Mitochondrial hydrogen peroxide production by pyruvate dehydrogenase and α-ketoglutarate dehydrogenase in oxidative eustress and oxidative distress.

Pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (KGDH) are vital entry points for monosaccharides and amino acids into the Krebs cycle and thus integral for mitochondrial bioenergetics. Both complexes produce mitochondrial hydrogen peroxide (mH2O2) and are deactivated by electrophiles. Here, we provide an update on the role of PDH and KGDH in mitochondrial redox balance and their function in facilitating metabolic reprogramming for the propagation of oxidative eustress signals in hepatocytes and how defects in these pathways can cause liver diseases. PDH and KGDH are known to account for ∼45% of the total mH2O2 formed by mitochondria and display rates of production several-fold higher than the canonical source complex I. This mH2O2 can also be formed by reverse electron transfer (RET) in vivo, which has been linked to metabolic dysfunctions that occur in pathogenesis. However, the controlled emission of mH2O2 from PDH and KGDH has been proposed to be fundamental for oxidative eustress signal propagation in several cellular contexts. Modification of PDH and KGDH with protein S-glutathionylation (PSSG) and S-nitrosylation (PSNO) adducts serves as a feedback inhibitor for mH2O2 production in response to glutathione (GSH) pool oxidation. PSSG and PSNO adduct formation also reprogram the Krebs cycle to generate metabolites vital for interorganelle and intercellular signaling. Defects in the redox modification of PDH and KGDH cause the over generation of mH2O2, resulting in oxidative distress and metabolic dysfunction-associated fatty liver disease (MAFLD). In aggregate, PDH and KGDH are essential platforms for emitting and receiving oxidative eustress signals.

Mefunidone ameliorates diabetic kidney disease in STZ and db/db mice.

Diabetic kidney disease (DKD) is a major cause of end stage renal diseases worldwide. Despite successive interventions for delaying the progression of DKD, current treatments cannot reverse the pathological progression. Mefunidone (MFD) is a new compound with potent antifibrotic properties, but the effect of MFD on DKD remains unknown. Therefore, we investigated the protective effects of MFD in both models of the db/db type 2 diabetes (T2D) and streptozotocin (STZ)-induced type 1 diabetes (T1D) models. Compared with the model group, MFD treatment significantly reduced pathological changes observed by PAS staining, PASM staining, and Masson staining in vivo. To further elucidate the potential mechanisms, we discovered MFD treatment notably restored podocyte function, alleviated inflammation, abated ROS generation, inhibited the TGF-ß1/SAMD2/3 pathway, suppressed the phosphorylation levels of MAPKs (ERK1/2, JNK, and P38), and reduced epithelial-to-mesenchymal transition(EMT). In conclusion, these findings demonstrate the effectiveness of MFD in diabetic nephropathy and elucidate its possible mechanism.

Distress-Mediated Remodeling of Cardiac Connexin-43 in a Novel Cell Model for Arrhythmogenic Heart Diseases.

Gap junctions and their expression pattern are essential to robust function of intercellular communication and electrical propagation in cardiomyocytes. In healthy myocytes, the main cardiac gap junction protein connexin-43 (Cx43) is located at the intercalated disc providing a clear direction of signal spreading across the cardiac tissue. Dislocation of Cx43 to lateral membranes has been detected in numerous cardiac diseases leading to slowed conduction and high propensity for the development of arrhythmias. At the cellular level, arrhythmogenic diseases are associated with elevated levels of oxidative distress and gap junction remodeling affecting especially the amount and sarcolemmal distribution of Cx43 expression. So far, a mechanistic link between sustained oxidative distress and altered Cx43 expression has not yet been identified. Here, we propose a novel cell model based on murine induced-pluripotent stem cell-derived cardiomyocytes to investigate subcellular signaling pathways linking cardiomyocyte distress with gap junction remodeling. We tested the new hypothesis that chronic distress, induced by rapid pacing, leads to increased reactive oxygen species, which promotes expression of a micro-RNA, miR-1, specific for the control of Cx43. Our data demonstrate that Cx43 expression is highly sensitive to oxidative distress, leading to reduced expression. This effect can be efficiently prevented by the glutathione peroxidase mimetic ebselen. Moreover, Cx43 expression is tightly regulated by miR-1, which is activated by tachypacing-induced oxidative distress. In light of the high arrhythmogenic potential of altered Cx43 expression, we propose miR-1 as a novel target for pharmacological interventions to prevent the maladaptive remodeling processes during chronic distress in the heart.

