Nitric oxide and reactive oxygen species production causes progressive damage in rats after cessation of silica inhalation.

Our laboratory has previously reported results from a rat silica inhalation study which determined that, even after silica exposure ended, pulmonary inflammation and damage progressed with subsequent fibrosis development. In the present study, the relationship between silica exposure, nitric oxide (NO) and reactive oxygen species (ROS) production, and the resultant pulmonary damage is investigated in this model. Rats were exposed to silica (15 mg/m3, 6 h/day) for either 20, 40, or 60 days. A portion of the rats from each exposure were sacrificed at 0 days postexposure, while another portion was maintained without further exposure for 36 days to examine recovery or progression. The major findings of this study are: (1) silica-exposed rat lungs were in a state of oxidative stress, the severity of which increased during the postexposure period, (2) silica-exposed rats had significant increase in lung NO production which increased in magnitude during the postexposure period, and (3) the presence of silica particle(s) in an alveolar macrophage (AM) was highly associated with inducible nitric oxide synthase (iNOS) protein. These data indicate that, even after silica exposure has ended, and despite declining silica lung burden, silica-induced pulmonary NO and ROS production increases, thus producing a more severe oxidative stress. A quantitative association between silica and expression of iNOS protein in AMs was also determined, which adds to our previous observation that iNOS and NO-mediated damage are associated anatomically with silica-induced pathological lesions. Future studies will be needed to determine whether the progressive oxidative stress, and iNOS activation and NO production, is a direct result of silica lung burden or a consequence of silica-induced biochemical mediators.     

Reactive oxygen species: sources,consequences and targeted therapy in type 2 diabetes

Oxidative stress has been considered as a central mediator in the progression of diabetic complication. The intracellular reactive oxygen species (ROS) leads to oxidative stress and it is raised from the mitochondria as well as by activation of five major pathways: increased polyol pathway flux, activation of protein kinase C (PKC) pathway, increased formation of advanced glycation end products (AGEs), over activity of hexosamine pathway and increased production of angiotensin II. The increased ROS through these pathways leads to β-cell dysfunction and insulin resistance, responsible for cell damage and death. This review not only highlights the sources of ROS production and their involvement in the progression of diabetes, but also emphasizes on pharmacological interventions and targeting of ROS in type 2 diabetes. This review summarizes the ROS as potential therapeutic targets, based on a putative mechanism in the progression of the diabetes. It also summarizes current knowledge of ROS activation in type 2 diabetes as well as ROS as a possible target for its treatment. Eventually, it would be a promising target for various strategies and drugs to modulate ROS levels in diabetes.     

Reactive oxygen species and the central nervous system in salt-sensitive hypertension: possible relationship with obesity-induced hypertension

1. There are multiple and complex mechanisms of salt-induced hypertension; however, central sympathoexcitation plays an important role. In addition, the production of reactive oxygen species (ROS) is increased in salt-sensitive hypertensive humans and animals. Thus, we hypothesized that brain ROS overproduction may increase blood pressure (BP) by central sympathostimulation. 2. Recently, we demonstrated that ROS levels were elevated in the hypothalamus of salt-sensitive hypertensive animals. Moreover, intracerebroventricular anti-oxidants suppressed BP and renal sympathetic nerve activity more in salt-sensitive than non-salt-sensitive hypertensive rats. Thus, brain ROS overproduction increased BP through central sympathoexcitation in salt-sensitive hypertension. 3. Salt sensitivity of BP is enhanced in obesity and metabolic syndrome. Interestingly, it is also suggested that, in obesity-induced hypertension models, increases in BP are caused by brain ROS-induced central sympathoexcitation. 4. Recent studies suggest that increased ROS production in the brain and central sympathoexcitation may share a common pathway that increases BP in both salt- and obesity-induced hypertension.     

