Adaptive Antioxidant Response Research Articles

The adaptive antioxidant response during fasting-induced muscle atrophy is oppositely regulated by ZEB1 and ZEB2.

Reactive oxygen species (ROS) serve important homeostatic functions but must be constantly neutralized by an adaptive antioxidant response to prevent supraphysiological levels of ROS from causing oxidative damage to cellular components. Here, we report that the cellular plasticity transcription factors ZEB1 and ZEB2 modulate in opposing directions the adaptive antioxidant response to fasting in skeletal muscle. Using transgenic mice in which Zeb1 or Zeb2 were specifically deleted in skeletal myofibers, we show that in fasted mice, the deletion of Zeb1, but not Zeb2, increased ROS production and that the adaptive antioxidant response to fasting essentially requires ZEB1 and is inhibited by ZEB2. ZEB1 expression increased in fasted muscles and protected them from atrophy; conversely, ZEB2 expression in muscles decreased during fasting and exacerbated muscle atrophy. In fasted muscles, ZEB1 reduces mitochondrial damage and increases mitochondrial respiratory activity; meanwhile, ZEB2 did the opposite. Treatment of fasting mice with Zeb1-deficient myofibers with the antioxidant triterpenoid 1[2-cyano-3,12-dioxool-eana-1,9(11)-dien-28-oyl] trifluoro-ethylamide (CDDO-TFEA) completely reversed their altered phenotype to that observed in fasted control mice. These results set ZEB factors as potential therapeutic targets to modulate the adaptive antioxidant response in physiopathological conditions and diseases caused by redox imbalance.

Assessing the mechanisms and adjunctive therapy for arsenic-induced liver injury in rats.

Environmental arsenic exposure is a significant global public health concern. Previous studies have demonstrated the association between arsenic-induced liver injury and oxidative stress as well as ferroptosis. However, the knowledge of the interactions among these mechanisms remains limited. Moreover, there is a lack of research on potential therapeutic interventions for liver injury resulting from arsenic exposure. To address these limitations, we established a rat model with liver injury caused by arsenic exposure and investigated the impact of the nuclear factor E2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPx4) signaling pathway and ferroptosis on arsenic-induced liver injury. Our findings revealed that arsenic increased Nrf2 expression and decreased GPx4 expression in the rat liver. This was accompanied by a substantial generation of reactive oxygen species and disruption of the antioxidant defense system, ultimately promoting liver injury through ferroptosis. Subsequently, we conducted intervention experiments using Rosa roxburghii Tratt (RRT) in rats exposed to arsenic. The results showed that the detrimental effects mentioned earlier were partially alleviated following RRT intervention. This study offers preliminary evidence that persistent activation of Nrf2 by arsenic triggers an adaptive antioxidant response, leading to liver injury through the promotion of ferroptosis. Additionally, we discovered that RRT inhibits Nrf2-mediated adaptive antioxidant responses by reducing hepatic ferroptosis, thereby mitigating liver injury caused by arsenic exposure in rats. Our study contributes to a deeper understanding of the molecular mechanisms underlying liver injury resulting from arsenic exposure. Furthermore, our findings may facilitate the identification of a potential edible and medicinal plant extracts that could be utilized to develop a more effective adjunctive treatment approach.

Role of Natural and Synthetic Compounds in Modulating NRF2/KEAP1 Signaling Pathway in Prostate Cancer.

Prostate cancer is the second most common cancer in men worldwide. Prostate cancer can be treated by surgery or active surveillance when early diagnosed but, when diagnosed at an advanced or metastatic stage, radiation therapy or androgen-deprivation therapy is needed to reduce cancer progression. However, both of these therapies can cause prostate cancer resistance to treatment. Several studies demonstrated that oxidative stress is involved in cancer occurrence, development, progression and treatment resistance. The nuclear factor erythroid 2-related factor 2 (NRF2)/KEAP1 (Kelch-Like ECH-Associated Protein 1) pathway plays an important role in protecting cells against oxidative damage. Reactive oxygen species (ROS) levels and NRF2 activation can determine cell fate. In particular, toxic levels of ROS lead physiological cell death and cell tumor suppression, while lower ROS levels are associated with carcinogenesis and cancer progression. On the contrary, a high level of NRF2 promotes cell survival related to cancer progression activating an adaptive antioxidant response. In this review, we analyzed the current literature regarding the role of natural and synthetic compounds in modulating NRF2/KEAP1 signaling pathway in prostate cancer.

