Oxidative Stress-related Mechanisms Research Articles

Assessing Radiosensitivity: Effects of Acute Ionizing Radiation on Inflammation and Apoptosis in Macrophage Cell Line (RAW 264.7).

Introduction: The responses of biological systems to various types of radiation have multifaceted dimensions. In the field of ionizing radiation, in vitro external gamma radiation therapy has primarily been studied as a model to elucidate the challenges that biological systems face from radiation effects. Exposure of cells/organisms to gamma radiation results in a cascade of ionization events that can cause severe and irreversible biological damage. However, the biological responses and oxidative stress-related mechanisms under acute radiation conditions remain poorly understood in inflammatory systems. The present study aimed to provide a model of the effect of ionizing radiation on macrophages, which play a pivotal role in the mechanisms of inflammation, to assess the impact of radiotherapy as an approach to treating inflammatory diseases. Methods: A macrophage cell line (RAW 264.7) was cultured and exposed to different doses of gamma radiation (4, 6, 8, 10 Gy). Cell viability, apoptosis, cell cycle, migration, nitric oxide (NO) and prostaglandin E2 (PGE2) production, expression of pro-inflammatory and apoptotic genes, and cytokine secretion of macrophages were also evaluated. Results: The results showed that gamma radiation at 4 Gy had a low effect on macrophage characteristics and cytokine secretion patterns. In contrast, higher doses (8 and 10 Gy) increased DNA damage, expression of apoptotic genes, and secretion of NO and PGE2 cytokines. 6 Gy radiation, the maximum radiation dose, showed moderate non-destructive effects and inflammation process modulation. In this study, doses higher than 6 Gy of Gamma radiation caused cell mortality. Conclusion: It appears that 6 Gy of gamma radiation modulates the inflammatory cascade caused by macrophage cells.

Nrf2 as a Therapeutic Target in the Resistance to Targeted Therapies in Melanoma.

The use of specific inhibitors towards mutant BRAF (BRAFi) and MEK (MEKi) in BRAF-mutated patients has significantly improved progression-free and overall survival of metastatic melanoma patients. Nevertheless, half of the patients still develop resistance within the first year of therapy. Therefore, understanding the mechanisms of BRAFi/MEKi-acquired resistance has become a priority for researchers. Among others, oxidative stress-related mechanisms have emerged as a major force. The aim of this study was to evaluate the contribution of Nrf2, the master regulator of the cytoprotective and antioxidant response, in the BRAFi/MEKi acquired resistance of melanoma. Moreover, we investigated the mechanisms of its activity regulation and the possible cooperation with the oncogene YAP, which is also involved in chemoresistance. Taking advantage of established in vitro melanoma models resistant to BRAFi, MEKi, or dual resistance to BRAFi/MEKi, we demonstrated that Nrf2 was upregulated in melanoma cells resistant to targeted therapy at the post-translational level and that the deubiquitinase DUB3 participated in the control of the Nrf2 protein stability. Furthermore, we found that Nrf2 controlled the expression of YAP. Importantly, the inhibition of Nrf2, directly or through inhibition of DUB3, reverted the resistance to targeted therapies.

Dietary digestible carbohydrates are associated with higher prevalence of asthma in humans and with aggravated lung allergic inflammation in mice.