Intersections Between Mitochondrial Metabolism and Redox Biology Mediate Posttraumatic Osteoarthritis.

PURPOSE OF REVIEW: This review will cover foundational studies and recent findings that established key concepts for understanding the importance of redox biology to chondrocyte mitochondrial function and osteoarthritis pathophysiology after injury. RECENT FINDINGS: Articular chondrocyte mitochondria can be protected with a wide variety of antioxidants that will be discussed within a framework suggested by classic studies. These agents not only underscore the importance of thiol metabolism and associated redox function for chondrocyte mitochondria but also suggest complex interactions with signal transduction pathways and other molecular features of osteoarthritis that require more thorough investigation. Emerging evidence also indicates that reductive stress could occur alongside oxidative stress. Recent studies have shed new light on historic paradoxes in chondrocyte redox and mitochondrial physiology, leading to the development of promising disease-modifying therapies for posttraumatic osteoarthritis.

The significance of glutaredoxins for diabetes mellitus and its complications.

Diabetes mellitus is a non-communicable metabolic disease hallmarked by chronic hyperglycemia caused by beta-cell failure. Diabetic complications affect the vasculature and result in macro- and microangiopathies, which account for a significantly increased morbidity and mortality. The rising incidence and prevalence of diabetes is a major global health burden. There are no feasible strategies for beta-cell preservation available in daily clinical practice. Therefore, patients rely on antidiabetic drugs or the application of exogenous insulin. Glutaredoxins (Grxs) are ubiquitously expressed and highly conserved members of the thioredoxin family of proteins. They have specific functions in redox-mediated signal transduction, iron homeostasis and biosynthesis of iron-sulfur (FeS) proteins, and the regulation of cell proliferation, survival, and function. The involvement of Grxs in chronic diseases has been a topic of research for several decades, suggesting them as therapeutic targets. Little is known about their role in diabetes and its complications. Therefore, this review summarizes the available literature on the significance of Grxs in diabetes and its complications. In conclusion, Grxs are differentially expressed in the endocrine pancreas and in tissues affected by diabetic complications, such as the heart, the kidneys, the eye, and the vasculature. They are involved in several pathways essential for insulin signaling, metabolic inflammation, glucose and fatty acid uptake and processing, cell survival, and iron and mitochondrial metabolism. Most studies describe significant changes in glutaredoxin expression and/or activity in response to the diabetic metabolism. In general, mitigated levels of Grxs are associated with oxidative distress, cell damage, and even cell death. The induced overexpression is considered a potential part of the cellular stress-response, counteracting oxidative distress and exerting beneficial impact on cell function such as insulin secretion, cytokine expression, and enzyme activity.

Iron chelation mitigates mitochondrial dysfunction and oxidative stress by enhancing nrf2-mediated antioxidant responses in the renal cortex of a murine model of type 2 diabetes.

Renal iron overload is a common complication of diabetes that leads to oxidative stress and mitochondrial dysfunction in the kidneys. This study investigated the effects of iron chelation using deferiprone on mitochondrial dysfunction and oxidative stress in the renal cortex of a murine model of type 2 diabetes. Diabetic rats were treated with deferiprone (50 mg/kg BW) for 16 weeks. Our results show that iron chelation with deferiprone significantly increased the nuclear accumulation of Nrf2, a transcription factor that regulates the expression of antioxidant enzymes. This led to enhanced antioxidant capacity, reduced production of reactive oxygen species, and improved mitochondrial bioenergetic function in diabetic rats. However, chronic iron chelation led to altered mitochondrial respiration and increased oxidative stress in non-diabetic rats. In conclusion, our findings suggest that iron chelation with deferiprone protects mitochondrial bioenergetics and mitigates oxidative stress in the renal cortex, involving the NRF2 pathway in type 2 diabetes.

The Gut-Brain Axis as a Therapeutic Target in Multiple Sclerosis.

The CNS is very susceptible to oxidative stress; the gut microbiota plays an important role as a trigger of oxidative damage that promotes mitochondrial dysfunction, neuroinflammation, and neurodegeneration. In the current review, we discuss recent findings on oxidative-stress-related inflammation mediated by the gut-brain axis in multiple sclerosis (MS). Growing evidence suggests targeting gut microbiota can be a promising strategy for MS management. Intricate interaction between multiple factors leads to increased intra- and inter-individual heterogeneity, frequently painting a different picture in vivo from that obtained under controlled conditions. Following an evidence-based approach, all proposed interventions should be validated in clinical trials with cohorts large enough to reach significance. Our review summarizes existing clinical trials focused on identifying suitable interventions, the suitable combinations, and appropriate timings to target microbiota-related oxidative stress. Most studies assessed relapsing-remitting MS (RRMS); only a few studies with very limited cohorts were carried out in other MS stages (e.g., secondary progressive MS-SPMS). Future trials must consider an extended time frame, perhaps starting with the perinatal period and lasting until the young adult period, aiming to capture as many complex intersystem interactions as possible.

