metabolic disorders (IMD) characterized by the accumulation of fatty acids of different sizes of chain according to the affected enzyme. MethodsThis study evaluated the lipid peroxidation by the measurement of 8-isoprostanes, nitrosative stress parameters by the measurement of nitrite and nitrate content and DNA and RNA oxidative damage by the measurement of oxidized guanine species in urine samples from long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), medium-chain acyl-CoA dehydrogenase deficiency (MCADD) and multiple acyl-CoA dehydrogenase deficiency (MADD) patients. Also, we analyzed the in vitro DNA damage by comet assay induced by adipic acid, suberic acid, hexanoylglycine and suberylglycine, separated and in combination, as well as the effect of l-carnitine in human leukocytes. ResultsAn increase on 8-isoprostanes levels in all groups of patients was observed. The nitrite and nitrate levels were increased in LCHADD patients. DNA and RNA damage evaluation revealed increase on oxidized guanine species levels in LCHADD and MADD patients. The in vitro evaluation revealed an increase on the DNA damage induced by all metabolites, besides a potencialyzed effect. l-carnitine decreased the DNA damage induced by the metabolites. ConclusionThese results demonstrate that toxic metabolites accumulated could be related to the increased oxidative and nitrosative stress of FAOD patients and that the metabolites, separated and in combination, cause DNA damage, which was reduced by l-carnitine, demonstrating antioxidant protection. General significanceThis work demonstrated oxidative stress in FAOD patients and the genotoxic potential of MCADD metabolites and the protective effect of l-carnitine.

Association between DNA and RNA oxidative damage and mortality in septic patients

PurposeDNA and RNA oxidative damage occurs during sepsis. Higher urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels (from oxidation of guanosine from DNA) have been found in non-surviving patients than in surviving septic patients. However, the relation between DNA and RNA oxidative damage and mortality in septic patients has never been published; thus, the objective of this study was to determine the existence of this association. MethodsThis prospective and observational study including septic patients was conducted in 8 Spanish Intensive Care Units. Serum concentrations of the three oxidizied guanine species (OGS) (8-OHdG from DNA, 8-hydroxyguanosine from RNA, and 8-hydroxyguanine from DNA or RNA) were determined, and malondialdehyde (to estimate lipid peroxidation) in the diagnosis of sepsis. Mortality at 30 days was the end-point study. ResultsNon-surviving patients (n = 78) compared to surviving patients (n = 139) showed higher serum concentrations of OGS (p = .004) and malondialdehyde (p < .001). Simultaneously, an association between serum OGS concentrations and mortality in logistic regression analysis was found (OR = 1.105; 95% CI = 1.024–1.193; p = .01), and a positive correlation between serum levels of OGS and malondialdehyde (rho = 0.21; p = .002). ConclusionsThe new findings from our study were that oxidative DNA and RNA damage in septic patients was associated with mortality and lipid peroxidation.

Urinary bisphenol analogues concentrations and biomarkers of oxidative DNA and RNA damage in Chinese school children in East China: A repeated measures study

The associations between bisphenol analogues (BPs) exposure and oxidative damage was explored in this 3-year longitudinal study of 275 school children in East China. Nine BPs in first morning urine samples were measured to assess BPs exposure, and 8-hydroxydeoxyguanosine (8-OHdG) and 8-oxo-7,8-dihydroguanosine (8-OHG) were measured as biomarkers of oxidative DNA and RNA damage. Linear mixed model (LMM) was used for repeated measures analysis. School children were mainly exposed to BPA, BPS, BPF, and BPAF (detection frequencies: 97.9%, 42.2%, 13.3%, and 12.8%) with median concentrations of 1.55, 0.355, 0.236 and 0.238 μg g−1Cre, respectively. An interquartile range (IQR) increase in urinary BPA was significantly associated with 12.9% (95% CI: 6.1%, 19.6%) increase in 8-OHdG and 19.4% (95% CI: 11.7%, 27.1%) increase in 8-OHG, and for total of BPs (the sum of BPA, BPS, BPF, and BPAF), they were 17.4% (95% CI: 8.9%, 26.0%) for 8-OHdG and 25.9% (95% CI: 16.1%, 35.7%) for 8-OHG, respectively. BPS was positively associated with 8-OHG, but not with 8-OHdG. The study found positive associations of urinary levels of BPA and total BPs with 8-OHdG and 8-OHG and indicated that BPs exposure might cause oxidative RNA damage.

Short term biological variation of the DNA and RNA oxidative damage products urinary 8-oxo-dGsn and 8-oxo-Gsn

short term biological variation of the DNA and RNA oxidative damage products urinary 8-oxo-dGsn and 8-oxo-Gsn

The Association of Childhood Maltreatment With Lipid Peroxidation and DNA Damage in Postpartum Women.