Adaptive antioxidant response to mitochondrial fatty acid oxidation determines the proliferative outcome of cancer cells

Alterations in lipid catabolism have been broadly described in cancer cells and show tumor-type specific effects on proliferation and cell survival. The factor(s) responsible for this heterogeneity is currently unknown and represents the main limitation in the development of therapeutic interventions that impair lipid metabolism. In this study, we focused on hexanoic acid, a medium-chain fatty acid, that can quickly boost oxidative metabolism by passively crossing mitochondrial membranes. We demonstrated that the antioxidant adaptation of cancer cells to increased fatty acid oxidation is predictive of the proliferative outcome. By interfering with SOD1 expression and glutathione homeostasis, we verified that mitochondrial fatty acid oxidation has antitumor effects in cancer cells that efficiently buffer ROS. In contrast, increased ROS levels promote proliferation in cells with an imbalanced antioxidant response. In addition, an increase in mitochondrial mass and mitophagy activation were observed, respectively. Overall, these data demonstrate that the capacity to manage ROS from mitochondrial oxidative metabolism determines whether lipid catabolism is advantageous or detrimental for cancer cells.

Biochemical response of earthworm, Eisenia fetida to heavy metals toxicity

Soil heavy metal pollution is widespread and has severe adverse effects on soil organisms. Earthworms are the major soil organisms which perform several beneficial ecological functions butare vulnerable to damage from heavy metal pollution of soil. The present study was conducted to evaluate the potential toxicity of arsenic (As) and chromium (Cr) on the biochemical response of the earthworm, Eisenia fetida. Following exposure to various sub-lethal concentrations ofAs (34, 68, 102 and 136 mg/kg) and Cr(26, 51, 77 and 102 mg/kg ) for 28 days, the levels of several biochemical markers, including superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), Glutathione-S-transferase (GST) and malondialdehyde (MDA) content were assessed. The results showed that both heavy metals significantly (p<0.05) impacted the antioxidant enzyme activities and MDA content during the entire exposure period. Compared with the control, SOD, CAT, POD and GST activities increased significantly (p<0.05) by (6.21-23.23, 6.32-18.6, 15.87-34.18 and 0.84-5.45% respectively) at14th day, but after prolonged exposure, these activities were significantly (p<0.05) decreased (9.58-38.13, 10.09-30.03, 19.05-53.16 and 2.26-9.36% respectively) at 28th day. The contents of MDA showed significant (p<0.05) increase (17.84-45.59%) in all exposure groups for entire exposure period. Therefore, it can be concluded that antioxidants play a direct role in the adaptive response of E. fetida for survival in heavy metal contaminated soil. This adaptive antioxidant response can be used as an important biomarker to assess the toxicity of heavy metals in the soil ecosystems.

NRF2-ARE signaling is responsive to haloacetonitrile-induced oxidative stress in human keratinocytes