Dietary carbohydrates and fats are intrinsically correlated within the habitual diet. We aimed to disentangle the associations of starch and sucrose from those of fat, in relation to allergic sensitization, asthma and rhinoconjuctivitis prevalence in humans, and to investigate underlying mechanisms using murine models. Epidemiological data from participants of two German birth cohorts (age 15) were used in logistic regression analyses testing cross-sectional associations of starch and sucrose (and their main dietary sources) with aeroallergen sensitization, asthma and rhinoconjunctivitis, adjusting for correlated fats (saturated, monounsaturated, omega-6 and omega-3 polyunsaturated) and other covariates. For mechanistic insights, murine models of aeroallergen-induced allergic airway inflammation (AAI) fed with a low-fat-high-sucrose or -high-starch versus a high-fat diet were used to characterize and quantify disease development. Metabolic and physiologic parameters were used to track outcomes of dietary interventions and cellular and molecular responses to monitor the development of AAI. Oxidative stress biomarkers were measured in murine sera or lung homogenates. We demonstrate a direct association of dietary sucrose with asthma prevalence in males, while starch was associated with higher asthma prevalence in females. In mice, high-carbohydrate feeding, despite scant metabolic effects, aggravated AAI compared to high-fat in both sexes, as displayed by humoral response, mucus hypersecretion, lung inflammatory cell infiltration and TH 2-TH 17 profiles. Compared to high-fat, high-carbohydrate intake was associated with increased pulmonary oxidative stress, signals of metabolic switch to glycolysis and decreased systemic anti-oxidative capacity. High consumption of digestible carbohydrates is associated with an increased prevalence of asthma in humans and aggravated lung allergic inflammation in mice, involving oxidative stress-related mechanisms.

A Prognostic Risk Model of a Novel Oxidative Stress-Related Signature Predicts Clinical Prognosis and Demonstrates Immune Relevancy in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is among the most prevalent malignant lung cancers with a poor prognosis due to high invasiveness and lethality despite multiple treatments. Since the lung is an important organ associated with oxidative stress, and it has been confirmed that oxidative stress represents a potential cancer-specific depletion, it is of important significance to investigate and evaluate the clinical value of oxidative stress mechanisms regulating tumor cell apoptosis. Furthermore, there are few studies on the impact of the microenvironment on reaction to immune-checkpoint inhibitors (ICIs) in patients with LUAD. Based on the TCGA-LUAD dataset, which is stratified into a training set as well as a validation set in a ratio of 2 : 1, this investigation constructs and validates a prognostic predictive power of a gene signature model of oxidative stress-related prognostic signatures. To ascertain the differences between the high-risk score group and the low-risk score group in tumor-infiltrating lymphocytes and patients' response to ICI therapy. This oxidative stress-related prognostic gene signature is composed of MAP3K19 and NTSR1 and is an independent prognosis-related factor in the LUAD group. The outcome of patients having a low risk score is better, and the difference was statistically significant, and individuals with a low risk score had a larger number of infiltrating immune cell distribution in the tumor microenvironment, which was closely related to clinical outcome. Our study suggests that the synergistic effect of oxidative stress-related prognostic gene markers-MAP3K19 and NTSR1 has clinical significance in the prognosis identification and immunotherapy of LUAD patients. Thus, the results may help to better intersect the oxidative stress-related mechanisms in clinical value in LUAD but requires prospective validation.

Platelet Redox Imbalance in Hypercholesterolemia: A Big Problem for a Small Cell.

The imbalance between reactive oxygen species (ROS) synthesis and their scavenging by anti-oxidant defences is the common soil of many disorders, including hypercholesterolemia. Platelets, the smallest blood cells, are deeply involved in the pathophysiology of occlusive arterial thrombi associated with myocardial infarction and stroke. A great deal of evidence shows that both increased intraplatelet ROS synthesis and impaired ROS neutralization are implicated in the thrombotic process. Hypercholesterolemia is recognized as cause of atherosclerosis, cerebro- and cardiovascular disease, and, closely related to this, is the widespread acceptance that it strongly contributes to platelet hyperreactivity via direct oxidized LDL (oxLDL)-platelet membrane interaction via scavenger receptors such as CD36 and signaling pathways including Src family kinases (SFK), mitogen-activated protein kinases (MAPK), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In turn, activated platelets contribute to oxLDL generation, which ends up propagating platelet activation and thrombus formation through a mechanism mediated by oxidative stress. When evaluating the effect of lipid-lowering therapies on thrombogenesis, a large body of evidence shows that the effects of statins and proprotein convertase subtilisin/kexin type 9 inhibitors are not limited to the reduction of LDL-C but also to the down-regulation of platelet reactivity mainly by mechanisms sensitive to intracellular redox balance. In this review, we will focus on the role of oxidative stress-related mechanisms as a cause of platelet hyperreactivity and the pathophysiological link of the pleiotropism of lipid-lowering agents to the beneficial effects on platelet function.

