Marker Of Oxidative DNA Damage Research Articles

Association of 8-hydroxy-2’-deoxyguanosine with motoric cognitive risk in elderly Chinese people: RUGAO longevity and aging cross-sectional study

BackgroundMotor cognitive risk syndrome (MCR) represents a critical pre-dementia and disability state characterized by a combination of objectively measured slow walking speed and subjective memory complaints (SMCs). This study aims to identify risk factors for MCR and investigate the relationship between plasma levels of 8-hydroxy-2’-deoxyguanosine (8-OHdG) and MCR among Chinese community-dwelling elderly populations.MethodsA total of 1312 participants were involved in this study based on the data of the Rugao Longevity and Aging Study (RuLAS). The MCR was characterized by SMCs and slow walking speed. The SCCs were defined as a positive answer to the question ‘Do you feel you have more problems with memory than most?’ in a 15-item Geriatric Depression Scale. Slow walking speed was determined by one standard deviation or more below the mean value of the patient’s age and gender group. The plasma of 8-OHdG were measured by a technician in the biochemistry laboratory of the Rugao People’s Hospital during the morning of the survey.ResultsThe prevalence of MCR was found to be 7.9%. After adjusting for covariates, significant associations with MCR were observed in older age (OR 1.057; p = 0.018), history of cerebrovascular disease (OR 2.155; p = 0.010), and elevated 8-OHdG levels (OR 1.007; p = 0.003).ConclusionsThis study indicated the elevated plasma 8-OHdG is significantly associated with increased MCR risk in the elderly, suggesting its potential as a biomarker for early detection and intervention in MCR. This finding underscores the importance of monitoring oxidative DNA damage markers in predicting cognitive and motor function declines, offering new avenues for research and preventive strategies in aging populations.

Abstract LB144: The short-term associations of air pollutants with inflammation and oxidative stress markers in the Korean population

Abstract Inflammation and oxidative stress responses induced by air pollutants are major biological mechanisms that can lead to multiple chronic diseases. We investigated the association between short-term exposure to ambient air pollutants and circulating levels of inflammatory cytokines, as well as a urinary marker of oxidative DNA damage in Korean adults (n=2,199) from the Korea Genome and Epidemiology Study. Circulating levels of inflammatory cytokines, including IL-1β, IL-6, IL-8, IL-10, and TNF-α, as well as urinary levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), were selected as biomarkers of interest. We estimated a range of air pollutants, such as particulate matter (PM, PM10 and PM2.5) and nitrogen dioxide (NO2), utilizing a chemical transport model. The exposure duration was defined based on 1- to 7-day averages. To explore the association between air pollution and biomarkers, we utilized multivariable linear models adjusting for major covariates, including demographic, lifestyle, relative humidity, and temperature. PM10 was linked to increased levels of IL-1β, IL-10, TNF-α, and 8-OHdG, and PM2.5 was associated with elevated levels of IL-1β, IL-10, IL-8, TNF-α, and 8-OHdG. With each 10 μg/m3 increase in the weekly average of PM, the largest magnitude of percent changes were observed for IL-1β levels (PM10: 2.7%, 95% CI 0.6 to 4.8; PM2.5: 6.4%, 95% CI 2.4 to 10.5). NO2 showed statistically non-significant associations with any of the biomarkers. As a result, short-term exposure to ambient PM may trigger oxidative damage and pro-and anti-inflammatory responses. Citation Format: Kyoungho Lee, Ji Hyun Kim. The short-term associations of air pollutants with inflammation and oxidative stress markers in the Korean population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB144.

3-methyl-1H-indol-1-yl dimethylcarbamodithioate attenuates periodontitis through targeting MAPK signaling pathway-regulated mitochondrial function.

Periodontitis, the second most common oral disease, is primarily initiated by inflammatory responses and osteoclast differentiation, in which the MAPK signaling pathway and mitochondrial function play important roles. 3-methyl-1H-indol-1-yl dimethylcarbamodithioate (3o), a hybrid of indole and dithiocarbamate, was first synthesized by our group. It has shown anti-inflammatory activity against lipopolysaccharide-induced acute lung injury. However, it is not known if 3o can exert effects in periodontitis. Invitro study: LPS-induced macrophage inflammation initiation and a receptor activator of nuclear factor κB ligand-stimulated osteoclast differentiation model were established. Cell viability, inflammatory cytokines, osteoclast differentiation, the MAPK signaling pathway, and mitochondrial function before and after treatment with 3o were investigated. Invivo study: Alveolar bone resorption, inflammatory cytokine expression, osteoclast differentiation, and the underlying mechanisms were assessed in mice with periodontitis. Inflammatory cytokine expression and osteoclast differentiation appeared downregulated after 3o treatment. 3o inhibited the MAPK signaling pathway and restored mitochondrial function, including mitochondrial reactive oxygen species, mitochondrial membrane potential, and ATP production. Meanwhile, 3o reduced inflammation activation and bone resorption in mice with periodontitis, reflected by the decreased expression of inflammatory cytokines and osteoclasts, implying that 3o inhibited the MAPK signaling pathway and the mitochondrial oxidative DNA damage marker 8-OHdG. These results highlight the protective role of 3o in periodontitis in mice and reveal an important strategy for preventing periodontitis.