Voluntary wheel-running improved pulmonary fibrosis by reducing epithelial mesenchymal transformation.

AIMS: Pulmonary fibrosis seriously affects the health and life quality of patients. Exercise has been shown to have anti-inflammatory and antioxidant effects, but its effect on pulmonary fibrosis is unclear. In this study, the effect and mechanism of exercise on pulmonary fibrosis induced by paraquat were detected. MAIN METHODS: Three data sets were retrieved from GEO data. The biological significance of DEGs generation was determined by GO, KEGG, GSEA, and PPI. Thirty male BALB/C mice were randomly divided into control group, model group and exercise group. H&E staining, Masson staining, Immunohistochemistry and Western blot were used to explore the results. The levels of SOD, CAT, MDA, and GSH in lung tissue were analyzed with detection kits. The levels of inflammatory factors in serum and BALF were measured by ELISA. KEY FINDINGS: Compared with the control group, the infiltration of inflammatory cells and fibrotic lesions were increased in the model group. Compared with the model group, voluntary wheel-running reducing the EMT of alveolar epithelial cells, the activation of the Wnt/ß-catenin signaling pathway and the level of oxidative distress. Moreover, compared to model group, the serum IL-4, IL-10 and IFN-γ were increased, while the serum CXCL1 were decreased, while the levels of CXCL1, IL-6, IL-10, TNF-α and IFN-γ in the bronchoalveolar lavage fluid were decreased in exercise group. SIGNIFICANCE: Voluntary wheel-running reduced inflammatory infiltration and upregulated the expression of antioxidative distress proteins, further to improve the degree of EMT, and ultimately alleviated paraquat induced pulmonary fibrosis.

Cellular Functional, Protective or Damaging Responses Associated with Different Redox Imbalance Intensities: A Comprehensive Review.

Reactive species (RS) are produced in aerobic and anaerobic cells at different concentrations and exposure times, which may trigger diverse responses depending on the cellular antioxidant potential and defensive devices. Study searches were carried out using the PubMed database of the National Library of Medicine-National Institutes of Health. Cellular RS include reactive oxygen (ROS), nitrogen (RNS), lipid (RLS) and electrophilic species that determine either cell homeostasis or dysfunctional biomolecules. The complexity of redox signalling is associated with the variety of RS produced, the reactivity of the target biomolecules with RS, the multiplicity of the counteracting processes available, and the exposure time. The continuous distortion in the prooxidant/ antioxidant balance favoring the former is defined as oxidative stress, whose intensity determines (i) the basal not harmful unbalance (oxidative eustress) at RS levels in the pM to nM range that supports physiological processes (e.g., immune function, thyroid function, insulin action) and beneficial responses to external interventions via redox signalling; or (ii) the excessive, toxic distortion (oxidative distress) at RS levels exceeding those in the oxidative eustress zone, leading to the unspecific oxidation of biomolecules and loss of their functions causing cell death with associated pathological states. The cellular redox imbalance is a complex phenomenon whose underlying mechanisms are beginning to be understood, although how RS initiates cell signalling is a matter of debate. Knowledge of this aspect will provide a better understanding of how RS triggers the pathogenesis and progression of the disease and uncover future therapeutic measures.

Thiosulfate sulfurtransferase deficiency promotes oxidative distress and aberrant NRF2 function in the brain.

