Endogenous Antioxidant System Research Articles

Oxidative Stress and Dopaminergic Metabolism: A Major PD Pathogenic Mechanism and Basis of Potential Antioxidant Therapies

Reactive oxygen species (ROS)-induced oxidative stress triggers the vicious cycle leading to the degeneration of dopaminergic neurons in the nigra pars compacta. ROS produced during the metabolism of dopamine is immediately neutralized by the endogenous antioxidant defense system (EADS) under physiological conditions. Aging decreases the vigilance of EADS and makes the dopaminergic neurons more vulnerable to oxidative stress. As a result, ROS left over by EADS oxidize the dopamine-derived catechols and produces a number of reactive dopamine quinones, which are precursors to endogenous neurotoxins. In addition, ROS causes lipid peroxidation, uncoupling of the electron transport chain, and DNA damage, which lead to mitochondrial dysfunction, lysosomal dysfunction, and synaptic dysfunction. The mutations in genes such as DNAJC6, SYNJ1, SH3GL2, LRRK2, PRKN, and VPS35 caused by ROS have been associated with synaptic dysfunction and the pathogenesis of Parkinson’s disease (PD). The available drugs that are used against PD can only delay the progression of the disease, but they produce various side effects. Through their antioxidant activity, flavonoids can substantiate the EADS of dopaminergic neurons and disrupt the vicious cycle incepted by oxidative stress. In this review, we show how the oxidative metabolism of dopamine generates ROS and dopamine-quinones, which then exert unrestrained OS, causing mutations in several genes involved in the proper functioning of mitochondrion, synapse, and lysosome. Besides, we also present some examples of approved drugs used for the treatment of PD, therapies in the clinical trial phase, and an update on the flavonoids that have been tested to boost the EADS of dopaminergic neurons.

Enzyme-free method for preparation of sturgeon extracts with antioxidant, hepatoprotective and immune-enhancing functions

Sturgeon has a long lifespan and slow evolutionary rate due to their powerful endogenous antioxidant system. This work aimed to assess the in vitro and in vivo antioxidant activity of sturgeon extracts from both muscle and roe. The extraction process without enzyme hydrolysis is not only simple, but also can produce extracts with better free radicals scavenging abilities than enzymatic hydrolysates in both cellular and in vivo experiments. Moreover, in mouse models with liver injury and immunosuppression treatment, the sturgeon extracts demonstrated strong hepatoprotective and immune-enhancing functions, comparable to vitamin C and ginseng extract supplements, which were attributed to abundant antioxidant peptides of the extracts. The 15 isolated peptides exhibited diverse free radical scavenging ability. Therefore, the sturgeon extracts showed high potential to be applied in food and biomedical industries.

MnO2-coated nanodiamond-driven photodynamic therapy for enhanced antitumor effect by addressing hypoxia and glutathione depletion

The generation of reactive oxygen species (ROS) at the tumor site to induce destruction is emerging as a novel strategy for cancer treatment, which involves photodynamic therapy (PDT). Nevertheless, tumors typically create a hypoxic environment and are equipped with an endogenous antioxidant defense system that could potentially impede the efficiency of the therapeutic approach. To overcome these drawbacks, herein, a tumor microenvironment-responsive the ND-PAA-CD-Ce6@MnO2 (NPCC@M) delivery system was fabricated by disulfide bond coupling chlorin e6 (Ce6) to nanodiamond (ND) and further wrapped by MnO2 nanosheets to facilitate PDT. The use of disulfide bond not only stabilizes Ce6 in the blood circulation to prevent premature leakage, but also destroys the antioxidant barrier of overexpressed glutathione (GSH) in tumor cells. Moreover, the outer MnO2 was rapidly degraded by the endogenous hydrogen peroxide (H2O2) in the acidic pH and GSH within the tumor cells, which leads to an abundance of O2 and while increases the level of 1O2 under laser irradiation. The results eventually broke the redox homeostasis and attenuate hypoxia, thereby inducing apoptosis and necrosis of tumor cells. Detailed in vitro and in vivo biological effect has revealed a good biosafety profile and a high tumor suppression effect. Such a novel ND-based system with tumor microenvironment-modulating capability to elevate oxygen content and promote GSH consumption in tumor cells opens new opportunities for enhanced ROS treatment paradigms.