Dose-dependent exposure to indoxyl sulfate alters AHR signaling, sirtuins gene expression, oxidative DNA damage, and bone mineral status in rats

Indoxyl sulfate (IS), an agonist of aryl hydrocarbon receptors (AhR), can accumulate in patients with chronic kidney disease, but its direct effect on bone is not clear. The present study investigated the effect of chronic exposure to low (100 mg/kg b.w.; 100 IS) and high (200 mg/kg b.w.; 200 IS) dose of IS on bone AhR pathway, sirtuins (SIRTs) expression, oxidative DNA damage and bone mineral status in Wistar rats. The accumulation of IS was observed only in trabecular bone tissue in both doses. The differences were observed in the bone parameters, depending on the applied IS dose. The exposure to 100 IS increased AhR repressor (AhRR)-CYP1A2 gene expression, which was associated with SIRT-1, SIRT-3 and SIRT-7 expression. At the low dose group, the oxidative DNA damage marker was unchanged in the bone samples, and it was inversely related to the abovementioned SIRTs expression. In contrast, the exposure to 200 IS reduced the expression of AhRR, CYP1A, SIRT-3 and SIRT-7 genes compared to 100 IS. The level of oxidative DNA damage was higher in trabecular bone in 200 IS group. Femoral bone mineral density was decreased, and inverse relations were noticed between the level of trabecular oxidative DNA damage and parameters of bone mineral status. In conclusion, IS modulates AhR-depending signaling affecting SIRTs expression, oxidative DNA damage and bone mineral status in a dose dependent manner.

Lipoprotein(a) is associated with DNA damage in patients with heterozygous familial hypercholesterolemia

Heterozygous familial hypercholesterolemia (HeFH) is a common autosomal-dominant inherited disorder associated with atherosclerotic cardiovascular disease (ASCVD). HeFH subjects have a higher lipoprotein(a), i.e. Lp(a), concentration than the general population. Patients with FH are exposed to elevated levels of LDL from birth and ox-LDL may induce other oxidation pathways. The aim of the study was to determine the levels of markers of oxidative stress and DNA damage in patients with HeFH and describe the effect of Lp(a) on the resulting damage. Higher DNA damage was identified in patients with HeFH compared to the normolipidemic ones, and ASCVD was associated with greater damage. Oxidative stress markers were elevated in HeFH patients; however, only ox-LDL was higher in the ASCVD group and its level correlated with DNA damage. A positive correlation was found between DNA damage and Lp(a) concentration in the HeFH patients. Higher levels of Lp(a) were associated with greater DNA damage, especially in patients with HeFH and ASCVD. In HeFH patients, the optimal Lp(a) cut-off point associated with ASCVD is > 23.45 nmol/L, i.e. much lower than for the general population; however this cut-off point needs validation in a larger group of HeFH patients.

Effects of unburned tobacco smoke on inflammatory and oxidative mediators in the rat prefrontal cortex

Although the Food and Drug Administration has authorized the marketing of “heat-not-burn” (HnB) electronic cigarettes as a modified risk tobacco product (MRTP), toxicological effects of HnB smoke exposure on the brain are still unexplored. Here, paramagnetic resonance of the prefrontal cortex (PFC) of HnB-exposed rats shows a dramatic increase in reactive radical species (RRS) yield coupled with an inflammatory response mediated by NF-κB-target genes including TNF-α, IL-1β, and IL-6 and the downregulation of peroxisome proliferator-activated receptor (PPAR) alpha and gamma expression. The PFC shows higher levels of 8-hydroxyguanosine, a marker of DNA oxidative damage, along with the activation of antioxidant machinery and DNA repair systems, including xeroderma pigmentosum group C (XPC) protein complex and 8-oxoguanine DNA glycosylase 1. HnB also induces the expression of drug-metabolizing enzymes such as CYP1A1, CYP2A6, CYP2B6, and CYP2E, particularly involved in the biotransformation of nicotine and several carcinogenic agents such as aldehydes and polycyclic aromatic hydrocarbons here recorded in the HnB stick smoke. Taken together, these effects, from disruption of redox homeostasis, inflammation, PPAR manipulation along with enhanced bioactivation of neurotoxicants, and upregulation of cMYC protooncogene to impairment of primary cellular defense mechanisms, suggest a possible increased risk of brain cancer. Although the HnB device reduces the emission of tobacco toxicants, our findings indicate that its consumption may carry a risk of potential adverse health effects, especially in non-smokers so far. Further studies are needed to fully understand the long-term effects of these devices.