Air Quality and Cancer Prevalence Trends across the Sub-Saharan African Regions during 2005-2020.

Poor air quality and environmental pollution remain some of the main etiological factors leading to cancers and cancer-related deaths worldwide. As a result of human activities, deleterious airborne chemicals can be dispersed not only in the environment but also released in occupational environments and industrial areas. Air pollutants and cancer links are now established through various oxidative stress-related mechanisms and related DNA damages. Generally, ambient and indoor air pollutants have been understudied in sub-Saharan Africa (SSA) compared to other regions in the world. Our study not only highlights the deleterious effects of air pollutants in these developing countries, but it has strived to examine the trends and correlations between cancers and some air pollutants—carbon dioxide, other greenhouse gases, PM2.5, and human development index—in some SSA countries, where recent cancer burdens were reported as high. Our results showed strikingly higher yearly trends of cancers and above-mentioned air pollutant levels in some sub-Saharan countries during 2005–2020. Relative risks (RR) of these air pollutants-related cancer case rates were, however, below, or slightly above 1.0, or not statistically significant possibly due to other responsible and confounding factors which were not considered in our analyses due to data unavailability. We recommend new approaches to monitoring, minimizing, and creating awareness of the trends of hazardous air pollutants in sub-Saharan Africa, which will help ameliorate cancer prevalence and support the reduction in air pollution levels within regulatory limits, thereby relieving the cumulative burdens of cancers. Utilization of the findings from the study will support large-scale public health and health policy efforts on cancer management through environmental stewardship in SSA countries having the poorest outcome and the shortest survival rates from cancers.

Quantitative Fluorescence Imaging of the Intracellular Redox State by Real-Time Spatial and Temporal Simultaneous Analysis of O2•- Levels and Keap1 Translocation.

Dysregulated redox homeostasis under pathological conditions can eventually culminate in oxidative stress and associated disease damage. Spatial and temporal regulation of intracellular redox states involves two crucial parameters for elucidating oxidative stress-related molecular mechanisms. However, the lack of methods for real-time analysis of redox states is a considerable hurdle for the in-depth interpretation of pathogenic mechanisms. Herein, given the over-produced reactive oxygen species (ROS) and the translocation of redox-sensitive proteins as the potential biomarkers of oxidative stress, we developed a novel ROS-macromolecular protein synergistic imaging strategy that relied on a small-molecule fluorescent CPR-SK probe. The CPR-SK specifically activated the caffeic acid moieties or targeting peptides (EWWW) toward the biomarkers, including superoxide (O2•-) fluctuations and Keap1 translocation, achieving simultaneous real-time imaging of dual molecular events during oxidative stress. Importantly, in situ, CPR-SK exhibited both gentle elevation of O2•- and subsequent migration of Keap1 from the cytoplasm to the nucleus, which were key indicators for determining slight injuries induced by hepatic ischemia-reperfusion. The results clearly demonstrated that this spatiotemporal imaging method was a reliable tool for analyzing dynamic intracellular changes of the redox state and elucidating the molecular mechanisms of oxidative stress-related diseases.

Direct Interaction between N-Acetylcysteine and Cytotoxic Electrophile-An Overlooked In Vitro Mechanism of Protection.