Blood Radicals: Reactive Nitrogen Species,Reactive Oxygen Species,Transition Metal Ions,and the Vascular System

Free radicals, such as superoxide, hydroxyl and nitric oxide, and other reactive species, such as hydrogen peroxide, hypochlorous acid and peroxynitrite, are formed in vivo. Some of these molecules, e.g. superoxide and nitric oxide, can be physiologically useful, but they can also cause damage under certain circumstances. Excess production of reactive oxygen or nitrogen species (ROS, RNS), their production in inappropriate relative amounts (especially superoxide and NO ) or deficiencies in antioxidant defences may result in pathological stress to cells and tissues. This oxidative stress can have multiple effects. It can induce defence systems, and render tissues more resistant to subsequent insult. If oxidative stress is excessive or if defence and repair responses are inadequate, cell injury can be caused by such mechanisms as oxidative damage to essential proteins, lipid peroxidation, DNA strand breakage and base modification, and rises in the concentration of intracellular free Ca²⁺. Considerable evidence supports the view that oxidative damage involving both ROS and RNS is an important contributor to the development of atherosclerosis. Peroxynitrite (derived by reaction of superoxide with nitric oxide) and transition metal ions (perhaps released by injury to the vessel wall) may contribute to lipid peroxidation in atherosclerotic lesions.     

活性氧类物质在化学物诱导的细胞凋亡中的调节作用(英文)

细胞凋亡是在生理或病理条件下 ,为维持内环境的稳定的一种程序性细胞死亡。诱导细胞凋亡的因素可分为物理性、化学性和生物性因素。很多实验数据表明氧化应激在细胞凋亡的发生过程中具有重要作用。各种活性氧类物质如超氧阴离子、过氧化氢、羟自由基和一氧化氮均与细胞凋亡的发生有关。但是活性氧类物质诱导凋亡发生的机理尚未阐明。本综述在对细胞凋亡和氧化应激描述的基础上着重讨论活性氧类物质诱导细胞凋亡发生的可能机理。在以后的研究中 ,将着重于探讨化学物质通过产生活性氧类物质而影响细胞凋亡的机理及建立相关的生物标志物。     

Placental mitochondria and reactive oxygen species in the physiology and pathophysiology of pregnancy

Mitochondria are central to cell function. The placenta forms the interface between maternal and fetal systems, and placental mitochondria have critical roles in maintaining pregnancy. The placenta is unusual in having two adjacent cell layers (cytotrophoblasts and the syncytiotrophoblast) with vastly different mitochondria that have distinct functions in health and disease. Mitochondria both produce the majority of reactive oxygen species (ROS), and are sensitive to ROS. ROS are important in allowing cells to sense their environment through mitochondrial-centred signalling, and this signalling also helps cells/tissues adapt to changing environments. However, excessive ROS are damaging, and increased ROS levels are associated with pregnancy complications, including the important disorders preeclampsia and gestational diabetes mellitus. Here we review the function of placental mitochondria in healthy pregnancy, and also in pregnancy complications. Placental mitochondria are critical to cell function, and mitochondrial damage is a feature of pregnancy complications. However, the responsiveness of mitochondria to ROS signalling may be central to placental adaptations that mitigate damage, and placental mitochondria are an attractive target for the development of therapeutics to improve pregnancy outcomes.     

Reactive oxygen species contribute to lipopolysaccharide-induced teratogenesis in mice.

Lipopolysaccharide (LPS) has been associated with adverse developmental outcome, including embryonic resorption, fetal death and growth retardation, and preterm delivery. In the present study, we showed that an ip injection with LPS daily from gestational day (gd) 8 to gd 12 resulted in the incidence of external malformations. The highest incidence of malformed fetuses was observed in fetuses from dams exposed to 20 microg/kg LPS, in which 34.9% of fetuses per litter were externally malformed. In addition, 17.4% of fetuses per litter in 30 microg/kg group and 12.5% of fetuses per litter in 10 microg/kg group were externally malformed. Importantly, external malformations were also observed in fetuses from dams exposed to only two doses of LPS (20 microg/kg, ip) on gd 8, in which 76.5% (13/17) of litters and 39.1% of fetuses per litter were affected. LPS-induced teratogenicity seemed to be associated with oxidative stress in fetal environment, measured by lipid peroxidation, nitrotyrosine residues, and glutathione (GSH) depletion in maternal liver, embryo, and placenta. alpha-Phenyl-N-t-butylnitrone (PBN, 100 mg/kg, ip), a free radical spin-trapping agent, abolished LPS-induced lipid peroxidation, nitrotyrosine residues, and GSH depletion. Consistent with its antioxidant effects, PBN decreased the incidence of external malformations. Taken together, these results suggest that reactive oxygen species might be, at least partially, involved in LPS-induced teratogenesis.     