MYOKINE FUNDC5 COMPROMISES MITOCHONDRIAL DYSFUNCTION IN OSTEOARTHRITIS

Chondrocytic activity is downregulated by compromised autophagy and mitochondrial dysfunction to accelerate the development of osteoarthritis (OA). Irisin is a cleaved form of fibronectin type III domain containing 5 (FNDC5) and known to regulate bone turnover and muscle homeostasis. However, little is known about the role of irisin in chondrocytes and the development of OA. This talk will shed light on FNDC5 expression by human articular chondrocytes and compare normal and osteoarthritic cells with respect to autophagosome marker LC3-II and oxidative DNA damage marker 8-hydroxydeoxyguanosine (8-OHdG). In chondrocytes in vitro, irisin improves IL-1β-mediated growth inhibition, loss of specific cartilage markers and glycosaminoglycan production. Irisin further suppressed Sirt3 and UCP- 1 to improve mitochondrial membrane potential, ATP production, and catalase. This attenuated IL-1β-mediated production of reactive oxygen species, mitochondrial fusion, mitophagy, and autophagosome formation. In a surgical murine model of destabilization of the medial meniscus (DMM) intra-articular administration of irisin alleviates symptoms like cartilage erosion and synovitis. Furthermore, gait profiles of the treated limbs improved. In chondrocytes, irisin treatment upregulates autophagy, 8-OHdG and apoptosis in cartilage of DMM limbs. Loss of FNDC5 in chondrocytes correlates with human knee OA and irisin repressed inflammation-mediated oxidative stress and deficient extracellular matrix synthesis through retaining mitochondrial biogenesis and autophagy. The talk sheds new light on the chondroprotective actions of this myokine and highlights the remedial effects of irisin during progression of OA.

Involvement of oxidative stress in orofacial mechanical pain hypersensitivity following neonatal maternal separation in rats

Patients with persistent pain have sometimes history of physical abuse or neglect during infancy. However, the pathogenic mechanisms underlying orofacial pain hypersensitivity associated with early-life stress remain unclear. The present study focused on oxidative stress and investigated its role in pain hypersensitivity in adulthood following early-life stress. To establish an early-life stress model, neonatal pups were separated with their mother in isolated cages for 2 weeks. The mechanical head-withdrawal threshold (MHWT) in the whisker pad skin of rats received maternal separation (MS) was lower than that of non-MS rats at postnatal week 7. In MS rats, the expression of 8-hydroxy-deoxyguanosine, a marker of DNA oxidative damage, was enhanced, and plasma antioxidant capacity, but not mitochondrial complex I activity, decreased compared with that in non-MS rats. Reactive oxygen species (ROS) inactivation and ROS-sensitive transient receptor potential ankyrin 1 (TRPA1) antagonism in the whisker pad skin at week 7 suppressed the decrease of MHWT. Corticosterone levels on day 14 increased in MS rats. Corticosterone receptor antagonism during MS periods suppressed the reduction in antioxidant capacity and MHWT. The findings suggest that early-life stress potentially induces orofacial mechanical pain hypersensitivity via peripheral nociceptor TRPA1 hyperactivation induced by oxidative stress in the orofacial region.