Thiosulfate sulfurtransferase (TST, EC 2.8.1.1) was discovered as an enzyme that detoxifies cyanide by conversion to thiocyanate (rhodanide) using thiosulfate as substrate; this rhodanese activity was subsequently identified to be almost exclusively located in mitochondria. More recently, the emphasis regarding its function has shifted to hydrogen sulfide metabolism, antioxidant defense, and mitochondrial function in the context of protective biological processes against oxidative distress. While TST has been described to play an important role in liver and colon, its function in the brain remains obscure. In the present study, we therefore sought to address its potential involvement in maintaining cerebral redox balance in a murine model of global TST deficiency (Tst-/- mice), primarily focusing on characterizing the biochemical phenotype of TST loss in relation to neuronal activity and sensitivity to oxidative stress under basal conditions. Here, we show that TST deficiency is associated with a perturbation of the reactive species interactome in the brain cortex secondary to altered ROS and RSS (specifically, polysulfide) generation as well as mitochondrial OXPHOS remodeling. These changes were accompanied by aberrant Nrf2-Keap1 expression and thiol-dependent antioxidant function. Upon challenging mice with the redox-active herbicide paraquat (25 mg/kg i.p. for 24 h), Tst-/- mice displayed a lower antioxidant capacity compared to wildtype controls (C57BL/6J mice). These results provide a first glimpse into the molecular and metabolic changes of TST deficiency in the brain and suggest that pathophysiological conditions associated with aberrant TST expression and/or activity renders neurons more susceptible to oxidative stress-related malfunction.

Mitochondrial vulnerability to oxidation in human brain organoids modelling Alzheimer's disease.

Reactive Oxygen Species (ROS) and mitochondrial dysfunction are implicated in the pathogenesis of Alzheimer's disease (AD), a common neurodegenerative disorder characterized by abnormal metabolism of the amyloid precursor protein (APP) in brain tissue. However, the exact mechanism by which abnormal APP leads to oxidative distress remains unclear. Damage to mitochondrial membrane and inhibition of mitochondrial respiration are thought to contribute to the progression of the disease. However, the lack of suitable human models that replicate pathological features, together with impaired cellular pathways, constitutes a major challenge in AD studies. In this work, we induced pluripotency in patient-derived skin fibroblasts carrying the Swedish mutation in App (APPswe), to generate human brain organoids that model AD, and studied redox regulation and mitochondrial homeostasis. We found time-dependent increases in AD-related pathological hallmarks in APPswe brain organoids, including elevated Aß levels, increased extracellular amyloid deposits, and enhanced tau phosphorylation. Interestingly, using live-imaging spinning-disk confocal microscopy, we found an increase in mitochondrial fragmentation and a significant loss of mitochondrial membrane potential in APPswe brain organoids when subjected to oxidative conditions. Moreover, ratiometric dyes in a live imaging setting revealed a selective increase in mitochondrial superoxide anion and hydrogen peroxide levels in APPswe brain organoids that were coupled to impairments in cytosolic and mitochondrial redoxin protein expression. Our results suggest a selective increase in mitochondrial vulnerability to oxidative conditions in APPswe organoids, indicating that the abnormal metabolism of APP leads to specific changes in mitochondrial homeostasis that enhance the vulnerability to oxidation in AD.

Inflammatory stimulus worsens the effects of UV-A exposure on J774 cells.

UV-A radiation affects skin homeostasis by promoting oxidative distress. Endogenous photosensitizers in the dermis and epidermis of human skin absorb UV-A radiation forming excited states (singlet and triplet) and reactive oxygen species (ROS) producing oxidized compounds that trigger biological responses. The activation of NF-kB induces the expression of pro-inflammatory cytokines and can intensify the generation of ROS. However, there is no studies evaluating the cross talks between inflammatory stimulus and UV-A exposure on the levels of redox misbalance and inflammation. In here, we evaluated the effects of UV-A exposure on J774 macrophage cells previously challenged with LPS in terms of oxidative distress, release of pro-inflammatory cytokines, and activation of regulated cell death pathways. Our results showed that LPS potentiates the dose-dependent UV-A-induced oxidative distress and cytokine release, in addition to amplifying the regulated (autophagy and apoptosis) and non-regulated (necrosis) mechanisms of cell death, indicating that a previous inflammatory stimulus potentiates UV-A-induced cell damage. We discuss these results in terms of the current-available skin care strategies.

Pharmacological Ascorbate Elicits Anti-Cancer Activities against Non-Small Cell Lung Cancer through Hydrogen-Peroxide-Induced-DNA-Damage.