Reactive oxygen species modulators in pulmonary medicine

Adapted to effectively capture oxygen from inhaled air and deliver it to all other parts of the body, the lungs constitute the organ with the largest surface area. This makes the lungs more susceptible to airborne pathogens and pollutants that mediate pathologies through generation of reactive oxygen species (ROS). One pathological consequence of excessive levels of ROS production is pulmonary diseases that account for a large number of mortality and morbidity in the world. Of the various mechanisms involved in pulmonary disease pathogenesis, mitochondrial dysfunction takes prominent importance. Herein, we briefly describe the significance of oxidative stress caused by ROS in pulmonary diseases and some possible therapeutic strategies.     

Sodium chlorite increases production of reactive oxygen species that impair the antioxidant system and cause morphological changes in human erythrocytes

Sodium chlorite (NaClO₂) is used in the production of chlorine dioxide for bleaching and stripping of textiles, pulp, and paper. It is also used as disinfectant in municipal water treatment and as a component in therapeutic rinses and gels. The effect of NaClO₂ on human erythrocytes has been studied under in vitro conditions. Incubation of 5% suspension of erythrocytes with NaClO₂ (0.1–2.0 mM) at 37°C for 30 min resulted in marked cell lysis (1.2–3.8 fold) and increased their osmotic fragility. Several parameters were assayed in cell lysates prepared from NaClO₂‐treated and ‐untreated (control) erythrocytes. Compared to controls, exposure to NaClO₂ caused significant increase in protein oxidation (1.1–8.07 fold), lipid peroxidation (1.08–4.95 fold) with decrease in total sulfhydryl (?5 to ?61%), and glutathione levels (?7 to ?86%). Methemoglobin content was tremendously increased, by 5–52 fold when compared to control, while methemoglobin reductase activity decreased (?17 to ?93%) upon NaClO₂ treatment. NaClO₂ enhanced the generation of reactive oxygen species by 3–21 fold and lowered the metal reducing and free radical quenching ability of erythrocytes. It also caused an increase in nitric oxide levels (2.7–15.4 fold) showing generation of nitrosative stress too. The activities of major antioxidant and membrane bound enzymes were significantly altered. Gross morphological changes, from discocytes to echinocytes, were seen in NaClO₂‐treated erythrocytes under electron microscope. These results show that NaClO₂ induces oxidative stress in human erythrocytes, damages the membrane, and impairs the cellular antioxidant defence system. This oxidative damage can shorten the life span of erythrocytes in blood resulting in red cell senescence. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1343–1353, 2017.     

Curcumin inhibits reactive oxygen species formation and vascular hyperpermeability following haemorrhagic shock

1. Oxidative stress induced by reactive oxygen species (ROS) is a key mediator of haemorrhagic shock (HS)‐induced vascular hyperpermeability. In the present study, curcumin, a natural anti‐oxidant obtained from turmeric (Curcuma longa), was tested against HS‐induced hyperpermeability and associated ROS formation in rat mesenteric post‐capillary venules in vivo and in rat lung microvascular endothelial cells (RLMEC) in vitro. 2. In rats, HS was induced by withdrawing blood to reduce mean arterial pressure to 40 mmHg for 60 min, followed by resuscitation for 60 min. To investigate vascular permeability, rats were given fluorescein isothiocyanate (FITC)–albumin (50 mg/kg, i.v.). The FITC–albumin flux was measured in mesenteric post‐capillary venules by determining optical intensity intra‐ and extravascularly under intravital microscopy. Mitochondrial ROS formation was determined using dihydrorhodamine 123 in vivo. Parallel studies were conducted in vitro using serum collected after HS. The serum was tested on rat lung microvascular endothelial cell RLMEC monolayers. 3. In rats, HS induced a significant increase in vascular hyperpermeability and ROS formation in vivo (P < 0.05). Treatment with curcumin (20 μmol/L) attenuated both these effects (P < 0.05). In RLMEC in vitro, HS serum induced monolayer permeability and ROS formation. Curcumin (10 μmol/L) attenuated HS serum‐induced monolayer hyperpermeability and ROS formation. Curcumin (2–100 μmol/L) scavenged 2,2′‐azino‐bis(3‐ethylbenzthiazoline‐6‐sulphonic acid) and 1,1‐diphenyl‐2‐picrylhydrazyl radicals in vitro, indicating its potential as a free radical scavenger. 4. The present study demonstrates that curcumin is an inhibitor of vascular hyperpermeability following HS, with its protective effects mediated through its anti‐oxidant properties.     