Abstract 16902: Molecular Basis of the Vascular Cell Phenotypic Switch and Wall Remodeling in Abdominal Aortic Aneurysm: NOX4 NADPH Oxidase-Derived Mitochondrial Oxidative Stress and DNA Damage

Vascular cells phenotypic changes and wall remodeling are the hallmarks of abdominal aortic aneurysm (AAA) pathology. Mitochondrial oxidative stress (mtOS) is associated with the vascular smooth muscle cells (SMC) and macrophage phenotypic switch. We previously reported that NOX4 NADPH oxidase expression is increased in cardiovascular cells in response to pathological insult inducing mtOS and dysfunction and vascular disease progression. We tested the hypothesis that NOX4-dependent mtOS and DNA damage induce vascular phenotypic changes and remodeling resulting in AAA progression. In angiotensin II (Ang II)-induced AAA model Apoe -/- / Nox4 Tg mice with mitochondria-targeted overexpression of NOX4 had the highest, whereas Apoe -/- / Nox4 -/- displayed the lowest incidence of AAA, abdominal aorta area and diameter as compared with Apoe -/- mice. The aortic wall ROS levels, oxidative DNA damage and DNA damage response markers, elastin degradation index, MMP2 expression, and macrophage infiltration were significantly higher in AngII-treated Apoe -/- / Nox4 TG mice compared with Apoe -/- or Apoe -/- / Nox4 -/- mice. Spectral flow cytometry analysis of AAA cell suspension from Ang II-infused mice revealed a decrease in contractile SMCs but an increase in macrophage-like SMC populations, as well as increased number of infiltrating pro-inflammatory macrophages in Apoe -/- / Nox4 TG mice. As compared with wild-type or Nox4 -/- mice, Ang II-treated SMC from Nox4 TG mice showed significantly elevated mtOS, DNA damage, dysfunction, as well as activation of cGAS-STING pathway and NLRP3/AIM2 inflammasome expression. Flow cytometry analysis of Ang II-treated Nox4 TG mice SMC contained a lower proportion of cells with contractile markers (ACTA2 + , MYH11 + , TAGLN + ) and a higher proportion of cells with macrophage-like markers (CD68 + , CD11b + , LGALS3 + ). These data suggest that NOX4-dependent mitochondrial DNA damage and activation of DNA-sensing pathways have a causal role in AAA development, leading to macrophage-like SMCs, increased inflammation, and vessel wall remodeling. NOX4 inhibition and mitochondrial function augmentation may be beneficial in preserving aortic wall integrity in AAA-susceptible patients.

Differential Modulation of Markers of Oxidative Stress and DNA Damage in Arterial Hypertension.

Patients with arterial hypertension have an increased risk of developing tumors, particularly renal cell carcinoma. Arterial hypertension is linked to DNA damage via the generation of oxidative stress, in which an upregulated renin-angiotensin-aldosterone system plays a crucial role. The current study investigated surrogates of oxidative stress and DNA damage in a group of hypertensive patients (HypAll, n = 64) and subgroups of well (HypWell, n = 36) and poorly (HypPoor, n = 28) controlled hypertensive patients compared to healthy controls (n = 8). In addition, a longitudinal analysis was performed with some of the hypertensive patients. Markers for oxidative stress in plasma (SHp, D-ROM, and 3-nitrotyrosine) and urine (8-oxodG, 15-F2t-isoprostane, and malondialdehyde) and markers for DNA damage in lymphocytes (γ-H2AX and micronuclei) were measured. In HypAll, all markers of oxidative stress except malondialdehyde were increased compared to the controls. After adjustment for age, this association was maintained for the protein stress markers SHp and 3-nitrotyrosine. With regard to the markers for DNA damage, there was no difference between HypAll and the controls. Further, no significant differences became apparent in the levels of both oxidative stress and DNA damage between HypWell and HypPoor. Finally, a positive correlation between the development of blood pressure and oxidative stress was observed in the longitudinal study based on the changes in D-ROM and systolic blood pressure. In conclusion, we found increased oxidative stress in extensively treated hypertensive patients correlating with the level of blood-pressure control but no association with DNA damage.

Direct-Acting Antiviral Drug Modulates the Mitochondrial Biogenesis in Different Tissues of Young Female Rats.

(1) Background: Hepatitis C virus (HCV) infection is endemic in Egypt, with the highest prevalence rate worldwide. Sofosbuvir (SOF) is a nucleos(t)ide analog that specifically inhibits HCV replication. This study aimed to explore the possible effects of the therapeutic dose of SOF on the mitochondrial biogenesis and functions of the liver, muscle, and ovarian tissues of young normal female rats. (2) Methods: This study was conducted on 20 female Wistar rats, classified into two groups, the control group and the exposed group; the latter was orally supplemented with 4 mg/kg/day of SOF for 3 months. (3) Results: The exposure to SOF impairs mitochondrial biogenesis via mitochondrial DNA copy number decline and suppressed mitochondrial biogenesis-regulated parameters at mRNA and protein levels. Also, SOF suppresses the DNA polymerase γ (POLG) expression, citrate synthase activity, and mitochondrial NADH dehydrogenase subunit-5 (ND5) content, which impairs mitochondrial functions. SOF increased lipid peroxidation and oxidative DNA damage markers and decreased tissue expression of nuclear factor erythroid 2-related factor 2 (Nfe2l2). (4) Conclusions: The present findings demonstrate the adverse effects of SOF on mitochondrial biogenesis and function in different tissues of young female rats, which mostly appeared in ovarian tissues.