Humans are exposed to disinfection by-products through oral, inhalation, and dermal routes, during bathing and swimming, potentially causing skin lesions, asthma, and bladder cancer. Nuclear factor E2-related factor 2 (NRF2) is a master regulator of the adaptive antioxidant response via the antioxidant reaction elements (ARE) orchestrating the transcription of a large group of antioxidant and detoxification genes. Here we used an immortalized human keratinocyte model HaCaT cells to investigate NRF2-ARE as a responder and protector in the acute cytotoxicity of seven haloacetonitriles (HANs), including chloroacetonitrile (CAN), bromoacetonitrile (BAN), iodoacetonitrile (IAN), bromochloroacetonitrile (BCAN), dichloroacetonitrile (DCAN), dibromoacetonitrile (DBAN), and trichloroacetonitrile (TCAN) found in drinking water and swimming pools. The rank order of cytotoxicity among the HANs tested was IAN ≈ BAN ˃ DBAN ˃ BCAN ˃ CAN ˃ TCAN ˃ DCAN based on their LC50. The HANs induced intracellular reactive oxygen species accumulation and activated cellular antioxidant responses in concentration- and time-dependent fashions, showing elevated NRF2 protein levels and ARE activity, induction of antioxidant genes, and increased glutathione levels. Additionally, knockdown of NRF2 by lentiviral shRNAs sensitized the HaCaT cells to HANs-induced cytotoxicity, emphasizing a protective role of NRF2 against the cytotoxicity of HANs. These results indicate that HANs cause oxidative stress and activate NRF2-ARE-mediated antioxidant response, which in turn protects the cells from HANs-induced cytotoxicity, highlighting that NRF2-ARE activity could be a sensitive indicator to identify and characterize the oxidative stress induced by HANs and other environmental pollutants.

Redox Dysregulation in Aging and COPD: Role of NOX Enzymes and Implications for Antioxidant Strategies.

With a rapidly growing elderly human population, the incidence of age-related lung diseases such as chronic obstructive pulmonary disease (COPD) continues to rise. It is widely believed that reactive oxygen species (ROS) play an important role in ageing and in age-related disease, and approaches of antioxidant supplementation have been touted as useful strategies to mitigate age-related disease progression, although success of such strategies has been very limited to date. Involvement of ROS in ageing is largely attributed to mitochondrial dysfunction and impaired adaptive antioxidant responses. NADPH oxidase (NOX) enzymes represent an important enzyme family that generates ROS in a regulated fashion for purposes of oxidative host defense and redox-based signalling, however, the associations of NOX enzymes with lung ageing or age-related lung disease have to date only been minimally addressed. The present review will focus on our current understanding of the impact of ageing on NOX biology and its consequences for age-related lung disease, particularly COPD, and will also discuss the implications of altered NOX biology for current and future antioxidant-based strategies aimed at treating these diseases.

NRF2 deficiency sensitizes human keratinocytes to zinc oxide nanoparticles-induced autophagy and cytotoxicity

Zinc oxide nanoparticles (ZnO NPs) are one of the most commonly used metal oxide particles in many industrial fields. Many studies have shown that ZnO NPs induce harmful effects to human skin, but the mechanisms remain poorly understood. Our results showed that ZnO NPs concentration-dependently induced cytotoxicity, ROS accumulation, and mitochondrial dysfunction in HaCaT cells. The expressions of adaptive antioxidant response transcriptional factor NRF2 and autophagy-related proteins P62 and LC3 II/I were increased by ZnO NPs. Knock-down of NRF2 (NRF2-KD) sensitized the cells to ZnO NPs-induced autophagy and cytotoxicity while an autophagy inhibitor, 3-methyladenine, protected the cells from ZnO NPs-induced cell death. These results demonstrated that NRF2 deficiency sensitizes human keratinocytes to ZnO NPs induced autophagy and cytotoxicity, and proposed a key role of NRF2 in protecting skin cells against ZnO NPs through regulation of antioxidants and autophagy.