Requirement of reactive oxygen species generation in apoptosis of leukemia cells induced by 2-methoxyestradiol

Aim： To investigate the effects of 2-methoxyestradiol （2-ME） on 2 myeloid leukemia cell lines HL-60 and U937, and to explore its mechanisms. Methods： Human myeloid leukemia cells HL-60 and U937 were used. Measurement ofmitochondrial membrane potential （Dym） was performed using 5,5′＇,6,6′-Tetrachloro-1, 1′,3,3′- tetraethylbenzimidazolylcarbocyanine iodide （ JC- 1）. Apoptosis and cellular nitric oxide （NO） were detected by flow cytometry using Annexin V and NO sensor dye. Superoxide anion was measured with a fluorescent plate reader by dihydroethidium （DHE）. Cytotoxicity was analyzed by 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyl- tetrazolium assay. Results： 2-ME resulted in viability decrease in a dose-dependent manner. 2-ME treatment also generated reactive oxygen species （ROS）, including NO and superoxide anions, which resulted in mitochondria damage. 2-ME-induced apoptosis was correlated with an increase in ROS. The quenching of ROS with N-acetyl-L-cysteine protected leukemia cells from 2-ME cytotoxicity and prevented apoptosis induction by 2-ME. Furthermore, the addition of manumycin, a farnesyltransferase inhibitor, significantly enhanced apoptosis induced by 2-ME. Conclusion： Cellular ROS generation plays an important role in the cytotoxic effect of 2-ME. It is possible to use ROS generation agents, such as manumycin, to enhance the antileukemic effect. The combination strategy needs further in vivo justification and may have potential clinical application.     

Sildenafil attenuates oxidative stress and endothelial dysfunction in lead-induced hypertension

Lead (Pb) reduces NO bioavailability, impairs the antioxidant system, and increases the generation of reactive oxygen species (ROS). Pb-induced oxidative stress may be responsible for the associated endothelial dysfunction. Sildenafil has shown nitric oxide (NO)-independent action, including antioxidant effects. Therefore, we examined the effects of sildenafil on oxidative stress, reductions of NO and endothelial dysfunction in Pb-induced hypertension. Wistar rats were distributed into three groups: Pb, Pb + sildenafil and Sham. Blood pressure and endothelium-dependent vascular function were recorded. We also examined biochemical determinants of lipid peroxidation and antioxidant function. ROS levels, NO metabolites and NO levels in human umbilical vein endothelial cells (HUVECs) were also evaluated. Sildenafil prevents impairment of endothelium-dependent NO-mediated vasodilation and attenuates Pb-induced hypertension, reduces ROS formation, enhances superoxide dismutase (SOD) activity and antioxidant capacity in plasma and increases NO metabolites in plasma and HUVECs culture supernatants, while no changes were found on measurement of NO released from HUVECs incubated with plasma of the Pb and Pb + sildenafil groups compared with the sham group. In conclusion, sildenafil protects against ROS-mediated inactivation of NO, thus preventing endothelial dysfunction and attenuating Pb-induced hypertension, possibly through antioxidant effects.     

Redox Processes in Neurodegenerative Disease Involving Reactive Oxygen Species

Much attention has been devoted to neurodegenerative diseases involving redox processes. This review comprises an update involving redox processes reported in the considerable literature in recent years. The mechanism involves reactive oxygen species and oxidative stress, usually in the brain. There are many examples including Parkinson’s, Huntington’s, Alzheimer’s, prions, Down’s syndrome, ataxia, multiple sclerosis, Creutzfeldt-Jacob disease, amyotrophic lateral sclerosis, schizophrenia, and Tardive Dyskinesia. Evidence indicates a protective role for antioxidants, which may have clinical implications. A multifaceted approach to mode of action appears reasonable.     

Interplay of reactive oxygen species and nitric oxide in the pathogenesis of experimental lead-induced hypertension

1. Lead is a common environmental and industrial toxin that can cause a variety of acute and chronic illnesses. For example, chronic exposure to low levels of lead has been shown to raise arterial pressure and promote renal and cardiovascular complications. 2. Several mechanisms have been identified by which chronic lead exposure can cause hypertension and cardiovascular disease. In recent years, increasing evidence has emerged pointing to the role of oxidative stress as a major mediator of lead-induced hypertension. 3. The present article provides an overview of the published studies on this subject.     