In laboratory experiments, many electrophilic cytotoxic agents induce cell death accompanied by reactive oxygen species (ROS) production and/or by glutathione (GSH) depletion. Not surprisingly, millimolar concentrations of N-acetylcysteine (NAC), which is used as a universal ROS scavenger and precursor of GSH biosynthesis, inhibit ROS production, restore GSH levels, and prevent cell death. The protective effect of NAC is generally used as corroborative evidence that cell death induced by a studied cytotoxic agent is mediated by an oxidative stress-related mechanism. However, any simple interpretation of the results of the protective effects of NAC may be misleading because it is unable to interact with superoxide (O2•−), the most important biologically relevant ROS, and is a very weak scavenger of H2O2. In addition, NAC is used in concentrations that are unnecessarily high to stimulate GSH synthesis. Unfortunately, the possibility that NAC as a nucleophile can directly interact with cytotoxic electrophiles to form non-cytotoxic NAC–electrophile adduct is rarely considered, although it is a well-known protective mechanism that is much more common than expected. Overall, apropos the possible mechanism of the cytoprotective effect of NAC in vitro, it is appropriate to investigate whether there is a direct interaction between NAC and the cytotoxic electrophile to form a non-cytotoxic NAC–electrophilic adduct(s).

The Effect of Laminaria japonica on Metabolic Syndrome: A Systematic Review of Its Efficacy and Mechanism of Action.

Metabolic syndrome (MetS) is a medical condition characterized by abdominal obesity, insulin resistance, high blood pressure, and hyperlipidemia. An increase in the incidence of MetS provokes an escalation in health care costs and a downturn in quality of life. However, there is currently no cure for MetS, and the absence of immediate treatment for MetS has prompted the development of novel therapies. In accordance with recent studies, the brown seaweed Laminaria japonica (LJP) has anti-inflammatory and antioxidant properties, and so forth. LJP contains bioactive compounds used as food globally, and it has been used as a medicine in East Asian countries. We conducted a systematic review to examine whether LJP could potentially be a useful therapeutic drug for MetS. The following databases were searched from initiation to September 2021: PubMed, Web of Science, EMBASE, and Cochrane Central Register of Controlled Trials Library. Clinical trials and in vivo studies evaluating the effects of LJP on MetS were included. LJP reduces the oxidative stress-related lipid mechanisms, inflammatory cytokines and macrophage-related chemokines, muscle cell proliferation, and migration. Bioactive-glucosidase inhibitors reduce diabetic complications, a therapeutic target in obesity and type 2 diabetes. In obesity, LJP increases AMP-activated protein kinase and decreases acetyl-CoA carboxylase. Based on our findings, we suggest that LJP could treat MetS, as it has pharmacological effects on MetS.

Modulation of cellular redox environment as a novel therapeutic strategy for Parkinson's disease.

Parkinson's disease (PD) is an incurable neurodegenerative movement disorder. PD affects 2% of the population above 65 years old; however, with the growing number of senior citizens, PD prevalence is predicted to increase in the following years. Pathologically, PD is characterized by dopaminergic cell neurodegeneration in the substantia nigra, resulting in decreased dopamine levels in the nigrostriatal pathway, triggering motor symptoms. Although the pathological mechanisms leading to PD are still unclear, large evidence indicates that oxidative stress plays an important role, not only because it increases with age which is the most significant risk factor for PD development, but also as a result of alterations in several processes, particularly mitochondria dysfunction. The modulation of oxidative stress, especially using dietary mitochondriotropic antioxidants, represents a promising approach to prevent or treat PD. Although most mitochondria-targeted antioxidants with beneficial effects in PD-associated models have failed to show any therapeutic benefit in clinical trials, several questions remain to be clarified. Hereby, we review the role played by oxidative stress in PD pathogenesis, emphasizing mitochondria as reactive oxygen species (ROS) producers and as targets for oxidative stress-related dysfunctional mechanisms. In addition, we also describe the importance of using dietary-based mitochondria-targeted antioxidants as a valuable strategy to counteract the deleterious effects of ROS in pre-clinical and/or clinical trials of PD, pointing out their significance to slow, and possibly halt, the progression of PD.