Chondrocyte-targeted exosome-mediated delivery of Nrf2 alleviates cartilaginous endplate degeneration by modulating mitochondrial fission

BackgroundCartilaginous endplate (CEP) degeneration, which is an important contributor to intervertebral disc degeneration (IVDD), is characterized by chondrocyte death. Accumulating evidence has revealed that dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and dysfunction lead to apoptosis during CEP degeneration and IVDD. Exosomes are promising agents for the treatment of many diseases, including osteoporosis, osteosarcoma, osteoarthritis and IVDD. Despite their major success in drug delivery, the full potential of exosomes remains untapped.Materials and methodsIn vitro and in vivo models of CEP degeneration were established by using lipopolysaccharide (LPS). We designed genetically engineered exosomes (CAP-Nrf2-Exos) expressing chondrocyte-affinity peptide (CAP) on the surface and carrying the antioxidant transcription factor nuclear factor E2-related factor 2 (Nrf2). The affinity between CAP-Nrf2-Exos and CEP was evaluated by in vitro internalization assays and in vivo imaging assays. qRT‒PCR, Western blotting and immunofluorescence assays were performed to examine the expression level of Nrf2 and the subcellular localization of Nrf2 and Drp1. Mitochondrial function was measured by the JC-1 probe and MitoSOX Red. Mitochondrial morphology was visualized by MitoTracker staining and transmission electron microscopy (TEM). After subendplate injection of the engineered exosomes, the degree of CEP degeneration and IVDD was validated radiologically and histologically.ResultsWe found that the cargo delivery efficiency of exosomes after cargo packaging was increased by surface modification. CAP-Nrf2-Exos facilitated chondrocyte-targeted delivery of Nrf2 and activated the endogenous antioxidant defence system in CEP cells. The engineered exosomes inhibited Drp1 S616 phosphorylation and mitochondrial translocation, thereby preventing mitochondrial fragmentation and dysfunction. LPS-induced CEP cell apoptosis was alleviated by CAP-Nrf2-Exo treatment. In a rat model of CEP degeneration, the engineered exosomes successfully attenuated CEP degeneration and IVDD and exhibited better repair capacity than natural exosomes.ConclusionCollectively, our findings showed that exosome-mediated chondrocyte-targeted delivery of Nrf2 was an effective strategy for treating CEP degeneration.Graphic abstract CAP-Nrf2-Exos delivered Nrf2 into CEP cells and alleviated LPS-induced apoptosis by inhibiting Drp1-mediated mitochondrial fission

Ginseng fruit rare saponins (GFRS), a promising anti-wrinkle agent: Evidence of its antioxidant effect and its capacity to prevent matrix metalloproteinase (MMPs) expression in vitro and in vivo

Rare saponins show numerous significant biological activities, however, there has been no research on using ginseng fruit rare saponins (GFRS) to minimize skin wrinkles. This paper studied the anti-wrinkle effect, related mechanism, material basis of efficacy, and structure-activity relationship of GFRS in vivo and in vitro. The findings demonstrate that GFRS has potent collagenase and elastase inhibition capabilities in addition to superior ultraviolet absorption properties. Secondly, GFRS can strengthen the endogenous antioxidant defense system, thus lessening the UVB-induced ultraviolet damage that L929 cells and zebrafish experience. Matrix metalloproteinases (MMPs) studies have shown that GFRS could significantly inhibit the UVB-induced MMP1 and MMP9 proteins production. Finally, the main ginsenoside component in GFRS was identified by LC-MS, and 16 kinds of ginsenoside were analyzed, including rare ginsenoside such as Rg6, F4, and R/S-Rg3, which may be caused by the transformation of prototype saponins Re and Rd caused by citric acid heat treatment (CAHT). After doing a quantitative HPLC analysis on twelve of them, it was discovered that CAHT could enrich the content of rare saponins in GFS. By evaluating these ginsenoside’s anti-wrinkle properties. It is found that the main material basis for GFRS’s anti-wrinkle action may be ginsenoside Rg6 or F4. In summary, GFRS exhibits promising properties as an anti-wrinkle treatment because of its robust anti-oxidation, anti-collagenase, anti-elastase activity, favorable ultraviolet absorption effect, and capacity to regulate MMPs in vivo and in vitro models.