The lipolysis inhibitor acipimox reverses the cardiac phenotype induced by electronic cigarettes

Electronic cigarettes (e-cigarettes) are a prevalent alternative to conventional nicotine cigarettes among smokers and people who have never smoked. Increased concentrations of serum free fatty acids (FFAs) are crucial in generating lipotoxicity. We studied the effects of acipimox, an antilipolytic drug, on e-cigarette-induced cardiac dysfunction. C57BL/6J wild-type mice on high fat diet were treated with saline, e-cigarette with 2.4% nicotine [e-cigarette (2.4%)], and e-cigarette (2.4%) plus acipimox for 12 weeks. Fractional shortening and ejection fraction were diminished in mice exposed to e-cigarettes (2.4%) compared with saline and acipimox-treated mice. Mice exposed to e-cigarette (2.4%) had increased circulating levels of inflammatory cytokines and FFAs, which were diminished by acipimox. Gene Set Enrichment Analysis revealed that e-cigarette (2.4%)-treated mice had gene expression changes in the G2/M DNA damage checkpoint pathway that was normalized by acipimox. Accordingly, we showed that acipimox suppressed the nuclear localization of phospho-p53 induced by e-cigarette (2.4%). Additionally, e-cigarette (2.4%) increased the apurinic/apyrimidinic sites, a marker of oxidative DNA damage which was normalized by acipimox. Mice exposed to e-cigarette (2.4%) had increased cardiac Heme oxygenase 1 protein levels and 4-hydroxynonenal (4-HNE). These markers of oxidative stress were decreased by acipimox. Therefore, inhibiting lipolysis with acipimox normalizes the physiological changes induced by e-cigarettes and the associated increase in inflammatory cytokines, oxidative stress, and DNA damage.

Co-exposure to organic UV filters and phthalates and their associations with oxidative stress levels in children: A prospective follow-up study in China

Children are highly vulnerable to environmental pollutants, especially endocrine-disrupting chemicals (EDCs). Previous research has linked both organic UV filters and phthalates exposure to adiposity and pubertal development in children. Nevertheless, the individual and collective effects of these chemicals on this population remain poorly understood. In this study, twelve organic UV filters and metabolites, six phthalate metabolites and two oxidative stress biomarkers were analyzed in a prospective follow-up study in Shanghai, China after a baseline study conducted 1.5 years earlier. Results revealed a positive association between exposure to individual organic UV filters or their mixture and levels of 8-OHdG (β ranging from 0.242 to 0.588, P < 0.05), a marker of oxidative DNA damage. BP-3 and OD-PABA made a greater contribution to oxidative DNA damage than other UV filters. Levels of 8-OHdG were also positively correlated with single phthalate metabolites and their mixture, with MnBP and MMP contributing the most. Stratified analysis found that these associations were mainly observed in girls. Our mixture analysis revealed cumulative risks of oxidative DNA damage when there was co-exposure to these two kinds of EDCs. These results underscore the importance of considering the risks associated with organic UV filters and the necessity of evaluating the effects of all these pollutants, both individually and in mixtures.

Maternal oxidative stress during pregnancy associated with emotional and behavioural problems in early childhood: implications for foetal programming