Dimethyl phthalate induces blood immunotoxicity through oxidative damage and caspase-dependent apoptosis

Dimethyl phthalate (DMP), a low-molecular-weight phthalate ester, exists in ectoparasiticides, plastics, and insect repellants, and has been linked to neurotoxic, reproductive, and endocrine disruptive responses. However, its blood immunotoxic effects and mechanism are still poorly understood. In this study, rats were exposed to gradient concentrations of DMP through intragastric administration to assess the blood immunotoxic effects in the combined assay of biomarker, cytometry, and transcriptomics. DMP treatment altered the redox status of rats, thus causing oxidative damage. Significantly decreased blood cell counts and disordered antibody and cytokine secretion were observed in treated rats, suggesting the suppressed immune defense and destructed inflammatory regulation. Flow cytometry showed that in lymphocytes, especially CD3+CD4+ T cells, the occurrence of apoptosis/necrosis was positively related to DMP exposure level. Transcriptomics revealed an oxidative stress-related mechanism. The overexpression of the Bcl-2 family genes and the activation of the Fas/FasL pathway triggered downstream caspase cascade and caused reactive oxygen species signaling-mediated apoptosis/necrosis. To the best of our knowledge, it was the first report that the exposure to low-molecular-weight phthalate esters potentially triggered blood immunotoxicity. The result and underlying mechanisms can provide an essential basis for understanding phthalate ester toxicity and usage regulation.

MO279: Vitamin D Supplementation Attenuates Hyperandrogenemia-Associated Acute Kidney Injury in Female Sprague-Dawley Rats

Abstract BACKGROUND AND AIMS Polycystic ovary syndrome (PCOS) is closely related to the onset and development of metabolic abnormalities. However, the correlation between PCOS and kidney injury has not been clarified, and the underlying mechanism remains unknown. Vitamin D therapy has beneficial effects in women with PCOS and renal injuries. Therefore, this study was designed to explain the mechanisms responsible for kidney damages in a model of hyperandrogenic rats and the healing effects of vitamin D. METHOD Female Sprague-Dawley rats were randomly divided into five groups (n = 10): (i) control, (ii) sham, (iii) dehydroepiandrosterone (DHEA, 6 mg/100 g day-1 S.Q.), (iv) DHEA + vitamin D (1000 IU/Kg; 3 days/week), and (v) vitamin D. Plasma total testosterone, plasma creatinine (Cr), blood urea nitrogen (BUN), plasma and tissue levels of total oxidant status (TOS), total antioxidant capacity (TAC) and oxidative stress index (OSI), and histopathological changes of ovary and kidney were determined. RESULTS Plasma testosterone increased 9-fold in DHEA-treated rats compared with controls. They also had increased Cr, BUN, and severe renal tubular injury. Plasma and tissue TAC levels showed significant decreases, whereas TOS and OSI showed significant increases in the DHEA group. A significant injury in the glomerular and tubular parts of the kidney and ovarian follicular structure was observed in DHEA-administered rats. Vitamin D treatment attenuated TOS levels and significantly improved TAC levels. Kidneys and ovaries histopathological changes were significantly improved by vitamin D treatment. CONCLUSION Hyperandrogenemia causes systemic abnormalities through oxidative stress-related mechanisms, followed by obvious destruction to renal and ovarian tissues. Vitamin D supplementation attenuated these hyperandrogenemia-associated acute kidney injuries.

Particulate matter exposure during pregnancy increases risk of childhood asthma: modified by gender and NRF2 genotype.