Adaptogenic correction of free radical processes in liver tissue under the exposure to coal-rock dust on the body (experimental study)

Introduction. Damage to the liver under the conditions of long-term exposure to coal-rock dust on the body leads to significant impairment of its metabolic, detoxification, synthetic, and other functions. In this regard, it is relevant to search for early methods of prevention and correction of developing pathological changes in this organ. The purpose of the study is to experimentally study the effect of a complex drug with dihydroquercetin on the activity of free radical processes in the liver of laboratory rats over the dynamics of long-term exposure to coal-rock dust. Materials and methods. The work was carried out on male white rats weighing 200–250 g. The control group was kept under the standard vivarium conditions. The experimental group included rats that inhaled coal-rock dust in a priming chamber daily for 4 hours for 1, 3, 6, and 9 weeks and rats that received a daily complex drug with dihydroquercetin immediately before dust exposure. In the liver tissue, the activity of free radical oxidation and antioxidant defense enzymes (superoxide dismutase and catalase) was determined. Results. Priming rats with coal-rock dust for three weeks led to the gain in the intensity of free radical processes in the liver tissue: the initial level of accumulation of TBA-active oxidation products reliably raised by almost 2 times over the 1st week and 3 times over the 3rd week of the experiment compared to the control. An increase in the intensity of free radical oxidation was accompanied by activation of antioxidant defense enzymes - catalase - by 2.4 times at the 1st week and 1.6 times at the 3rd week of dust exposure. Raising the period of priming with dust up to 9 weeks led to multidirectional changes in oxidative metabolism in the liver tissue: at week 6, a decrease in the activity of superoxide dismutase was almost 3 times; at week 9, to a slight activation of antioxidant enzymes: superoxide dismutase by 55% and catalase by 36%.The most effective use of a complex drug with dihydroquercetin had been shown in short-term mode for three weeks, but not long-term (more than 6 weeks). The maximum antioxidant defense effect of dihydroquercetin was detected at the 3rd week of dust exposure – the level of free radical products decreased by 2 times and the activity of superoxide dismutase increased by 4 times. Limitations. Since the issue of organ-specific effects and the optimal duration of use of dihydroquercetin to increase resistance to free radical damage has been little elaborated, this imposes certain restrictions on its use for the correction and prevention of occupational diseases. Conclusion. The results obtained should be taken into account with long-term use of exogenous antioxidants in the correction and prevention of occupational diseases to support the level of endogenous antioxidant systems in the cell and the protective effect of dihydroquercetin for tissues most sensitive to the action of free radical processes.

Lonicera japonica Thunb. and its characteristic component chlorogenic acid alleviated experimental colitis by promoting Lactobacillus and fecal short‐chain fatty acids production

AbstractUlcerative colitis is intricately linked to intestinal oxidative stress and dysbiosis of the gut microbiota. Lonicera japonica Thunb. (LJ) is a traditional edible and medical flower in China, and chlorogenic acid (CGA) is one of its characteristic components. However, it remains unclear whether gut microbiota plays a role in the therapeutic effects of LJ and GCA on colitis. Here, we first observed that oral administration of LJ and CGA for 3 weeks dramatically promoted the growth of Lactobacillus and fecal short‐chain fatty acids (SCFAs) production in healthy mice. Subsequently, the alleviating effects of LJ and CGA on colitis were explored with a dextran sulfate sodium‐induced colitis mice model. The intervention of LJ and CGA notably alleviated inflammation, intestinal barrier impairment, and oxidative stress in colitis and led to a significant elevation in Lactobacillus and fecal SCFAs. Eventually, the key role of gut microbiota and their metabolites on the therapeutic effects was validated by performing fecal microbiota transplantation and sterile fecal suspensions transplantation from LJ and CGA‐treated healthy mice to colitis mice. Our findings demonstrated that consumption of LJ and CGA could benefit the host both in healthy condition and colitis. The beneficial effects were attributed to the improvement of the endogenous antioxidant system and promotion of the probiotic Lactobacillus and SCFAs production. Our study highlighted the great potential of LJ and CGA to be consumed as functional foods and provided novel mechanisms by which they alleviated colitis.