Lack of impairment of nitric oxide-mediated responses in a rat model of high-renin hypertension

1. Angiotensin (Ang) II triggers the expression of a pro- oxidant phenotype in the vascular wall, suggesting that activation of the renin-angiotensin system (RAS) causes endothelial dysfunction in various pathological situations, such as hypertension. However, this hypothesis has been mostly tested in a setting of exogenous administration of AngII. 2. We tested the hypothesis of a role for endogenous activation of the RAS leading to oxidant stress and endothelial dysfunction in a high-renin model of hypertension (i.e. two-kidney, one-clip hypertension) in rats. One month after clipping or sham surgery, aorta were isolated from untreated rats or rats treated by the angiotensin AT1 receptor antagonist irbesartan (10 mg/kg per day). Mesenteric artery segments were also isolated from normotensive or hypertensive rats. 3. Hypertension reduced the relaxations to acetylcholine but did not affect the ratio of contractions to phenylephrine in the presence compared with the absence of a nitric oxide (NO) synthase inhibitor, used as an index of basal release of NO. 4. The free radical scavenger tempol reduced the contractions to phenylephrine in the absence, but not in the presence, of an inhibitor of NO synthesis. This index of free radical-mediated degradation of NO was not affected by hypertension. In parallel, hypertension did not affect the expression of p22phox, a component of the free radical generating enzyme reduced nicotinamide adenine dinucleotide phosphate oxidase. 5. Chronic treatment with the AT1 receptor antagonist decreased blood pressure, moderately improved the response to acetylcholine, but did not affect basal NO release in hypertensive rats, although it did increase basal NO release in normotensive rats. 6. Thus, this model of hypertension is characterized by an impaired stimulated NO release but not of basal NO release in isolated arteries. Furthermore, there was no functional evidence of an increased oxidative stress-mediated impairment of NO release. This is not in favour of a direct link between activation of the RAS and development of endothelial dysfunction in experimental hypertension.     

Reactive oxygen species in cardiac signalling: from mitochondria to plasma membrane ion channels

1. Reactive oxygen species (ROS) have been considered deleterious to cell function and there is good evidence to suggest that they play a role in the pathophysiology of a number of cardiac disease states. However, ROS are also now being recognized as important regulators of cell function by altering the redox state of proteins. 2. Possible sources of production of ROS in cardiac myocytes are the mitochondria and nicotinamide adenine dinucleotide phosphate-oxidase. The generation of ROS and anti-oxidant defence mechanisms in the heart are discussed. 3. The evidence for a role for ROS in the development of disease states, such as atherosclerosis, ischaemia, cardiac hypertrophy and hypertension, is presented. It is now recognized that cardiac ion channel function is regulated by ROS. Implications with respect to cardiac arrhythmia are discussed.     

Mechanisms of augmented vasoconstriction induced by 5-hydroxytryptamine in aortic rings from spontaneously hypertensive rats

Background and purpose:To test whether development of enhanced vasoconstriction to 5-hydroxytryptamine (5-HT; serotonin) in SHR was temporally related to hypertension, elevated vascular superoxide (O(2)(-)) levels, decreased NO bioavailability, or increased contractile effects of cyclooxygenase or rho-kinase and/or PKC.Experimental approach:We examined systolic blood pressure (SBP), vascular O(2)(-), and 5-HT-induced contractile responses of aortic segments from 4- and 8-week-old WKY and SHR.Key results:SBP was 35% higher in SHR than WKY at 4 weeks and 60% higher at 8 weeks. Contractile responses to 5-HT were similar in WKY and SHR at 4 weeks, but were markedly augmented in SHR at 8 weeks. The NO synthase inhibitor, L-NAME, enhanced contractile responses to 5-HT markedly in both strains at 4 weeks and in WKY at 8 weeks, but only very modestly in SHR at 8 weeks. These functional differences were associated with higher O(2)(-) levels in SHR versus WKY at 8 weeks, but not at 4 weeks. The rho-kinase inhibitor, Y-27632, and the PKC inhibitor, Ro 31-8220, each only modestly attenuated contractions in WKY and SHR in each age group, and their effects in each strain were more pronounced at 8 weeks. The cyclooxygenase inhibitor, indomethacin, had no effect on contractile responses.Conclusions and implications:Development of augmented vascular contractile responses to 5-HT in SHR is preceded by hypertension. It is associated with increased vascular O(2)(-) levels and reduced modulatory effects of NO, and is unlikely to be due to enhanced activity of rho-kinase, PKC or cyclooxygenase.British Journal of Pharmacology (2008) 155, 210-216; doi:10.1038/bjp.2008.247; published online 16 June 2008.     