Exposure to particulate matter (PM) has been known to develop asthma in children and the oxidative stress-related mechanisms are suggested. For the development of asthma, not only the exposure dose but also the critical window and the risk modifying factors should be evaluated. We investigated whether prenatal exposure to PM10 increases the risk of childhood asthma and evaluated the modifying factors, such as gender and reactive oxidative stress-related gene. A general population-based birth cohort, the Panel Study of Korean Children (PSKC), including 1572 mother-baby dyads was analyzed. Children were defined to have asthma at age 7 when a parent reported physician-diagnosed asthma. Exposure to PM10 during pregnancy was estimated by land-use regression models based on national monitoring system. TaqMan method was used for genotyping nuclear factor, erythroid 2-related factor, NRF2 (rs6726395). A logistic Bayesian distributed lag interaction model (BDLIM) was used to evaluate the associations between prenatal PM10 exposure and childhood asthma by gender and NRF2. Exposure to PM10 during pregnancy was associated with the development of asthma (aOR 1.03, 95% CI 1.001.06). Stratifying by gender and NRF2 genotype, exposure to PM10 during 26-28 weeks gestation increased the risk of childhood asthma, especially in boys with NRF2 GG genotype. A critical window for PM10 exposure on the development of childhood asthma was during 26-28 weeks of gestation, and this was modified by gender and NRF2 genotype.

In vitro toxicological evaluation of mesoporous silica microparticles functionalised with carvacrol and thymol

The cytotoxicity of carvacrol- and thymol-functionalised mesoporous silica microparticles (MCM-41) was assessed in the human hepatocarcinoma cell line (HepG2). Cell viability, lactate dehydrogenase (LDH) activity, reactive oxygen species (ROS) production, mitochondrial membrane potential (ΔΨm), lipid peroxidation (LPO) and apoptosis/necrosis analyses were used as endpoints. The results showed that both materials induced cytotoxicity in a time- and concentration-dependent manner, and were more cytotoxic than free essential oil components and bare MCM-41. This effect was caused by cell-particle interactions and not by degradation products released to the culture media, as demonstrated in the extract dilution assays. LDH release was a less sensitive endpoint than the MTT (thiazolyl blue tetrazolium bromide) assay, which suggests the impairment of the mitochondrial function as the primary cytotoxic mechanism. In vitro tests on specialised cell functions showed that exposure to sublethal concentrations of these materials did not induce ROS formation during 2 h of exposure, but produced LPO and ΔΨm alterations in a concentration-dependent manner when cells were exposed for 24 h. The obtained results generally support the hypothesis that the carvacrol- and thymol-functionalised MCM-41 microparticles induced toxicity in HepG2 cells by an oxidative stress-related mechanism that resulted in apoptosis through the mitochondrial pathway.

Oxidative Stress-Related Mechanisms in Melanoma and in the Acquired Resistance to Targeted Therapies.

Melanoma is a highly aggressive cancer with the poorest prognosis, representing the deadliest form of skin cancer. Activating mutations in BRAF are the most frequent genetic alterations, present in approximately 50% of all melanoma cases. The use of specific inhibitors towards mutant BRAF variants and MEK, a downstream signaling target of BRAF in the MAPK pathway, has significantly improved progression-free and overall survival in advanced melanoma patients carrying BRAF mutations. Nevertheless, despite these improvements, resistance still develops within the first year of therapy in around 50% of patients, which is a significant problem in managing BRAF-mutated advanced melanoma. Understanding these mechanisms is one of the mainstreams of the research on BRAFi/MEKi acquired resistance. Both genetic and epigenetic mechanisms have been described. Moreover, in recent years, oxidative stress has emerged as another major force involved in all the phases of melanoma development, from initiation to progression until the onsets of the metastatic phenotype and chemoresistance, and has thus become a target for therapy. In the present review, we discuss the current knowledge on oxidative stress and its signaling in melanoma, as well as the oxidative stress-related mechanisms in the acquired resistance to targeted therapies.