Targeted activation of Nrf2 prevents losses in leg muscle mass and strength during 2 weeks of immobilization in young adults

Introduction: Leg immobilization results in substantial losses in muscle mass and strength. Strategies aimed at minimizing these losses have proven largely ineffective. Elevated oxidative stress has been identified as a potential mechanism contributing to these losses. Therefore, we tested the hypothesis that PB125, an activator of Nrf2 (the master regulator of the endogenous antioxidant system), and MitoQ, a mitochondrial-targeted antioxidant, would decrease the deleterious effects of limb immobilization on muscle mass and strength. Methods: A double-blind, placebo-controlled trial was performed in a cohort of twenty young healthy adults (6M/14F, Age: 28±7 y; Height: 169±7 cm; Mass: 70±14 kg). Participants were randomized into either placebo (n=7), PB125 (n=6), or MitoQ (n=7). Supplementation and measures of physical activity using an accelerometer began 2 weeks prior to single leg immobilization and continued through 2 weeks of immobilization. Knee extensor muscle strength was tested before and after immobilization using isometric maximal voluntary contractions (MVC) and isokinetic contractions (120 and 60 degrees/s). Muscle mass was determined by MRI, and thigh lean muscle volume from image slices between the patellar tendon and gluteal muscle were assessed. Results: Physical activity, measured by steps per day, decreased by 55-65% during limb immobilization for all groups (p <0.05). Isometric muscle strength was significantly decreased following placebo (145±40 to 119±27 kg; p <0.05) and MitoQ (148±36 to 118±36 kg; p <0.05), but not PB125 (140±55 to 144±71 kg, p=0.7). Similarly, isokinetic muscle strength measured at 120 and 60 degrees/s was significantly decreased in placebo and MitoQ but preserved with PB125. Lean muscle volume in the immobilized limb significantly decreased by ~4% in placebo (p<0.05) and MitoQ (p<0.05) but was preserved with PB125 (p =0.55). Conclusions: Targeted activation of Nrf2 with PB125 preserved muscle mass and strength following 2 weeks of leg immobilization. In contrast, both placebo and MitoQ had no impact on immobilization-induced losses in muscle mass and strength. These findings provide novel evidence that targeting Nrf2 offsets the detrimental skeletal muscle effects of limb immobilization in young, healthy individuals. NIH-R01HL142603 and VA Merit-I01CX001999. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Lycopene as a Therapeutic Agent against Aflatoxin B1-Related Toxicity: Mechanistic Insights and Future Directions.

Aflatoxin (AFT) contamination poses a significant global public health and safety concern, prompting widespread apprehension. Of the various AFTs, aflatoxin B1 (AFB1) stands out for its pronounced toxicity and its association with a spectrum of chronic ailments, including cardiovascular disease, neurodegenerative disorders, and cancer. Lycopene, a lipid-soluble natural carotenoid, has emerged as a potential mitigator of the deleterious effects induced by AFB1 exposure, spanning cardiac injury, hepatotoxicity, nephrotoxicity, intestinal damage, and reproductive impairment. This protective mechanism operates by reducing oxidative stress, inflammation, and lipid peroxidation, and activating the mitochondrial apoptotic pathway, facilitating the activation of mitochondrial biogenesis, the endogenous antioxidant system, and the nuclear factor erythroid 2-related factor 2 (Nrf2)/kelch-like ECH-associated protein 1 (KEAP1) and peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) pathways, as well as regulating the activities of cytochrome P450 (CYP450) enzymes. This review provides an overview of the protective effects of lycopene against AFB1 exposure-induced toxicity and the underlying molecular mechanisms. Furthermore, it explores the safety profile and potential clinical applications of lycopene. The present review underscores lycopene's potential as a promising detoxification agent against AFB1 exposure, with the intent to stimulate further research and practical utilization in this domain.

Effects of Green and Gold Kiwifruit Varieties on Antioxidant Neuroprotective Potential in Pigs as a Model for Human Adults.