Liver-specific Nrf2 deficiency accelerates ethanol-induced lethality and hepatic injury in vivo

Alcoholic liver disease (ALD) is a major cause of morbidity and mortality from liver disorders. Various mechanisms, including oxidative stress and impaired lipid metabolism, have been implicated in the pathogenesis of ALD. Our previous studies showed that nuclear factor erythroid-derived 2-like 2 (Nrf2) is a master regulator of adaptive antioxidant response and lipid metabolism by using a liver-specific Nrf2 knockout (Nrf2(L)-KO) mouse model. In the current study, an ALD model was developed by a Lieber-DeCarli liquid-based ethanol diet given to this Nrf2(L)-KO mouse strain. We found that Nrf2(L)-KO mice were quite sensitive to lethality from 6.3% ethanol diet. We thus decreased the ethanol concentration to 4.2% to obtain tissues to analyze the role of hepatic Nrf2 in the development of ALD. We found that mild hepatic steatosis occurred with both liquid control and 4.2% ethanol diet feeding, which contain 35% fat. Both the fatty acid β-oxidation marker peroxisome proliferators-activated receptor α (PPARα), and lipogenesis regulator PPARγ were reduced with ethanol feeding in Nrf2(L)-KO mice, compared to Nrf2 floxed control mice (Nrf2-LoxP). However, Nrf2(L)-KO livers showed more cell injury than the livers of Nrf2-LoxP mice. Consistent with these data, there was increased proportion of apoptotic cells in the liver of ethanol-fed Nrf2(L)-KO mice comparing Nrf2-LoxP controls. Mechanistically, Nrf2 mediated expression of ethanol detoxification enzymes, such as alcohol dehydrogenase 1 and aldehyde dehydrogenase1a1, likely contributed to the sensitivity to ethanol toxicity. In conclusion, hepatic Nrf2 is critical to the development of ALD, particularly the morbidity and liver injury.

Modulation by Ozone Therapy of Oxidative Stress in Chemotherapy-Induced Peripheral Neuropathy: The Background for a Randomized Clinical Trial.

(1) Background: Chemotherapy-induced peripheral neuropathy (CIPN) decreases the quality of life of patients and can lead to a dose reduction and/or the interruption of chemotherapy treatment, limiting its effectiveness. Potential pathophysiological mechanisms involved in the pathogenesis of CIPN include chronic oxidative stress and subsequent increase in free radicals and proinflammatory cytokines. Approaches for the treatment of CIPN are highly limited in their number and efficacy, although several antioxidant-based therapies have been tried. On the other hand, ozone therapy can induce an adaptive antioxidant and anti-inflammatory response, which could be potentially useful in the management of CIPN. (2) Methods: The aims of this works are: (a) to summarize the potential mechanisms that could induce CIPN by the most relevant drugs (platinum, taxanes, vinca alkaloids, and bortezomib), with particular focus on the role of oxidative stress; (b) to summarize the current situation of prophylactic and treatment approaches; (c) to describe the action mechanisms of ozone therapy to modify oxidative stress and inflammation with its potential repercussions for CIPN; (d) to describe related experimental and clinical reports with ozone therapy in chemo-induced neurologic symptoms and CIPN; and (e) to show the main details about an ongoing focused clinical trial. (3) Results: A wide background relating to the mechanisms of action and a small number of experimental and clinical reports suggest that ozone therapy could be useful to prevent or improve CIPN. (4) Conclusions: Currently, there are no clinically relevant approaches for the prevention and treatment of stablished CIPN. The potential role of ozone therapy in this syndrome merits further research. Randomized controlled trials are ongoing.

First morphological-level insights into the efficiency of green tea catechins and grape seed procyanidins on a transgenic mouse model of celiac disease enteropathy.

Alternative or complementary treatments to a gluten-free diet are urgently needed for Celiac Disease. By exploiting the health-promoting properties of polyphenols on a transgenic mouse model of Celiac Disease enteropathy, this study provides the first in vivo evidence regarding the ability of 1 mg day-1 doses of green tea catechins and grape seed procyanidins to ameliorate some of the most characteristic histological changes of gliadin-treated DQ8 mice, including villus flattening, crypt hyperplasia, and infiltration of intraepithelial lymphocytes. Mechanistically, polyphenols were found to increase the intestinal nucleophilic tone of DQ8 mice by orchestrating an adaptive antioxidant response characterized by enhanced GSR enzyme activity and GSH content. Taken together, this work constitutes a highly relevant breakthrough as it provides the fundamental basis concerning the significance of natural polyphenols to be used in, for instance, the development of innovative functional foods aimed at CD individuals.