Intrarenal oxygen in diabetes and a possible link to diabetic nephropathy

Diabetic nephropathy is a major cause of morbidity and mortality. The exact mechanism mediating the negative influence of hyperglycaemia on renal function remains unclear, although several hypotheses have been postulated. The cellular mechanisms include glucose-induced excessive formation of reactive oxygen species, increased glucose flux through the polyol pathway and formation of advanced glycation end-products. The renal effects in vivo of each and every one of these mechanisms are even less clear. However, there is growing evidence that hyperglycaemia results in altered renal oxygen metabolism and decreased renal oxygen tension and that these changes are linked to altered kidney function. Clinical data regarding renal oxygen metabolism and oxygen tension are currently rudimentary and our present understanding regarding renal oxygenation during diabetes is predominantly derived from data obtained from animal models of experimental diabetic nephropathy. This review will present recent findings regarding the link between hyperglycaemia and diabetes-induced alterations in renal oxygen metabolism and renal oxygen availability. A possible link between reduced renal oxygen tension and the development of diabetic nephropathy includes increased polyol pathway activity and oxidative stress, which result in decreased renal oxygenation and subsequent activation of hypoxia-inducible factors. This initiates increased gene expression of numerous genes known to be involved in development of diabetic nephropathy.     

雷公藤甲素对人肝细胞L-02氧化损伤的初步研究

目的 研究雷公藤甲素对正常人肝细胞株L-02细胞凋亡和活性氧生成的影响.方法 体外培养L-02细胞,MTT法检测雷公藤甲素对L-02细胞的毒性作用,H2DCFH-DA探针流式细胞仪检测细胞中ROS生成量,并测定细胞SOD活性、MDA含量及LDH释放量的变化.结果 雷公藤甲素诱导L-02细胞中ROS生成,且随时间的延长而增多,至12h时达峰值(P＜0.01);同时,雷公藤甲素也能诱导细胞中MDA含量及LDH释放量的增加,诱导SOD活性的降低.结论 雷公藤甲素体外诱导人正常肝细胞L-02细胞凋亡可能与其促进活性氧生成有关.     

Reactive oxygen species damage drives cardiac and mitochondrial dysfunction following acute nano-titanium dioxide inhalation exposure

Nanotechnology offers innovation in products from cosmetics to drug delivery, leading to increased engineered nanomaterial (ENM) exposure. Unfortunately, health impacts of ENM are not fully realized. Titanium dioxide (TiO₂) is among the most widely produced ENM due to its use in numerous applications. Extrapulmonary effects following pulmonary exposure have been identified and may involve reactive oxygen species (ROS). The goal of this study was to determine the extent of ROS involvement on cardiac function and the mitochondrion following nano-TiO₂ exposure. To address this question, we utilized a transgenic mouse model with overexpression of a novel mitochondrially-targeted antioxidant enzyme (phospholipid hydroperoxide glutathione peroxidase; mPHGPx) which provides protection against oxidative stress to lipid membranes. MPHGPx mice and littermate controls were exposed to nano-TiO₂ aerosols (Evonik, P25) to provide a calculated pulmonary deposition of 11?µg/mouse. Twenty-four hours following exposure, we observed diastolic dysfunction as evidenced by E/A ratios greater than 2 and increased radial strain during diastole in wild-type mice (p?2 exposure. To investigate the cellular mechanisms associated with the observed cardiac dysfunction, we focused our attention on the mitochondrion. We observed a significant increase in ROS production (p?p?2 exposure which were attenuated in mPHGPx transgenic mice. In summary, nano-TiO₂ inhalation exposure is associated with cardiac diastolic dysfunction and mitochondrial functional alterations, which can be mitigated by the overexpression of mPHGPx, suggesting ROS contribution in the development of contractile and bioenergetic dysfunction.