Kiwifruit (KF) has shown neuroprotective potential in cell-based and rodent models by augmenting the capacity of endogenous antioxidant systems. This study aimed to determine whether KF consumption modulates the antioxidant capacity of plasma and brain tissue in growing pigs. Eighteen male pigs were divided equally into three groups: (1) bread, (2) bread + Actinidia deliciosa cv. 'Hayward' (green-fleshed), and (3) bread + A. chinensis cv. 'Hort16A' (yellow-fleshed). Following consumption of the diets for eight days, plasma and brain tissue (brain stem, corpus striatum, hippocampus, and prefrontal cortex) were collected and measured for biomarkers of antioxidant capacity, enzyme activity, and protein expression assessments. Green KF significantly increased ferric-reducing antioxidant potential (FRAP) in plasma and all brain regions compared with the bread-only diet. Gold KF increased plasma ascorbate concentration and trended towards reducing acetylcholinesterase activity in the brain compared with the bread-only diet. Pearson correlation analysis revealed a significant positive correlation between FRAP in the brain stem, prefrontal cortex, and hippocampus with the total polyphenol concentration of dietary interventions. These findings provide exploratory evidence for the benefits of KF constituents in augmenting the brain's antioxidant capacity that may support neurological homeostasis during oxidative stress.

698 Animal Model of a Common HFE Mutation Modifies Recovery Following Intracerebral Hemorrhage

INTRODUCTION: Intracerebral hemorrhage (ICH) is a devastating disease with a one-year mortality rate of 45%. In the setting of an ICH, the breakdown of blood releases iron into the brain parenchyma. This excess iron contributes to stroke-induced neurodegeneration as it creates a cytotoxic environment through increased oxidative stress. Genetic variations in iron metabolism such as the H63D HFE mutation have been shown to modify disease progression in neurodegenerative diseases such as Parkinson’s, but have not been studied in ICH. METHODS: An autologous blood infusion model was utilized to create an ICH in the right caudate of H67D (human homolog of the H63D HFE mutation) and WT mice. Motor recovery was assessed using latency to fall from rotarod. 3-days post-ICH, the extent of neurodegeneration and mitochondrial damage in glial cells in the perihematomal area were measured using Fluorojade-B (FJB) and Cytochrome-C (CytC) immunofluorescent staining respectively. Levels of key regulatory proteins in the antioxidant and iron storage systems (Nrf2, GPX4, and FTH1) were evaluated using immunoblotting. RESULTS: H67D mice demonstrated significantly increased motor recovery at two- and three-days post-ICH compared to WT. H67D mice displayed significantly decreased degenerated neurons and CytC+ glial cells in the perihematomal region compared to WT. Furthermore, levels of Nrf2, GPX4, and FTH1 were significantly increased in the ICH-affected hemisphere of H67D mice. CONCLUSIONS: Our data suggest that the H67D HFE mutation modifies ICH recovery through significant improvements in motor recovery and decreases in damaged cells in the perihematomal region. The mechanism appears to be an upregulation of the endogenous antioxidant systems. These data suggest that a study determining the impact of HFE mutations on clinical outcomes in ICH is warranted. Given the prevalence of the H63D HFE mutation in humans, the impact of this mutation on ICH could be highly significant.

Ameliorative Potentials of Persea americana Mill (Avocado) Seed Extract on Acetaminophen-induced Hepatic Insufficiency in Rats

Aim: The ability of ethylacetate extract of Persea americana Mill (avocado) seed to ameliorate the hepatotoxic effect of acetaminophen in rats was assessed. Methodology: Thirty experimental rats were placed in 6 groups of 5 animals per group. Two animal groups received distilled water and the drug vehicle, dimethyl sulphoxide (DMSO). Four other groups received acetaminophen (750 mg/kg bw/day) in DMSO for 3 days with 3 of the 4 groups receiving, after 3 days of acetaminophen administration and for 11 days, Persea americana seed extracts (150-, 350 mg/kg bw) and silymarin (200 mg/kg bw). Animals were sacrificed and both serum and liver tissue analysed for markers of liver integrity (AST, ALT, ALP), liver function (total protein, albumin, total cholesterol, triglyceride), antioxidant status (SOD, Catalase) and liver architecture. Results: The result showed induction of hepatotoxicity by acetaminophen with increased AST, ALT, ALP and decreased SOD and CAT activities. Hepatotoxicity was also observed as increase in total and conjugated bilirubin and decrease in total cholesterol and triglyceride. Administration of Persea americana seed ethylacetate extract reversed the status of the parameters towards normal (except for AST, total protein and albumin). Also the liver architecture which hitherto revealed inflammation, fatty changes and hepatocyte necrosis also reversed to mild inflammation to normal histology. The action of the extract was dose dependent and its effectiveness comparable to silymarin (200 mg/kg bw). Conclusion: The ethylacetate extract of Persia americana showed ameliorative effect against acetaminophen-induced hepatotoxicity at higher dose, with potentials to reverse disruptions in liver integrity and function, and restore balance in endogenous antioxidant system.