Fasting Drives Nrf2-Related Antioxidant Response in Skeletal Muscle.

A common metabolic condition for living organisms is starvation/fasting, a state that could play systemic-beneficial roles. Complex adaptive responses are activated during fasting to help the organism to maintain energy homeostasis and avoid nutrient stress. Metabolic rearrangements during fasting cause mild oxidative stress in skeletal muscle. The nuclear factor erythroid 2-related factor 2 (Nrf2) controls adaptive responses and remains the major regulator of quenching mechanisms underlying different types of stress. Here, we demonstrate a positive role of fasting as a protective mechanism against oxidative stress in skeletal muscle. In particular, by using in vivo and in vitro models of fasting, we found that typical Nrf2-dependent genes, including those controlling iron (e.g., Ho-1) and glutathione (GSH) metabolism (e.g., Gcl, Gsr) are induced along with increased levels of the glutathione peroxidase 4 (Gpx4), a GSH-dependent antioxidant enzyme. These events are associated with a significant reduction in malondialdehyde, a well-known by-product of lipid peroxidation. Our results suggest that fasting could be a valuable approach to boost the adaptive anti-oxidant responses in skeletal muscle.

Bilirubin metabolism and its role in atherosclerosis

Hemoglobin is not an guiltless bystander of the pathophysiology in a number of atherosclerotic diseases. Heme, which is released from hemoglobin or other heme proteins, triggers various pathophysiological consequence, including heme stress as well as intracellular stress. Although heme serves key functions and is tightly controlled, high levels of free heme, which may occur in various pathophysiological conditions, are may hazardous via pro-oxidant, pro-inflammatory, and cytotoxic effects. 
 Heme oxygenases are heat shock protein enzymes that use heme as a substrate and function as an essential antioxidant adaptive response by all human cells. A major function of heme oxygenases is clearance of heme that accumulate in tissues due to erythrocyte turnover. The potentially toxic free heme is converted by heme oxygenases into carbon monoxide, iron, and biliverdin, the latter of which is reduced to bilirubin. In literature the heme degradation pathway has been demonstrated to play a protective role against the development of atherosclerosis. Because growing evidence suggests that oxidative stress is involved in atherosclerosis.
 This review documents the roles of bilurubin in atherosclerosis and focuses on the clinical significance as a potential therapeutic target in atherosclerotic diseases, such as coronary artery disease.

Acute effects of diclofenac on zebrafish: Indications of oxidative effects and damages at environmentally realistic levels of exposure

With the increasing awareness about the contamination of the aquatic environment by pharmaceuticals, there is a growing need to study their adverse effects on aquatic organisms. Diclofenac is a non-steroidal anti-inflammatory drug (NSAID), whose wide use contributes for its presence in freshwater ecosystems, increasing the probability of causing deleterious changes in aquatic biota. This study evaluated possible oxidative stress effects in Danio rerio embryos and larvae when exposed to a range of ecologically relevant concentrations of diclofenac. It was possible to conclude that diclofenac caused a scenario of oxidative stress, since all tested toxicological parameters were responsive to the drug. In general, diclofenac caused not only significant anti-oxidant adaptive responses for most levels of exposure, but also peroxidative damage. This work evidenced the responsiveness of D. rerio towards diclofenac in environmentally relevant concentrations, which shows that these organisms might face a scenario of oxidative stress in their natural habitat.