Insights into the Relation between Oxidative Stress and Malaria: A Mechanistic and Therapeutic Approach

The mortality rate due to malaria has increased tremendously in the last decade. Even though the causative agent of this disease is known, the preventive measures are not potent enough to control the spread of this disease. Malarial infection involves a strong interrelationship between oxidative stress and pathogenesis. This review addresses the various oxidative stress-related mechanisms associated with vector defense, host immunity, plasmodial pathogenesis, and corresponding therapeutic strategies. The mechanisms involving host and vector defense show both similarity and contradiction to the processes involving plasmodial pathogenesis under different circumstances. Therefore, corresponding ameliorative peculiarities are observed in the therapeutic mechanisms adopted by the anti-malarial drugs. The malarial parasite augments oxidative stress to weaken the host and exerts antioxidant effects against host defense mechanisms. However, the anti-malarial drugs induce oxidative insult to reduce parasitic load and exert antioxidant effects against parasite infection-induced oxidative stress in host. Thus, the anti-malarial drugs exhibit antioxidant activity in hosts and/or pro-oxidant activity in parasites.

Childhood psychosocial stress is linked with impaired vascular endothelial function, lower SIRT1, and oxidative stress in young adulthood.

Adverse childhood experiences (ACEs) are psychosocial stressors that occur during sensitive developmental windows and are associated with increased lifetime cardiovascular disease (CVD) risk in a dose-dependent manner. Vascular endothelial dysfunction is a pathophysiological mechanism that promotes hypertension and CVD and may be a mechanism by which ACEs contribute to lifetime CVD risk. We examined whether exposure to ACEs is associated with reduced vascular endothelial function (VEF) in otherwise healthy, young adult women (20.7 ± 3 yr) with (ACE+) versus without (ACE-) ACEs, explored whether differences in circulating sirtuin 1 (SIRT1) or systemic oxidative stress could explain ACEs-related differences in VEF, and examined the ability of a pilot, 8-wk exercise intervention to augment VEF and SIRT1 or reduce oxidized LDL cholesterol (oxLDL) in ACE+ young adult women. Forty-two otherwise healthy young adults completed this study. Prior to the intervention, VEF (P = 0.002) and SIRT1 (P = 0.004) were lower in the ACE+ than ACE- group, but oxLDL concentrations were not different (P = 0.77). There were also significant relationships (P ≤ 0.04) among flow-mediated dilation (FMD), SIRT1, and oxLDL in the ACE+, but not ACE- group. Adjusting for circulating SIRT1 and oxLDL reduced the differences in FMD observed between groups (P = 0.10), but only SIRT1 was a significant adjuster of the means (P < 0.05). Finally, the exercise intervention employed was unable to enhance VEF or SIRT1 in the ACE+ exercise group. Our data suggest that ACEs likely increase susceptibility to hypertension and CVD by causing endothelial dysfunction, perhaps through a SIRT1 pathway-related mechanism.NEW & NOTEWORTHY Our study provides novel evidence that young adult women with moderate-to-severe adverse childhood experience (ACE) exposure present impaired endothelial function and lower circulating sirtuin 1 (SIRT1) concentrations than age-matched controls. However, an 8-wk exercise intervention was unable to augment endothelial function or SIRT1 concentrations in a subset of those with ACEs. Our data suggest that ACEs-related impairments in endothelial function may be secondary to decreased NO bioavailability via SIRT1 and/or oxidative stress-related mechanisms.

Green Tea and Epigallocatechin Gallate (EGCG) for the Management of Nonalcoholic Fatty Liver Diseases (NAFLD): Insights into the Role of Oxidative Stress and Antioxidant Mechanism.