Childhood maltreatment (CM) is associated with an increased risk for the development of psychiatric and somatic disorders in later life. A potential link could be oxidative stress, which is defined as the imbalance between the amount of reactive oxygen species (ROS) and the neutralizing capacity of anti-oxidative defense systems. However, the findings linking CM with oxidative stress have been inconsistent so far. In this study, we aimed to further explore this association by investigating biological markers of DNA and lipid damage due to oxidation in a comprehensive approach over two study cohorts of postpartum women (study cohort I and study cohort II). The severity of CM experiences (maltreatment load) was assessed in both studies using the Childhood Trauma Questionnaire. In study cohort I (N = 30), we investigated whether CM was associated with higher levels of structural DNA damage in peripheral blood mononuclear cells (PBMC) by two methods that are highly sensitive for detecting nuclear DNA strand breaks (comet assay and γH2AX staining). In study cohort II (N = 117), we then assessed in a larger cohort, that was specifically controlled for potential confounders for oxidative stress measurements, two established serum and plasma biomarkers of oxidative stress, one representing oxidative DNA and RNA damage (8-hydroxy-2′-deoxyguanosine and 8-hydroxyguanosine; 8-OH(d)G) and the other representing lipid peroxidation (8-isoprostane). In study cohort I, the analyses revealed no significant main effects of maltreatment load on cellular measures of nuclear DNA damage. The analyses of peripheral oxidative stress biomarkers in study cohort II revealed a significant main effect of maltreatment load on free 8-isoprostane plasma levels, but not on total 8-isprostane plasma levels and 8-OH(d)G serum levels. Taken together, by combining different methods and two study cohorts, we found no indications for higher oxidative DNA damages with higher maltreatment load in postpartum women. Further research is needed to investigate whether this increase in free 8-isoprostane is a marker for oxidative stress or whether it is instead functionally involved in ROS-related signaling pathways that potentially regulate inflammatory processes following a history of CM.

Evaluation of bisphenol A exposure induced oxidative RNA damage by liquid chromatography-mass spectrometry

Highlighted evidence suggests the possible implication of bisphenol A (BPA) exposure on a variety of biological functions, such as DNA damage. Similar to DNA, exposed to BPA may also have potential risks to RNA damage due to its induction of reactive oxygen species. However, there are no related research reports about such health risks of BPA. Therefore, this work tried to investigate the BPA exposure induced oxidative RNA damage by detecting urinary nucleosides, the end-products of RNA metabolism. An ultra-high performance liquid chromatography-Orbitrap mass spectrometry method was applied to selectively and sensitively determine urinary nucleosides. As a result, 66 nucleosides were identified and the effects of BPA exposure on these nucleosides in rat urine samples were evaluated. The nucleosides showed different changing tendency along with different exposure dose of BPA. The strongest effect was observed in high does-exposure rats, indicating dose-response relationship between BPA-treatment and urinary nucleosides. Significant change of some nucleosides, including 8-oxoguanosine, was observed in the high-dose exposure group, suggesting obvious RNA damage to rats. To the best of our knowledge, it is the first study about the RNA damage induced by BPA exposure. The results provided a new perspective on the toxic effects of BPA exposure.

Functions of Conserved Domains of Human Polynucleotide Phosphorylase on RNA Oxidation.

Human polynucleotide phosphorylase (hPNPase), an exoribonuclease that is primarily localized in mitochondria, plays an important role in reducing oxidized RNA and protecting cells under oxidative stress conditions. hPNPase contains two catalytic domains (RPH1 and RPH2) and two RNA binding domains (KH and S1), and an N-terminal mitochondrial translocation signal (MTS). In this study, we examined the potential roles of each domain in hPNPase function on controlling RNA oxidative damage. DNA encoding full-length hPNPase and its domain-deletion mutants were introduced into HeLa cells, and the levels of an oxidized RNA lesion, 8-hydroxyguanosine (8-oxo-Guo) were determined in mitochondrial and cytoplasmic RNA under oxidative stress conditions. Our study showed that the S1 RNA binding domain is crucial for reducing 8-oxo-Guo in both cytoplasm and mitochondria, while the MTS is required for 8-oxo-Guo reduction in mitochondria.

Oxidation of 5-methylaminomethyl uridine (mnm⁵U) by Oxone Leads to Aldonitrone Derivatives.

Oxidative RNA damage is linked to cell dysfunction and diseases. The present work focuses on the in vitro oxidation of 5-methylaminomethyl uridine (mnm5U), which belongs to the numerous post-transcriptional modifications that are found in tRNA. The reaction of oxone with mnm5U in water at pH 7.5 leads to two aldonitrone derivatives. They form by two oxidation steps and one dehydration step. Therefore, the potential oxidation products of mnm5U in vivo may not be only aldonitrones, but also hydroxylamine and imine derivatives (which may be chemically more reactive). Irradiation of aldonitrone leads to unstable oxaziridine derivatives that are susceptible to isomerization to amide or to hydrolysis to aldehyde derivative.

