Effect Of Antioxidant Therapy Research Articles

S-methyl-L-cysteine Protects against Antimycin A-induced Mitochondrial Dysfunction in Neural Cells via Mimicking Endogenous Methionine-centered Redox Cycle

SummaryMitochondrial superoxide overproduction is believed to be responsible for the neurotoxicity associated with neurodegeneration. Mitochondria-targeted antioxidants, such as MitoQ, have emerged as potentially effective antioxidant therapies. Methionine sulfoxide reductase A (MsrA) is a key mitochondrial-localized endogenous antioxidative enzyme and it can scavenge oxidizing species by catalyzing the methionine (Met)-centered redox cycle (MCRC). In this study, we observed that the natural L-Met acted as a good scavenger for antimycin A-induced mitochondrial superoxide overproduction in PC12 cells. This antioxidation was largely dependent on the Met oxidase activity of MsrA. S-methyl-L-cysteine (SMLC), a natural analogue of Met that is abundantly found in garlic and cabbage, could activate the Met oxidase activity of MsrA to scavenge free radicals. Furthermore, SMLC protected against antimycin A-induced mitochondrial membrane depolarization and alleviated 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity. Thus, our data highlighted the possibility for SMLC supplement in the detoxication of mitochondrial damage by activating the Met oxidase activity of MsrA.

Systemic Redox Imbalance in Patients with Chronic Granulomatous Disease.

The aim of our study was to evaluate redox status, enzymatic and non-enzymatic antioxidant barriers, oxidative damage of proteins, lipids and DNA, as well as concentration of coenzyme Q10 and vitamins A and E in patients with chronic granulomatous disease (CGD). The study was performed on fifteen Caucasian individuals (median age 24 years and seven months) diagnosed with CGD. The mutation in the NCF1 gene was confirmed in ten patients, and in the CYBB gene in five patients. We demonstrated high levels of total oxidant status (TOS) and oxidative stress index (OSI), lipids (↑8-isoprostanes (8-isoP), ↑4-hydroxynonenal (4-HNE)), proteins (↑advanced oxidation protein products (AOPP)) and DNA (↑8-hydroxy-2’-deoxyguanosine (8-OHdG)) oxidation products in CGD individuals as compared to sex- and age-matched healthy controls. We showed enhanced serum enzymatic activity of catalase (CAT) and superoxide dismutase-1 (SOD) and significantly decreased coenzyme Q10 concentration. Our study confirmed redox disturbances and increased oxidative damage in CGD patients, and indicated the need to compare redox imbalance depending on the type of mutation and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The question regarding effectiveness of antioxidant therapy in patients with CGD is open, and the need to establish guidelines in this area remains to be addressed.

Evaluation of Sperm Mitochondrial Function: A Key Organelle for Sperm Motility.

Introduction: The role of nutraceuticals in the treatment of male infertility, especially in the “idiopathic form”, remains the subject of significant debate. Many antioxidants improve sperm motility but the exact mechanism by which they act is still unclear. Although several studies have shown a correlation between sperm motility and mitochondrial function, the effects of antioxidant therapy on mitochondrial membrane potential (MMP) are poorly studied. The first aim of this review was to evaluate the efficacy of antioxidants on mitochondrial function and, consequently, on sperm motility in male infertile patients. Material and Methods: we performed a systematic search of all randomized controlled and uncontrolled studies available in the literature that reported sperm motility and MMP at baseline and after antioxidant administration in-vivo and in-vitro in patients with idiopathic asthenozoospermia. Pubmed, MEDLINE, Cochrane, Academic One Files, Google Scholar and Scopus databases were used. Results: Unexpectedly, among 353 articles retrieved, only one study met our inclusion criteria and showed a significant effect of myoinositol on both MMP and sperm motility. We then summarized the main knowledge on anatomy and metabolism of sperm mitochondria, techniques allowing to assess sperm mitochondria function and its relationships with low sperm motility. Finally, we paid special attention to the effect of antioxidant/prokinetic molecules for the treatment of asthenozoospermia. Conclusions: This is the first systematic review that has attempted to evaluate the effects of antioxidants on MMP and sperm motility. Although results are not conclusive due to the dearth of studies, the close relationship between mitochondria and sperm motility is clear. The investigation of this correlation could provide valuable information to be exploited in clinical practice for the treatment of male infertility.