Childhood mental disorders, including emotional and behavioural problems (EBP) are increasingly prevalent. Higher maternal oxidative stress (OS) during pregnancy (matOSpreg) is linked to offspring mental disorders. Environmental factors contribute to matOSpreg. However, the role of matOSpreg in childhood EBP is unclear. We investigated the associations between (i) matOSpreg and offspring EBP; (ii) social and prenatal environmental factors and matOSpreg; and (iii) social and prenatal factors and childhood EBP and evaluated whether matOSpreg mediated these associations. Maternal urinary OS biomarkers, 8-hydroxyguanosine (8-OHGua; an oxidative RNA damage marker) and 8-hydroxy-2′-deoxyguanosine (8-OHdG; an oxidative DNA damage marker), at 36 weeks of pregnancy were quantified by liquid chromatography-mass spectrometry in a population-derived birth cohort, Barwon Infant Study (n = 1074 mother-infant pairs). Social and prenatal environmental factors were collected by mother-reported questionnaires. Offspring total EBP was measured by Child Behavior Checklist Total Problems T-scores at age two (n = 675) and Strengths and Difficulties Questionnaire Total Difficulties score at age four (n = 791). Prospective associations were examined by multivariable regression analyses adjusted for covariates. Mediation effects were evaluated using counterfactual-based mediation analysis. Higher maternal urinary 8-OHGua at 36 weeks (mat8-OHGua36w) was associated with greater offspring total EBP at age four (β = 0.38, 95% CI (0.07, 0.69), P = 0.02) and age two (β = 0.62, 95% CI (−0.06, 1.30), P = 0.07). Weaker evidence of association was detected for 8-OHdG. Five early-life factors were associated with both mat8-OHGua36w and childhood EBP (P-range < 0.001–0.05), including lower maternal education, socioeconomic disadvantage and prenatal tobacco smoking. These risk factor-childhood EBP associations were partly mediated by higher mat8-OHGua36w (P-range = 0.01–0.05). Higher matOSpreg, particularly oxidant RNA damage, is associated with later offspring EBP. Effects of some social and prenatal lifestyle factors on childhood EBP were partly mediated by matOSpreg. Future studies are warranted to further elucidate the role of early-life oxidant damage in childhood EBP.

Young people exposure to antibiotics: Implication for health risk and the impact from eating habits of takeaway food

Exposure to antibiotics, mainly from animal food ingestion, may have adverse effects on human health. Takeaway food is the preferred choice for the dietary of most Chinese young people nowadays, but the relationship between takeaway eating and antibiotic exposure is not yet adequately understood. In the present study, 297 young people were recruited to collect urine samples and questionnaires with an emphasis on their takeaway eating habits. The internal exposure to 16 antibiotics and three metabolites was measured in urine samples by high-performance liquid chromatography-tandem mass spectrometry, as well as a DNA oxidative damage marker, 8-hydroxydeoxyguanosine (8-OHdG). At least one kind of antibiotic was found in over 90 % of urine samples, with total concentrations from 0.667 to 3.02 × 104 ng/mL. High exposure levels of antibiotics were more likely to be found in individuals with a larger body mass index. The concentrations of six antibiotics were significantly different among people with different overall weekly eating frequencies, usually an upward trend. The estimated daily intakes of antibiotics were on the levels of 0.001–1.0 μg/kg/day, mainly contributed by clarithromycin, ciprofloxacin and oxytetracycline, indicating a potential health risk based on the microbiological effect. A significantly positive correlation was found between DNA oxidative damage and exposure for four categories of antibiotics, conformed by both Spearman correlation and multiple linear regression analysis. The levels of 8-OHdG were 355 %, 239 %, 234 %, and 334 % higher with elevated levels of phenicols, macrolides, tetracyclines and sulfonamides from quartiles 2 to 4. Our results suggest that high-frequency consumption of takeaways may exacerbate oxidative stress trends through human exposure to antibiotics.

Comparison of Possible Changes in Oxidative Stress, DNA Damage, and Inflammatory Markers in Children/Adolescents Diagnosed with Sluggish Cognitive Tempo and Children/Adolescents Diagnosed with Attention-Deficit/Hyperactivity Disorder.

Background: There has been a debate on whether sluggish cognitive tempo (SCT) differs from attention-deficit/hyperactivity disorder (ADHD). Although there have been many studies on metabolic parameters in relation to ADHD, no similar studies have been conducted on patients with SCT. We investigated whether there are differences between SCT and ADHD in terms of these factors. Subjects and Methods: Sixty-two participants with ages ranging from 11 to 18 who have diagnosis of ADHD (33 subjects) and SCT (29 subjects) were included in this study. The parents of all participants completed the 48-item Conners' Parent Rating Scale (CPRS) and the Barkley Child Attention Scale (BCAS) forms, and all participants' blood was taken to compare metabolic, oxidative stress, and antioxidant status of the SCT and ADHD groups. A child and adolescent psychiatrist interviewed the parents and children to assess the diagnosis of SCT and ADHD using standard diagnostic procedures. Results: In the comparison between the SCT and ADHD groups in terms of metabolic parameters, statistically significant differences were found in terms of total oxidant status, total antioxidant status, Oxidative Stress Index, total thiol, native thiol, disulfide, interleukin (IL)-1β, IL-6, and DNA damage (p < 0.05), but not in terms of tumor necrosis factor-α (p > 0.05). Conclusions: Our data showed that these two disorders may be different, but we believe that the data that indicate their differences remain inconclusive overall, but this study may be a potential pathway for future research.