Non-small cell lung cancer (NSCLC) poses a significant global health burden with unsatisfactory survival rates, despite advancements in diagnostic and therapeutic modalities. Novel therapeutic approaches are urgently required to improve patient outcomes. Pharmacological ascorbate (P-AscH-; ascorbate at millimolar concentration in plasma) emerged as a potential candidate for cancer therapy for recent decades. In this present study, we explore the anti-cancer effects of P-AscH- on NSCLC and elucidate its underlying mechanisms. P-AscH- treatment induces formation of cellular oxidative distress; disrupts cellular bioenergetics; and leads to induction of apoptotic cell death and ultimately reduction in clonogenic survival. Remarkably, DNA and DNA damage response machineries are identified as vulnerable targets for P-AscH- in NSCLC therapy. Treatments with P-AscH- increase the formation of DNA damage and replication stress markers while inducing mislocalization of DNA repair machineries. The cytotoxic and genotoxic effects of P-AscH- on NSCLC were reversed by co-treatment with catalase, highlighting the roles of extracellular hydrogen peroxide in anti-cancer activities of P-AscH-. The data from this current research advance our understanding of P-AscH- in cancer treatment and support its potential clinical use as a therapeutic option for NSCLC therapy.

The antioxidant glutathione.

Reduced glutathione (GSH) is an essential non-enzymatic antioxidant in mammalian cells. GSH can act directly as an antioxidant to protect cells against free radicals and pro-oxidants, and as a cofactor for antioxidant and detoxification enzymes such as glutathione peroxidases, glutathione S-transferases, and glyoxalases. Glutathione peroxidases detoxify peroxides by a reaction that is coupled to GSH oxidation to glutathione disulfide (GSSG). GSSG is converted back to GSH by glutathione reductase and cofactor NADPH. GSH can regenerate vitamin E following detoxification reactions of vitamin E with lipid peroxyl radicals (LOO). GSH is a cofactor for GST during detoxification of electrophilic substances and xenobiotics. Dicarbonyl stress induced by methylglyoxal and glyoxal is alleviated by glyoxalase enzymes and GSH. GSH regulates redox signaling through reversible oxidation of critical protein cysteine residues by S-glutathionylation. GSH is involved in other cellular processes such as protein folding, protecting protein thiols from oxidation and crosslinking, degradation of proteins with disulfide bonds, cell cycle regulation and proliferation, ascorbate metabolism, apoptosis and ferroptosis.

Multiple Actions of H2S-Releasing Peptides in Human ß-Amyloid Expressing C. elegans.

Alzheimer's disease (AD) is a debilitating progressive neurodegenerative disorder characterized by the loss of cognitive function. A major challenge in treating this ailment fully is its multifactorial nature, as it is associated with effects like deposition of Aß plaques, oxidative distress, inflammation of neuronal cells, and low levels of the neurotransmitter acetylcholine (ACh). In the present work, we demonstrate the design, synthesis, and biological activity of peptide conjugates by coupling a H2S-releasing moiety to the peptides known for their Aß antiaggregating properties. These conjugates release H2S in a slow and sustained manner, due to the formation of self-assembled structures and delivered a significant amount of H2S within Caenorhabditis elegans. These conjugates are shown to target multiple factors responsible for the progression of AD: notably, we observed reduction in oxidative distress, inhibition of Aß aggregation, and significantly increased ACh levels in the C. elegans model expressing human Aß.

GSTO1, GSTO2 and ACE2 Polymorphisms Modify Susceptibility to Developing COVID-19.

Based on the close relationship between dysregulation of redox homeostasis and immune response in SARS-CoV-2 infection, we proposed a possible modifying role of ACE2 and glutathione transferase omega (GSTO) polymorphisms in the individual propensity towards the development of clinical manifestations in COVID-19. The distribution of polymorphisms in ACE2 (rs4646116), GSTO1 (rs4925) and GSTO2 (rs156697) were assessed in 255 COVID-19 patients and 236 matched healthy individuals, emphasizing their individual and haplotype effects on disease development and severity. Polymorphisms were determined by the appropriate qPCR method. The data obtained showed that individuals carrying variant GSTO1*AA and variant GSTO2*GG genotypes exhibit higher odds of COVID-19 development, contrary to ones carrying referent alleles (p = 0.044, p = 0.002, respectively). These findings are confirmed by haplotype analysis. Carriers of H2 haplotype, comprising GSTO1*A and GSTO2*G variant alleles were at 2-fold increased risk of COVID-19 development (p = 0.002). Although ACE2 (rs4646116) polymorphism did not exhibit a statistically significant effect on COVID-19 risk (p = 0.100), the risk of COVID-19 development gradually increased with the presence of each additional risk-associated genotype. Further studies are needed to clarify the specific roles of glutathione transferases omega in innate immune response and vitamin C homeostasis once the SARS-CoV-2 infection is initiated in the host cell.

Hormesis and Oxidative Distress: Pathophysiology of Reactive Oxygen Species and the Open Question of Antioxidant Modulation and Supplementation.