Nitrooxidative Stress and Neuroinflammation Caused by Air Pollutants Are Associated with the Biological Markers of Neurodegenerative Diseases.

Millions of people around the world are exposed to air pollutants, such as particulate matter 2.5 (PM2.5) and ozone (O3). Such exposure usually does not exclude these two types of pollutants and their harmful effects could be additive or synergistic. O3 is a highly oxidizing gas that reacts with the cellular environment just as PM2.5, triggering nitrooxidative damage. Once nitrooxidative stress overcomes the endogenous antioxidant system, an acute neuroinflammatory process is generated, and once it becomes chronic, it favors the formation of neurodegenerative disease markers. The presence of these markers becomes potentially dangerous in people who have a genetic predisposition and are at a higher risk of developing neurodegenerative diseases such as Alzheimer's and Parkinson's. Our experimental approach for nitrooxidative damage and neuroinflammation caused by air pollutants has focused on the exposure of rats to O3 in an isolated chamber. The hippocampus is the most studied brain structure because of its neuronal connectivity network with the olfactory epithelium, its weak antioxidant defense, and its fundamental roll in cognitive processes. However, other brain structures may exhibit a different degree of damage upon exposure to O3 and PM2.5, making their involvement an important factor in developing other CNS diseases. The age spectrum for augmented sensibility to air pollutants seems to mostly affect the pre-postnatal (autism spectrum) period and the elderly (neurodegenerative). Thus, a new approach could be the estimation of the damage caused by PM2.5 and O3 through a controlled exposure paradigm to determine the extent of damage caused by both pollutants.

The Role of Oxidative Stress in Tumorigenesis and Progression.

Oxidative stress refers to the imbalance between the production of reactive oxygen species (ROS) and the endogenous antioxidant defense system. Its involvement in cell senescence, apoptosis, and series diseases has been demonstrated. Advances in carcinogenic research have revealed oxidative stress as a pivotal pathophysiological pathway in tumorigenesis and to be involved in lung cancer, glioma, hepatocellular carcinoma, leukemia, and so on. This review combs the effects of oxidative stress on tumorigenesis on each phase and cell fate determination, and three features are discussed. Oxidative stress takes part in the processes ranging from tumorigenesis to tumor death via series pathways and processes like mitochondrial stress, endoplasmic reticulum stress, and ferroptosis. It can affect cell fate by engaging in the complex relationships between senescence, death, and cancer. The influence of oxidative stress on tumorigenesis and progression is a multi-stage interlaced process that includes two aspects of promotion and inhibition, with mitochondria as the core of regulation. A deeper and more comprehensive understanding of the effects of oxidative stress on tumorigenesis is conducive to exploring more tumor therapies.

The Effects of Chia Defatted Flour as a Nutritional Supplement in C57BL/6 Mice Fed a Low-Quality Diet.

Today, consumption of diets rich in saturated fat and fructose, associated with a variety of metabolic deregulations, has increased. The aim of this study was to evaluate the effect of dietary supplementation with a residue of defatted chia seed on a diet with low nutritional quality. To do this, C57BL/6 male mice were fed with the Control (C), Low-Nutritional-Quality (LNQ), or supplemented-with-chia-defatted-flour (LNQ+C) diets. After 12 weeks, the glucose and lactate levels were determined in the serum, liver, and kidney, along with reactive oxygen species (ROS) levels, antioxidant enzyme activity, reduced glutathione (GSH), and protein oxidation (AOPP). The LNQ diet increased the glucose and lactate levels (+25% and +50% approx. in the liver, with respect to the control group) and generated oxidative stress by modifying the levels of ROS and the activity of antioxidant enzymes, causing oxidative damage to proteins (+12% in the liver, with respect to the control). Chia supplementation helped to restore the glucose to control levels and modulate the endogenous antioxidant system, resulting in a decrease in protein oxidation products with no differences compared to the control group. In conclusion, supplementation with chia showed beneficial effects on the general health of mice, even when fed a low-nutritional-quality diet.