Reactive Oxygen Species‐Responsive Nanoparticles for the Treatment of Ischemic Stroke

AbstractIschemic stroke is a leading cause of death and long‐term disability worldwide, yet availability of current treatments is limited. The downstream events resulting from cerebral ischemia lead to an imbalance in the production of harmful reactive oxygen species (ROS) over endogenous antioxidant mechanisms. Thus, treatments that can reduce this imbalance can limit the extent of injury resulting from ischemic stroke. In this work, the potential of novel ROS‐scavenging PEGylated polymeric nanoparticles (NPs) composed of poly(propylene sulfide) (PPS) (PPS‐NPs) for ischemic stroke therapy is evaluated in vitro and in a mouse model of stroke. In vitro results show that PPS‐NPs display remarkable anti‐oxidant and anti‐inflammatory properties, whilst exhibiting negligible cytotoxicity. NPs administered intravenously rapidly accumulate in ischemic brain regions as visualized through fluorescence imaging, reduced infarct volume, blood‐brain barrier damage, neuronal loss, and neuroinflammation as determined by immunohistochemistry, and improved recovery of neurological function as determined through behavioral analyses. Crucially, the data show that the therapeutic time window for administration of PPS‐NPs extends up to 3 h, a clinically relevant time window for stroke. The findings provide new strong evidence that these NPs may be an effective antioxidant therapy for ischemic stroke.

Metabolic Therapy in hypertensive encephalopathy: emphasis on comorbidity of pathology

The development of primary and repeated disorders of cerebral circulation, vascular dementia, transient ischemic attacks, which are a consequence of the development of acute pathology in patients with hypertensive encephalopathy, lead to a state of persistent disability and disability. Today, the emphasis of treatment is placed on the important role of oxygen deficiency, which leads to the restriction of aerobic energy production due to disturbances in the energy-synthesizing function of the mitochondrial respiratory chain, depletion of endogenous antioxidant stores and activation of lipid peroxidation of cell membranes, leading to death of brain cells. By 2018, a large evidence base for the effectiveness of the use of metabolic therapy in neurology, which takes into account an important factor of the impact of comorbidity of the pathology. The effectiveness of antioxidant therapy in acute and chronic cerebrovascular diseases is confirmed by the fact that the antioxidant improves energy metabolism in the cell, and as a metabolite of the tricarboxylic acid cycle (succinate, which provides pronounced antioxidant and antihypoxic properties) has a positive effect on the main links of pathogenesis of diseases associated with processes freely Radical oxidation. It is proved that the preparation of Mexicor reduces the manifestation of oxidative stress, inhibits free radical peroxide oxidation of lipids, improves cellular energy metabolism, activates the energy-synthesizing functions of mitochondria, enhances compensatory activation of aerobic glycolysis and reduces the degree of inhibition of oxidative processes in the Krebs cycle. The drug Mexocor has a wide spectrum of pharmacological action, which allows it to be used successfully in acute and chronic cerebrovascular diseases, accompanied by vascular comorbidity.

5 - ABCB10 deletion in cardiomyocytes leads to mitochondrial dysfunction and early death

Oxidative stress is a major driver of the pathophysiology of various cardiovascular diseases; however, there are currently no effective antioxidant therapies. We have identified the mitochondrial transporter ABCB10 as a potential component of a novel cardiac antioxidant system. Hearts from mice with a heterozygous deletion of ABCB10 had decreased cardiac function and increased oxidative stress after ischemia reperfusion; perfusion with an antioxidant corrected the phenotype suggesting the potential of ABCB10 as an antioxidant. To test the role of ABCB10 in cardiomyocytes, we developed a cardiomyocyte-specific ABCB10 homozygous knockout mouse (CM-ABCB10 -/-) using Myh6 cre. Mitochondria were isolated from the hearts of CM-ABCB10 -/- and wild type control mice (WT). Reactive oxygen species (ROS) production was measured using Amplex Ultra Red, and oxygen consumption was measured using Seahorse. CM-ABCB10 -/- mice died earlier than WT cre+ controls. At 10 months of age, only 29% of CM-ABCB10 -/- mice were alive (n=5/17), compared to 86% of wild type cre+ controls (n=13/15, p

Blood and brain biomarkers of oxidative stress and inflammation in type 1 Gaucher disease: Effect of antioxidant therapy

Blood and brain biomarkers of oxidative stress and inflammation in type 1 Gaucher disease: Effect of antioxidant therapy

Catechin loaded PLGA submicron-sized fibers reduce levels of reactive oxygen species induced by MWCNT in vitro