Nonalcoholic fatty liver diseases (NAFLD) represent a set of liver disorders progressing from steatosis to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma, which induce huge burden to human health. Many pathophysiological factors are considered to influence NAFLD in a parallel pattern, involving insulin resistance, oxidative stress, lipotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, inflammatory cascades, fibrogenic reaction, etc. However, the underlying mechanisms, including those that induce NAFLD development, have not been fully understood. Specifically, oxidative stress, mainly mediated by excessive accumulation of reactive oxygen species, has participated in the multiple NAFLD-related signaling by serving as an accelerator. Ameliorating oxidative stress and maintaining redox homeostasis may be a promising approach for the management of NAFLD. Green tea is one of the most important dietary resources of natural antioxidants, above which epigallocatechin gallate (EGCG) notably contributes to its antioxidative action. Accumulative evidence from randomized clinical trials, systematic reviews, and meta-analysis has revealed the beneficial functions of green tea and EGCG in preventing and managing NAFLD, with acceptable safety in the patients. Abundant animal and cellular studies have demonstrated that green tea and EGCG may protect against NAFLD initiation and development by alleviating oxidative stress and the related metabolism dysfunction, inflammation, fibrosis, and tumorigenesis. The targeted signaling pathways may include, but are not limited to, NRF2, AMPK, SIRT1, NF-κB, TLR4/MYD88, TGF-β/SMAD, and PI3K/Akt/FoxO1, etc. In this review, we thoroughly discuss the oxidative stress-related mechanisms involved in NAFLD development, as well as summarize the protective effects and underlying mechanisms of green tea and EGCG against NAFLD.

Involvement of NRF2 in Breast Cancer and Possible Therapeutical Role of Polyphenols and Melatonin.

Oxidative stress is defined as a disturbance in the prooxidant/antioxidant balance in favor of the former and a loss of control over redox signaling processes, leading to potential biomolecular damage. It is involved in the etiology of many diseases, varying from diabetes to neurodegenerative diseases and cancer. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor and reported as one of the most important oxidative stress regulators. Due to its regulatory role in the expression of numerous cytoprotective genes involved in the antioxidant and anti-inflammatory responses, the modulation of NRF2 seems to be a promising approach in the prevention and treatment of cancer. Breast cancer is the prevalent type of tumor in women and is the leading cause of death among female cancers. Oxidative stress-related mechanisms are known to be involved in breast cancer, and therefore, NRF2 is considered to be beneficial in its prevention. However, its overactivation may lead to a negative clinical impact on breast cancer therapy by causing chemoresistance. Some known “oxidative stress modulators”, such as melatonin and polyphenols, are suggested to play an important role in the prevention and treatment of cancer, where the activation of NRF2 is reported as a possible underlying mechanism. In the present review, the potential involvement of oxidative stress and NRF2 in breast cancer will be reviewed, and the role of the NRF2 modulators—namely, polyphenols and melatonin—in the treatment of breast cancer will be discussed.

Oxidative Stress-Related Mechanisms in Schizophrenia Pathogenesis and New Treatment Perspectives.

Schizophrenia is recognized to be a highly heterogeneous disease at various levels, from genetics to clinical manifestations and treatment sensitivity. This heterogeneity is also reflected in the variety of oxidative stress-related mechanisms contributing to the phenotypic realization and manifestation of schizophrenia. At the molecular level, these mechanisms are supposed to include genetic causes that increase the susceptibility of individuals to oxidative stress and lead to gene expression dysregulation caused by abnormal regulation of redox-sensitive transcriptional factors, noncoding RNAs, and epigenetic mechanisms favored by environmental insults. These changes form the basis of the prooxidant state and lead to altered redox signaling related to glutathione deficiency and impaired expression and function of redox-sensitive transcriptional factors (Nrf2, NF-κB, FoxO, etc.). At the cellular level, these changes lead to mitochondrial dysfunction and metabolic abnormalities that contribute to aberrant neuronal development, abnormal myelination, neurotransmitter anomalies, and dysfunction of parvalbumin-positive interneurons. Immune dysfunction also contributes to redox imbalance. At the whole-organism level, all these mechanisms ultimately contribute to the manifestation and development of schizophrenia. In this review, we consider oxidative stress-related mechanisms and new treatment perspectives associated with the correction of redox imbalance in schizophrenia. We suggest that not only antioxidants but also redox-regulated transcription factor-targeting drugs (including Nrf2 and FoxO activators or NF-κB inhibitors) have great promise in schizophrenia. But it is necessary to develop the stratification criteria of schizophrenia patients based on oxidative stress-related markers for the administration of redox-correcting treatment.