Nanomaterials-Induced Redox Imbalance: Challenged and Opportunities for Nanomaterials in Cancer Therapy.

Cancer cells typically display redox imbalance compared with normal cells due to increased metabolic rate, accumulated mitochondrial dysfunction, elevated cell signaling, and accelerated peroxisomal activities. This redox imbalance may regulate gene expression, alter protein stability, and modulate existing cellular programs, resulting in inefficient treatment modalities. Therapeutic strategies targeting intra- or extracellular redox states of cancer cells at varying state of progression may trigger programmed cell death if exceeded a certain threshold, enabling therapeutic selectivity and overcoming cancer resistance to radiotherapy and chemotherapy. Nanotechnology provides new opportunities for modulating redox state in cancer cells due to their excellent designability and high reactivity. Various nanomaterials are widely researched to enhance highly reactive substances (free radicals) production, disrupt the endogenous antioxidant defense systems, or both. Here, the physiological features of redox imbalance in cancer cells are described and the challenges in modulating redox state in cancer cells are illustrated. Then, nanomaterials that regulate redox imbalance are classified and elaborated upon based on their ability to target redox regulations. Finally, the future perspectives in this field are proposed. It is hoped this review provides guidance for the design of nanomaterials-based approaches involving modulating intra- or extracellular redox states for cancer therapy, especially for cancers resistant to radiotherapy or chemotherapy, etc.

Options for Topical Treatment of Oxidative Eye Diseases with a Special Focus on Retinopathies.

Antioxidants, usually administered orally through the systemic route, are known to counteract the harmful effects of oxidative stress on retinal cells. The formulation of these antioxidants as eye drops might offer a new option in the treatment of oxidative retinopathies. In this review, we will focus on the use of some of the most potent antioxidants in treating retinal neuropathies. Melatonin, known for its neuroprotective qualities, may mitigate oxidative damage in the retina. N-acetyl-cysteine (NAC), a precursor to glutathione, enhances the endogenous antioxidant defense system, potentially reducing retinal oxidative stress. Idebenone, a synthetic analogue of coenzyme Q10, and edaravone, a free radical scavenger, contribute to cellular protection against oxidative injury. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, possesses anti-inflammatory and antioxidant effects that could be beneficial in cases of retinopathy. Formulating these antioxidants as eye drops presents a localized and targeted delivery method, ensuring effective concentrations reach the retina. This approach might minimize systemic side effects and enhance therapeutic efficacy. In this paper, we also introduce a relatively new strategy: the alkylation of two antioxidants, namely, edaravone and EGCG, to improve their insertion into the lipid bilayer of liposomes or even directly into cellular membranes, facilitating their crossing of epithelial barriers and targeting the posterior segment of the eye. The synergistic action of these antioxidants may offer a multifaceted defense against oxidative damage, holding potential for the treatment and management of oxidative retinopathies. Further research and clinical trials will be necessary to validate the safety and efficacy of these formulations, but the prospect of antioxidant-based eye drops represents a promising avenue for future ocular therapies.

ANTIOXIDANTS, BIOCHEMICAL, AND HEMATOLOGICAL PARAMETERS CHANGE IN WORKERS OCCUPATIONALLY EXPOSED TO RADON INHALATION AT CERTAIN CONSTRUCTION MATERIAL INDUSTRIES IN ERBIL, IRAQ

This study examined the effects of radon on the endogenous antioxidants, biochemical, and hematological parameters of workers in Erbil, Iraqi Kurdistan. This was carried out to ascertain how radon affects the health of those who work in certain factories producing building materials. The case study group consisted of 70 workers, who were then divided into seven subgroups (gypsum, cement plant, lightweight block, marble, red brick 1, crushed stone, and concrete block 2), while the control group consisted of 20 healthy volunteers. The total antioxidant capacity (TAC), levels of carcinoembryonic antigen (CEA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX), the complete blood count (CBC), and liver function tests were evaluated. The statistical analysis revealed that the antioxidant activities and CEA levels between the case study group and the control group differed significantly. Also, antioxidant enzyme activities and indoor radon concentration, the annual effective dosage, were found to be highly significantly correlated by Pearson and Spearman analyses in the case study group. Additionally, the results demonstrated a substantial correlation in the data between the levels of CEA biomarkers and radon (r=0.478, p˂0.000). The present results showed that radon concentration increased alanine aminotransferase (ALT) activity in a radon concentration-dependent manner (r=0.263 and p ˂0.05). The aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin activities, on the other hand, were not significantly affected by radon. The most significantly influenced CBC parameter was the low white blood cells (WBC) in the case study group compared to the controls. Low platelet count (PLT) was the second-highest problematic metric. The other CBC values, however, did not significantly differ between the research group and the control group. This study offers a preliminary image of the endogenous antioxidant systems in employees, especially to show a connection between radon and the occurrence of cancer among workers in Iraq Kurdistan Region.