Alterations of redox homeostasis leads to a condition of resilience known as hormesis that is due to the activation of redox-sensitive pathways stimulating cell proliferation, growth, differentiation, and angiogenesis. Instead, supraphysiological production of reactive oxygen species (ROS) exceeds antioxidant defence and leads to oxidative distress. This condition induces damage to biomolecules and is responsible or co-responsible for the onset of several chronic pathologies. Thus, a dietary antioxidant supplementation has been proposed in order to prevent aging, cardiovascular and degenerative diseases as well as carcinogenesis. However, this approach has failed to demonstrate efficacy, often leading to harmful side effects, in particular in patients affected by cancer. In this latter case, an approach based on endogenous antioxidant depletion, leading to ROS overproduction, has shown an interesting potential for enhancing susceptibility of patients to anticancer therapies. Therefore, a deep investigation of molecular pathways involved in redox balance is crucial in order to identify new molecular targets useful for the development of more effective therapeutic approaches. The review herein provides an overview of the pathophysiological role of ROS and focuses the attention on positive and negative aspects of antioxidant modulation with the intent to find new insights for a successful clinical application.

H2O2/Ca2+/Zn2+ Complex Can Be Considered a "Collaborative Sensor" of the Mitochondrial Capacity?

In order to maintain a state of well-being, the cell needs a functional control center that allows it to respond to changes in the internal and surrounding environments and, at the same time, carry out the necessary metabolic functions. In this review, we identify the mitochondrion as such an "agora", in which three main messengers are able to collaborate and activate adaptive response mechanisms. Such response generators, which we have identified as H2O2, Ca2+, and Zn2+, are capable of "reading" the environment and talking to each other in cooperation with the mitochondrion. In this manner, these messengers exchange information and generate a holistic response of the whole cell, dependent on its functional state. In this review, to corroborate this claim, we analyzed the role these actors, which in the review we call "sensors", play in the regulation of skeletal muscle contractile capacities chosen as a model of crosstalk between Ca2+, Zn2+, and H2O2.

Impact of Glucocorticoid on a Cellular Model of Parkinson's Disease: Oxidative Stress and Mitochondrial Function.

Stress seems to contribute to the neuropathology of Parkinson's disease (PD), possibly by dysregulation of the hypothalamic-pituitary-adrenal axis. Oxidative distress and mitochondrial dysfunction are key factors involved in the pathophysiology of PD and neuronal glucocorticoid-induced toxicity. Animal PD models have been generated to study the effects of hormonal stress, but no in vitro model has yet been developed. Our aim was to examine the impact of corticosterone (CORT) administration on a dopaminergic neuronal cell model of PD induced by the neurotoxin MPP+, as a new combined PD model based on the marker of endocrine response to stress, CORT, and oxidative-mitochondrial damage. We determined the impact of CORT, MPP+ and their co-incubation on reactive oxygen species production (O2-•), oxidative stress cellular markers (advanced-oxidation protein products and total antioxidant status), mitochondrial function (mitochondrial membrane potential and mitochondrial oxygen consumption rate) and neurodegeneration (Fluoro-Jade staining). Accordingly, the administration of MPP+ or CORT individually led to cell damage compared to controls (p < 0.05), as determined by several methods, whereas their co-incubation produced strong cell damage (p < 0.05). The combined model described here could be appropriate for investigating neuropathological hallmarks and for evaluating potential new therapeutic tools for PD patients suffering mild to moderate emotional stress.

Dietary Oxidative Distress: A Review of Nutritional Challenges as Models for Poultry, Swine and Fish.

The redox system is essential for maintaining cellular homeostasis. When redox homeostasis is disrupted through an increase of reactive oxygen species or a decrease of antioxidants, oxidative distress occurs resulting in multiple tissue and systemic responses and damage. Poultry, swine and fish, raised in commercial conditions, are exposed to different stressors that can affect their productivity. Some dietary stressors can generate oxidative distress and alter the health status and subsequent productive performance of commercial farm animals. For several years, researchers used different dietary stressors to describe the multiple and detrimental effects of oxidative distress in animals. Some of these dietary challenge models, including oxidized fats and oils, exposure to excess heavy metals, soybean meal, protein or amino acids, and feeding diets contaminated with mycotoxins are discussed in this review. A better understanding of the oxidative distress mechanisms associated with dietary stressors allows for improved understanding and evaluation of feed additives as mitigators of oxidative distress.