Reactive oxygen species (ROS) are common products of normal aerobic cellular metabolism, but high levels of ROS lead to oxidative stress and cellular damage. Therefore, effective antioxidant therapies are needed to prevent ROS overproduction. This study reports the development of poly(l-lactide-co-glycolide) (PLGA) bicomponent fibers loaded with selected amounts of the natural polyphenolic antioxidant catechin. Thereby a novel route based on emulsion electrospinning is investigated to obtain tailored and sustained release rates for chatechin. The activity of the released catechin was assessed for its influence on multi-walled carbon nanotube (MWCNT) induced formation of reactive oxygen species (ROS) in the human alveolar epithelial the cell line A549.Homogenous fiber morphologies were obtained at specified ranges of PLGA concentrations within the emulsions including the formation of a core – sheath structure localizing the drug within the fiber core. In vitro measurements of the delivery showed moderate burst release kinetics in a first phase followed by a linear and smooth release at long term. In combination with polymer degradation studies a mostly diffusion controlled release mechanism was revealed exhibiting only marginal degradation of the polymer during the time span of the drug delivery. As a proof of concept, the activity of released catechin in A549 cells stimulated with MWCNTs was determined and revealed a high reduction of ROS production in a dose dependent manner. This effect diminishes over time indicating a depletion of catechin.

Adjuvant antioxidant therapy in varicocele infertility

Infertility affects an estimated 15% of couples globally. Male factor infertility accounts for about a half of infertility cases. About 40% of infertile men have varicocele. The aim of this study was to investigate the efficacy and safety of a complex of acetyl-L-carnitine, L-carnitine fumarate and alpha-lipoic acid (SpermActin-forte) (SA) for adjuvant antioxidant therapy after microsurgical varicocelectomy (MVE) in men with varicocele and assess its impact on the level of DNA fragmentation in sperm cells. This is an open, prospective, randomized trial comprising 114 men aged 25-45 (mean 34.1+/-12.1) years who underwent MVE. The patients were allocated to receive either adjuvant SA (n=38), SA in combination with a vitamin complex (VC) (n=38) or no adjuvant therapy (n=38). The efficacy was assessed at 3 months by testing standard semen parameters and the level of sperm DNA fragmentation. MVE led to a 21.7% increase in the progressive sperm motility compared to the baseline level. In patients receiving SA, this was by 76.7% due to active sperm motility (category A) at 3 months. MVE with concurrent supplementation of SA resulted in a 22.3% decrease in the level of sperm DNA fragmentation at 3 months. When used in the postoperative period after MVE, SA and VC resulted in a 27% increase in the sperm concentration at 3 months. There were no side effects of pharmacotherapy. The statistical significance of the change in variables was calculated using the Wilcoxon test. Critical level =0.05 was established for all criteria. Using nutraceuticals (SA) after MVE is an effective and safe adjuvant antioxidant therapy of male infertility in patients with varicocele which leads to an improvement in the basic sperm parameters (sperm concentration and motility) and a decrease in the level of sperm DNA fragmentation in the short term. Adjuvant antioxidant therapy of varicocele infertility potentiates the effects of monotherapy (both medical and surgical), leads to an increase in its effectiveness and shortens the time to pregnancy. Further studies in this field are needed to assess long-term outcomes of the treatment.

Antioxidant mechanism of mitochondria-targeted plastoquinone SkQ1 is suppressed in aglycemic HepG2 cells dependent on oxidative phosphorylation

Previously suggested antioxidant mechanisms for mitochondria-targeted plastoquinone SkQ1 included: i) ion-pairing of cationic SkQ1+ with free fatty acid anions resulting in uncoupling; ii) SkQ1H2 ability to interact with lipoperoxyl radical; iii) interference with electron flow at the inner ubiquinone (Q) binding site of Complex III (Qi), involving the reduction of SkQ1 to SkQ1H2 by ubiquinol. We elucidated SkQ1 antioxidant properties by confocal fluorescence semi-quantification of mitochondrial superoxide (Jm) and cytosolic H2O2 (Jc) release rates in HepG2 cells. Only in glycolytic cells, SkQ1 prevented the rotenone-induced enhancement of Jm and Jc but not basal releases without rotenone. The effect ceased in glutaminolytic aglycemic cells, in which the redox parameter NAD(P)H/FAD increased after rotenone in contrast to its decrease in glycolytic cells. Autofluorescence decay indicated decreased NADPH/NADH ratios with rotenone in both metabolic modes. SkQ1 did not increase cell respiration and diminished Jm established high by antimycin or myxothiazol but not by stigmatellin. The revealed SkQ1 antioxidant modes reflect its reduction to SkQ1H2 at Complex I IQ or Complex III Qi site. Both reductions diminish electron diversions to oxygen thus attenuating superoxide formation. Resulting SkQ1H2 oxidizes back to SkQ1at the second (flavin) Complex I site, previously indicated for MitoQ10. Regeneration proceeds only at lower NAD(P)H/FAD in glycolytic cells. In contrast, cyclic SkQ1 reduction/SkQ1H2 oxidation does not substantiate antioxidant activity in intact cells in the absence of oxidative stress (neither pro-oxidant activity, representing a great advantage). A targeted delivery to oxidative-stressed tissues is suggested for the effective antioxidant therapy based on SkQ1.