Antioxidative and neurotoxicity effects of acute and chronic exposure of the estuarine polychaete Hediste diversicolor to paracetamol

The presence of anthropogenic drugs in the aquatic ecosystems is a reality nowadays, and a large number of studies have been reporting their putative toxic effects on wildlife. However, the majority of the studies published so far uses standard organisms, whose probability of becoming in contact with drugs in real scenarios of contamination is at least, low. The use of autochthonous organisms in ecotoxicity testing is thus mandatory, and the present study aimed to assess the feasibility of assessing oxidative based stress responses (enzymatic defenses, such as catalase, glutathione-s-transferases, and lipid peroxidation; neurotoxicity as an indirect outcome of oxidizing conditions) on a polychaete species, Hediste diversicolor, after being acutely and chronically exposed to the widely employed drug paracetamol. H. diversicolor showed to be responsive to paracetamol exposure. Data obtained after acute exposure to paracetamol showed that no antioxidant adaptive response was established, but cholinesterasic activity was enhanced. On the contrary, long term exposure of H. diversicolor individuals to paracetamol resulted in clear pro-oxidative effects, with catalase and cholinesterase inhibition, and a significant reduction in the levels of lipoperoxidation. Considering that some of the tested levels (especially those of the chronic test) were already reported in the wild, the here-obtained results are of high environmental significance. In addition, chronic exposure regime yielded more significant results, with important modification of more parameters, suggesting that realistic conditions of exposure are more suited for an integrated assessment of toxicity of drugs in aquatic organisms.

Biofloc technology with addition of different carbon sources altered the antibacterial and antioxidant response in Macrobrachium rosenbergii to acute stress

The objective of this study was to evaluate the immune response of Macrobrachium rosenbergii to acute stress, including the pathogen challenge, acute H2O2 and pH stress, to explore the application of biofloc systems in prawn farming. All 780 prawns (0.19 ± 0.01 g) were randomly distributed into one control group with 1/3 water changed daily (no carbon source addition) and three biofloc groups with glucose, sucrose and molasses addition (limited-exchanged water), respectively. The biofloc volume dynamics in the water showed that carbon addition significantly promoted the biofloc formation in all biofloc groups (P < .05), meanwhile, during the 45-day rearing period, biofloc improved water quality by consuming the element N accumulated in the water, then leading to the decrease in the concentration of TAN and NO2−-N. However, no significant difference was found in the survival and the growth of prawns between the biofloc groups and the control group (P > .05). Furthermore, the relative gene expression levels of prophenoloxidase (ProPO), catalase (CAT) and superoxide dismutase (SOD) of prawns in the biofloc groups were significantly higher than that in the control group during the acute H2O2 and pH stress (P < .05), as well as the relative gene expression of crustin (CRU) in the biofloc groups was higher than that in the control group during the H2O2 stress (P < .05), which exhibited a stronger adaptive antioxidant and antibacterial response in prawns reared with biofloc, thereby a higher relative percent survival of prawns was recorded in the biofloc groups during pathogen challenge test. Taken together, biofloc system appeared to help prawns to better resist the environment stress.

Nrf2 in adipocytes.

White adipocytes play a key role in maintaining whole body energy homeostasis by forming white adipose tissue (WAT). The impairment of WAT formation or WAT dysfunction is clearly associated with severe metabolic disorders. Mature adipocytes are derived from differentiated preadipocytes and are pivotal in energy storage and metabolism. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a member of a family of CNC-bZIP proteins which exert their transcriptional control on genes harboring antioxidant response elements (ARE) in partnership with small musculoaponeurotic fibrosarcoma proteins. The activation of Nrf2-ARE coordinated by specific repressor Kelch-like ECH-associated protein 1 (Keap1) regulates networks of genes controlling diverse homeostatic processes involving adaptive antioxidant response and detoxification among many other adaptive responses. Interestingly, accumulating evidence indicates that Nrf2 may act as a transcription factor in regulating the formation and function of adipose tissues, including adipogenesis, lipid metabolism and insulin sensitivity. In this mini-review, an overview on the distinct roles of Nrf2 in adipocytes is provided. While highlighting the regulatory role of Nrf2 in adipogenesis, recent key findings on Nrf2 in insulin signal transduction and energy metabolism of adipocytes are also summarized.

Evaluation of hepatic and renal effects in rat dams and their offspring after exposure to paracetamol during gestation and lactation.