Oxidative DNA and RNA damage and their prognostic values during Salmonella enteritidis-induced intestinal infection in rats

Emerging evidence suggests that microbial pathogens may induce oxidative stress in infected hosts. The aim of the present study was to investigate the relationship between changes in oxidative stress and intestinal infection with and without antibiotic treatment in animal models. Sprague-Dawley (SD) rats were divided into three groups: rats infected with Salmonella enterica serovar Enteritidis (S. enteritidis), rats infected with S. enteritidis followed by norfloxacin treatment, and the control group. To evaluate oxidative stress changes, levels of 8-oxo-7,8-dihydroguanosine (8-oxo-Gsn) and 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxo-dGsn), which represented oxidative damage to RNA and DNA, respectively, were analysed in urine and tissue samples. In urine, the level of 8-oxo-Gsn increased significantly after oral exposure to S. enteritidis (p ≤ 0.001) and returned to baseline after recovery. Notably, norfloxacin treatment decreased the level of 8-oxo-Gsn in urine significantly (p = 0.001). Changes of 8-oxo-Gsn measured in tissues from the small intestine, colon, liver and spleen were consistent with 8-oxo-Gsn measured in urine. Our study suggested that 8-oxo-Gsn in urine may serve as a highly sensitive biomarker for evaluating the severity of S. enteritidis infection and the effectiveness of antibiotic treatment against infection.

Increased oxidative damage of RNA in liver injury caused by hepatitis B virus (HBV) infection

To evaluate the urinary levels of 8-oxo-7,8-dihydro-2′deoxyguanosine (8-oxo-dGsn) and 8-oxo-7,8-dihydroguanosine (8-oxo-Gsn) in liver injury patients with hepatitis B virus (HBV) infection and to explore the relationship between urinary 8-oxo-dGsn or 8-oxo-Gsn and degree of liver damage. We enrolled 138 liver injury patients with HBV infection and 169 age- and sex-matched healthy controls in this study. A sensitive and accurate isotope-diluted liquid chromatograph mass spectrometer/mass spectrometer (LC-MS/MS) method was used to measure the urinary levels of 8-oxo-Gsn and 8-oxo-dGsn. Simultaneously, pathological analysis of liver biopsy tissues was carried out, and immunohistochemistry was carried out for 8-oxo-Guo, 8-oxo-dGuo and MTH1 protein in some liver injury tissues. We analysed the correlation between the degrees of inflammation and fibrosis and levels of 8-oxo-Gsn and 8-oxo-dGsn. We also analysed the levels of urinary 8-oxo-Gsn and 8-oxo-dGsn with clinical data of HBeAg, HBsAg, and HBV genotype and detected the levels of plasma aspartate aminotransferase, alanine aminotransferase (AST), platelet, alkaline phosphatase, prothrombin time (PT) and HBV DNA, and calculated the aspartate amino transferase-to–platelet ratio index (APRI) score. Nonparametric correlations were used to evaluate the correlation between 8-oxo-Gsn, 8-oxo-dGsn or APRI and various laboratory biochemical indicators. Results showed that the levels of urinary 8-oxo-Gsn and 8-oxo-dGsn in patients with liver injury were significantly higher than those of healthy controls (both p < .001). Urinary 8-oxo-Gsn was significantly associated with AST, APRI and PT (p = .013, p = .026 and p = .049). The receiver operating characteristic curves of 8-oxo-Gsn were 0.696 (0.632–0.759) and 0.731 (0.672–0.790) for inflammatory activity and fibrosis, respectively. Patients with higher levels of urinary 8-oxo-Gsn are more likely to have a high degree of fibrosis and urinary 8-oxo-Gsn may have a great potential in assessing liver fibrosis.

Theoretical Insights on the Inefficiency of RNA Oxidative Damage under Aerobic Conditions.

Oxidative damage to RNA has been linked to change or loss of RNA function and development of many human age-related diseases. However, knowledge on the nature of RNA oxidative damage is relatively limited. In this study, oxidative damage to RNA is investigated under anaerobic and aerobic conditions by exploring the properties and reactions of 5-hydroxyl-2'-uridin-6-yl and its peroxyl diastereoisomers in the RNA strand, respectively. Selective addition of OH to the nucleic base from the 5'-end is studied at the molecular level for the first time, explaining the large number of the 5S-isomer available for further reactions. Our results provide clear evidence that the efficiency of C2'-H2' bond activation in the peroxyl isomers is lower than in the carbon radical species. An exception is observed for the isomer cis-(5S,6R)-A1, whose internucleotidyl H2'-abstraction barrier is far smaller than that in the corresponding C6-yl radical. However, analysis of the equilibrium species distribution reveals that the amount of cis-(5S,6R)-A1 is very small among the peroxyl diastereoisomers, and hence the resulting products from direct strand scission should be a less important component in RNA oxidative damage. The species with maximum distribution is the cis-(5S,6R)-B1 isomer, which is derived from cis-(5S,6R)-A1 and has a moderate intranucleotidyl H2'-abstraction barrier. More importantly, the reaction is mildly exothermic. These results show that the main fraction of the intranucleotidyl H2'-abstraction intermediates can be formed from the cis-(5S,6R)-B1 isomer. The absolute reduction potentials, the hydrogen atom binding energies, and the key structural parameters of the C6-peroxyl species are used to understand the diverse reactivity of the cis-(5S,6R) diastereoisomers toward the C2'-H2' bonds activation. The present study shows that in addition to the selectivity of the OH radical addition, there is a strong correlation between the conformation of the modified uracil base and its reactivity in RNA oxidative damage.