Urinary levels of cortisol but not catecholamines are associated with those of 8-hydroxy-2'-deoxyguanosine in uncomplicated primary hypertension.

The relationships between stress hormones and oxidative DNA damage have not yet been explored in human hypertension. We investigated the associations of urinary levels of cortisol or catecholamines with those of 8-hydroxy-2'-deoxyguanosine, a marker of oxidative DNA damage in primary hypertension. Untreated 156 primary hypertensives without apparent cardiovascular diseases were entered into the study. Following blood sampling after an overnight fast, 24-h blood pressure monitoring and 24-h urinary sampling were performed simultaneously to determine 24-h averaged values for blood pressure and urinary levels of cortisol, catecholamines and 8-hydroxy-2'-deoxyguanosine. Urinary cortisol significantly correlated positively with urinary 8-hydroxy-2'-deoxyguanosine in all studied participants (r = 0.334, P < 0.001). Contrary, either urinary adrenaline or urinary noradrenaline did not significantly correlate with urinary 8-hydroxy-2'-deoxyguanosine (r = 0.050, P = 0.553 or r = 0.063, P = 0.435). Additionally, the positive association of urinary cortisol with urinary 8-hydroxy-2'-deoxyguanosine remained highly significant after the adjustments for multiple confounders of oxidative stress such as age, gender, body mass index, smoking status, 24-h blood pressure, C-reactive protein and estimated glomerular filtration rate (partial r = 0.323, P < 0.001), although only approximately 10% of the variance in urinary cortisol was attributable to differences in urinary 8-OHdG (partial r2 = 0.104). Thus, our data indicate that cortisol but not catecholamines could at least partially contribute to the occurrence of oxidative DNA damage in primary hypertensives. The present study suggested the possibility that the overactivation of hypothalamic-pituitary-adrenal axis rather than sympathoadrenal system could enhance oxidative stress and attendant DNA oxidation in uncomplicated primary hypertension.

The ameliorative effect of Piper trioicum in attenuating cognitive deficit in scopolamine induced neurotoxicity in experimental rats

Ethnopharmacological relevanceIn traditional system of medicine, Piper species, or its components are widely used to treat many diseases including memory improvement. One of the wild species Piper trioicum Roxb. (Piperaceae) is found in South Asian countries. The whole plant is used as folk medicine to improve memory.Aim of the study: To our knowledge, no previous research has investigated the neuroprotective activities of P. trioicum. So, we studied the ameliorative effect of P. trioicum in attenuating cognitive deficit in scopolamine induced neurotoxicity in experimental rats. Materials and methodsWistar rats were exposed to scopolamine (3 mg/kg, i. p.) for 14 consecutive days, and the effect of P. trioicum (HAPT; oral, 300, 400 mg/kg) on scopolamine-invoked neurotoxicity in brain were studied. During the experimental period, behaviour analyses of rats were observed 30 min post-drug administration. The role of antioxidants of HAPT in scavenging cellular oxygen/peroxyl radicals were studied. Acetylcholinesterase and butyrylcholinesterase inhibitions, and mode of inhibition kinetics of HAPT were studied. Pathogenic cellular oxidative (MDA, GSH, SOD, and CAT), DNA damage (8-oxodG), neurochemical (acetyl- and, butyryl-cholinesterase), β-secretase (BACE-1 and 2), MAPτ, and neuroinflammation (IL-6, TNF-α) biomarkers in extension to the histopathological observation of brain cortex were studied. GC-MS/MS analysis was carried out to investigate the presence of bioactive constituents in HAPT. ResultsHAPT, a rich source of phenol and flavonoid type antioxidants were responsible in quenching oxygen/peroxyl radicals and protected the cellular membrane, and lipoproteins against ROS in DPPH, ORAC, and CAPe tests. HAPT inhibited acetylcholinesterase and butyrylcholinesterase activities, and showed competitive-inhibition (reversible) towards cholinesterase activities. HAPT-400 significantly improved the learning and memory-impairment by restoring oxidative MDA, GSH, SOD, CAT, and DNA damage (8-oxodG) markers of serum, and cortex. It also improved acetyl- and, butyryl-cholinesterase, β-secretase, and MAPτ level in brain by restoring proinflammatory cytokines IL-6, and TNF-α indicators in neurotoxic rats. GC-MS/MS reported therapeutic significance active compounds were molecular-docked towards target proteins, found that proscillaridin showed the highest affinity towards AChE, BuChE, BACE1, and BACE2 with binding energy of ΔGb −9.1, ΔGb −10.2, ΔGb −11.4 and ΔGb −11.5 Kcal/mol, respectively. Cymarin and morphine-3-glucuronide showed the second highest binding affinity towards AChE (ΔGb −8.8) and BuChE (ΔGb −10.0), respectively. In BACE-1, betulin showed the second highest binding affinity ΔGb −10.7 Kcal/mol and in BACE-2, morphine-3-glucuronide showed the second highest binding affinity ΔGb −9.8 Kcal/mol. ConclusionsSynergistic impact of proscillaridin, Cymarin, morphine-3-glucuronide, betulin like compounds in HAPT improved memory impairment, healing of tissue architecture of cortex with the restoration of neurochemical, neuroinflammation, and oxidative indicators in neurotoxic rats.