Paracetamol (PAR) is the analgesic and antipyretic of choice for pregnant and nursing women. PAR may reach the fetus and/or neonate through the placenta and/or milk and effect development. This study evaluated possible hepatic and renal effects in rat dams and their offspring exposed to PAR using a human-relevant route of administration and doses from Gestational Day 6 to Postnatal Day (PND) 21. Dams were gavaged daily with PAR (35 or 350mg kg-1) or water (CON). Dams and pups were killed on PND21 and 22 respectively, and blood was collected for biochemical analysis (aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea and creatinine). The kidneys and liver were isolated and processed for histopathological assessment and evaluation of oxidative stress markers. Compared with the CON groups, pups exposed to 350mg kg-1 PAR had increased renal reduced glutathione (GSH), whereas dams exposed to both doses of PAR increased serum AST. PAR administration did not affect parameters of general toxicity or renal and hepatic oxidative stress. In conclusion, maternal exposure to human-relevant doses of PAR by gavage was not associated with hepatic or renal toxicity in the pups or dams, but PAR was not devoid of effects. Exposure to PAR increased renal GSH in pups, which could suggest an adaptive antioxidant response, and affected maternal serum AST activity.

Modulation of Oxidative Stress by Ozone Therapy in the Prevention and Treatment of Chemotherapy-Induced Toxicity: Review and Prospects.

(1) Background: Cancer is one of the leading causes of mortality worldwide. Radiotherapy and chemotherapy attempt to kill tumor cells by different mechanisms mediated by an intracellular increase of free radicals. However, free radicals can also increase in healthy cells and lead to oxidative stress, resulting in further damage to healthy tissues. Approaches to prevent or treat many of these side effects are limited. Ozone therapy can induce a controlled oxidative stress able to stimulate an adaptive antioxidant response in healthy tissue. This review describes the studies using ozone therapy to prevent and/or treat chemotherapy-induced toxicity, and how its effect is linked to a modification of free radicals and antioxidants. (2) Methods: This review encompasses a total of 13 peer-reviewed original articles (most of them with assessment of oxidative stress parameters) and some related works. It is mainly focused on four drugs: Cisplatin, Methotrexate, Doxorubicin, and Bleomycin. (3) Results: In experimental models and the few existing clinical studies, modulation of free radicals and antioxidants by ozone therapy was associated with decreased chemotherapy-induced toxicity. (4) Conclusions: The potential role of ozone therapy in the management of chemotherapy-induced toxicity merits further research. Randomized controlled trials are ongoing.

Time-course effects of antioxidants and phase II enzymes on diesel exhaust particles-induced oxidative damage in the mouse lung

Mechanisms responsible for diesel exhaust particle (DEP)-induced toxicity in respiratory disorders are poorly understood, recent experimental and controlled exposure studies suggested that oxidative stress might be involved. To investigate the time-course effects DEP on nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator in cellular adaptive antioxidant response, mice were intratracheal instilled with 100 μg DEP/mouse and sacrificed after 30 min, 6 h, 12 h, 24 h, 48 h, and 72 h. We measured reactive oxygen species (ROS) as well as Nrf2 and antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and phase II enzymes including heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase-1 (NQO1), glutamate–cysteine ligase catalytic subunit (GCLC), glutamate–cysteine ligase modifier subunit (GCLM) in the lungs. Additionally, histopathological changes were examined. At 6 h, ROS peaked, most of the enzymes were activated, and the histology showed the lungs were damaged. At 12 h, ROS returned to normal level and CAT activity decreased, while protein expression of Nrf2, HO-1, NQO1, GCLC, and GCLM increased, and the lungs were recovering from damage. After 24 h, ROS started to decrease and Nrf2 showed a decreasing trend at both gene and protein levels, while the lung damage had been entirely restored. These results suggested that a single exposure to DEP induce transient oxidative stress in the lungs, with time-dependent effects on Nrf2 and antioxidant enzymes and phase II enzymes.