Expanding the Frontiers of Guardian Antioxidant Selenoproteins in Cardiovascular Pathophysiology.

Significance: Physiological levels of reactive oxygen and nitrogen species (ROS/RNS) function as fundamental messengers for many cellular and developmental processes in the cardiovascular system. ROS/RNS involved in cardiac redox-signaling originate from diverse sources, and their levels are tightly controlled by key endogenous antioxidant systems that counteract their accumulation. However, dysregulated redox-stress resulting from inefficient removal of ROS/RNS leads to inflammation, mitochondrial dysfunction, and cell death, contributing to the development and progression of cardiovascular disease (CVD). Recent Advances: Basic and clinical studies demonstrate the critical role of selenium (Se) and selenoproteins (unique proteins that incorporate Se into their active site in the form of the 21st proteinogenic amino acid selenocysteine [Sec]), including glutathione peroxidase and thioredoxin reductase, in cardiovascular redox homeostasis, representing a first-line enzymatic antioxidant defense of the heart. Increasing attention has been paid to emerging selenoproteins in the endoplasmic reticulum (ER) (i.e., a multifunctional intracellular organelle whose disruption triggers cardiac inflammation and oxidative stress, leading to multiple CVD), which are crucially involved in redox balance, antioxidant activity, and calcium and ER homeostasis. Critical Issues: This review focuses on endogenous antioxidant strategies with therapeutic potential, particularly selenoproteins, which are very promising but deserve more detailed and clinical studies. Future Directions: The importance of selective selenoproteins in embryonic development and the consequences of their mutations and inborn errors highlight the need to improve knowledge of their biological function in myocardial redox signaling. This could facilitate the development of personalized approaches for the diagnosis, prevention, and treatment of CVD. Antioxid. Redox Signal. 40, 369-432.

Dithiothreitol reduces oxidative stress and necrosis caused by ultraviolet A radiation in L929 fibroblasts.

Ultraviolet A (UVA) radiation, present in sunlight, can induce cell redox imbalance leading to cellular damage and even cell death, compromising skin health. Here, we evaluated the in vitro antioxidant and photochemoprotective effect of dithiothreitol (DTT). DTT neutralized the free radicals 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS·+), 2,2-diphenyl-1-picrylhydrazyl (DPPH·), and superoxide anion (O2·-) in in vitro assays, as well as the ferric ion (Fe3+) in the ferric reducing antioxidant power (FRAP) assay. We also evaluated the effect of DTT pre-treatment in L929 dermal fibroblasts and DTT (50 and 100µM) led to greater cell viability following UVA-irradiation compared to cells that were untreated. Furthermore, the pre-treatment of cells with DTT prevented the increase of intracellular reactive oxygen species (ROS) production, including hydrogen peroxide (H2O2), lipid peroxidation, and DNA condensation, as well as the decrease in mitochondrial membrane potential (Δψm), that occurred following irradiation in untreated cells. The endogenous antioxidant system of cells was also improved in irradiated cells that were DTT pre-treated compared to the untreated cells, as the activity of the superoxide dismutase (SOD) and catalase (CAT) enzymes remained as high as non-irradiated cells, while the activity levels were depleted in the untreated irradiated cells. Furthermore, DTT reduced necrosis in UVA-irradiated fibroblasts. Together, these results showed that DTT may have promising use in the prevention of skin photoaging and photodamage induced by UVA, as it provided photochemoprotection against the harmful effects of this radiation, reducing oxidative stress and cell death, due mainly to its antioxidant capacity.