Indoor (residential) and ambient particulate matter associations with urinary oxidative stress biomarkers in a COPD cohort

ObjectivesOxidative stress contributes to chronic obstructive pulmonary disease (COPD) pathophysiology. Associations between indoor (residential) exposure to particulate matter ≤2.5 μm in diameter (PM2.5) and one of its components, black carbon (BC), and oxidative stress are ill-defined. MethodsBetween 2012 and 2017, 140 patients with COPD completed in-home air sampling over one week intervals, followed by collection of urine samples to measure oxidative stress biomarkers, malondialdehyde (MDA), a marker of lipid peroxidation, and 8-hydroxy-2′ -deoxyguanosine (8-OHdG), a marker of oxidative DNA damage. Ambient (central site) BC and PM2.5 were measured, and the ratio of indoor/ambient sulfur in PM2.5, a surrogate for residential ventilation and particle infiltration, was used to estimate indoor BC and PM2.5 of outdoor origin. Mixed effects linear regression models with a participant-specific random intercept were used to assess associations with oxidative biomarkers, adjusting for personal characteristics. ResultsThere were positive associations (% increase per IQR; 95 % CI) of directly measured indoor BC with total MDA (6.96; 1.54, 12.69) and 8-OHdG (4.18; −0.67, 9.27), and similar associations with both indoor BC of outdoor origin and ambient BC. There were no associations with directly measured indoor PM2.5, but there were positive associations between indoor PM2.5 of outdoor origin and total MDA (5.40; −0.91, 12.11) and 8-OHdG (8.02; 2.14, 14.25). ConclusionsIn homes with few indoor combustion sources, directly measured indoor BC, estimates of indoor BC and PM2.5 of outdoor origin, and ambient BC, were positively associated with urinary biomarkers of oxidative stress. This suggests that the infiltration of particulate matter from outdoor sources, attributable to traffic and other sources of combustion, promotes oxidative stress in COPD patients.

Association of Apolipoprotein E4-related Microvascular Disease in the Alzheimer’s Disease Hippocampal CA1 Stratum Radiatum

Current data suggest a hypothesis of vascular pathogenesis for the development and progression of Alzheimer’s disease (AD). To investigate this, we studied the association of apolipoprotein E4 (APOE4) gene on microvessels in human autopsy-confirmed AD with and without APOE4, compared with age/sex-matched control (AC) hippocampal CA1 stratum radiatum. AD arterioles (without APOE4 gene) had mild oxidative stress and loss of vascular endothelial growth factor (VEGF) and endothelial cell density, reflecting aging progression. In AD + APOE4, an increase in strong oxidative DNA damage marker 8-hydroxy-2′-deoxyguanosine (8-OHdG), VEGF, and endothelial cell density were associated with increased diameter of arterioles and perivascular space dilation. In cultured human brain microvascular cells (HBMECs), treatment of ApoE4 protein plus amyloid-β (Aβ) oligomers increased superoxide production and the apoptotic marker cleaved caspase 3, sustained hypoxia inducible factor-1α (HIF-1α) stability that was associated with an increase in MnSOD, VEGF, and cell density. This cell over-proliferation was inhibited with the antioxidants N-acetyl cysteine and MnTMPyP, the HIF-1α inhibitor echinomycin, the VEGFR-2 receptor blocker SU1498, the protein kinase C (PKC) ε knock-down (KD) and the extracellular signal-regulated kinase 1/2 (ERK) inhibitor FR180204. The PKCε KD and echinomycin decreased VEGF and/or ERK. In conclusion, AD capillaries and arterioles in hippocampal CA1 stratum radiatum of non-APOE4 carriers are related with aging, while those in APOE4 carriers with AD are related with pathogenesis of cerebrovascular disease.