The Role of ROS in COPD Progression and Therapeutic Strategies

The atmosphere is replete with a mixture of toxic substances. Inhalation of toxic substances produces a variety of insults on the pulmonary system. Lung poisons include industrial materials and a large number of environmental contaminants. This review will give an in-depth knowledge of how the development and progression of chronic obstructive pulmonary disease (COPD) are associated with increased oxidative stress or reduced antioxidant resources. It has been documented that several indicators of oxidative stress, such as hydrogen peroxide exhalation, lipid peroxidation products, and degraded proteins, are indeed elevated in COPD patients, and as a result, the antioxidant capacity decreases. The fall in antioxidant capacity of blood from COPD patients should not only be regarded as a reflection of the occurrence of oxidative stress but also as evidence that oxidative stress spreads out to the circulation and can therefore generate a systemic effect. An effective wide-spectrum antioxidant therapy that has good bioavailability and potency is a good approach to redressing the lungs antioxidant capacity to control the localized oxidative and inflammatory processes that occur in the pathogenesis of COPD.

Mitochondria-Targeted Antioxidants for the Treatment of Cardiovascular Disorders.

The heart continuously supplies blood to the entire body throughout the lifetime, requiring a huge amount of the bioenergy molecule adenosine triphosphate (ATP). As the major subcellular organs that produce ATP through oxidative phosphorylation and the citrate-synthesis cycle, mitochondria inevitably produce chemically reactive species as byproducts. Those species are known to be major effectors of mitochondrial dysfunction, many of which are involved in various cardiovascular diseases, causing apoptotic/necrotic loss of cardiac myocytes and/or defects in the energy balance within the myocardium. In this context, researchers have aimed to develop effective antioxidant therapies to treat cardiovascular disorders. This chapter presents an overview of the clinical trials related to antioxidant therapy and discusses the current clinical status of mitochondria-targeted antioxidants and potential future candidate molecules.

Resolution of mitochondrial oxidant stress improves aged-cardiovascular performance.

Senescence is a major factor that increases oxidative stress in mitochondria, which contributes toward the pathogenesis of heart disease. However, the effect of antioxidant therapy on cardiac mitochondria in aged-cardiac performance remains elusive. We postulated that the mitochondrial targeting of superoxide scavenging would have benefits in the aged heart. Generation of superoxide in the mitochondria and nicotinamide adenine dinucleotide phosphate oxidase activity increased in the heart of old mice compared with that in young mice. In old mice treated with a mitochondria-targeted antioxidant MitoTEMPO (180 µg/kg/day, 28 days) co-infusion using a subcutaneously implanted minipump, levels of superoxide in the mitochondria and nicotinamide adenine dinucleotide phosphate oxidase activity as well as hydrogen peroxide decreased markedly in cardiomyocytes. Treatment with MitoTEMPO in old mice improved the systolic and diastolic function assessed by echocardiography. Endothelium-dependent vasodilation in isolated coronary arteries and endothelial nitric-oxide synthase phosphorylation were impaired in old mice compared with that in young mice and were improved by MitoTEMPO treatment. Mitochondria from the old mice myocardium showed lower rates of complex I-dependent and II-dependent respiration compared with that from young mice. Supplementation of MitoTEMPO in old mice improved the respiration rates and efficiency of ATP generation in mitochondria to a level similar to that of young mice. Resolution of oxidative stress in mitochondria by MitoTEMPO in old mice restored cardiac function and the capacity of coronary vasodilation to the same magnitude observed in young mice. An antioxidant strategy targeting mitochondria could have a therapeutic benefit in heart disease with senescence.

The effectiveness of antioxidant therapy in aspirin resistance, diabetes population for prevention of thrombosis.

Thrombosis as the main complication of coronary heart disease (CHD) represents the primary cause of morbidity and mortality in patients with diabetes mellitus (DM). In the course of diabetes mellitus some coagulation abnormalities occur, that may result in a thrombogenic propensity. Aspirin (ASA) as a platelet-inhibiting agent through inactivation of Cyclooxygenase-1 (COX-1) is mostly used for the prevention and treatment of atherothrombotic disorders. ASA inhibits the COX-1 enzyme and therefore blocks platelet thromboxane A2 (TXA2) synthesis. However, some of the serious vascular events in high-risk vascular patients are attributable to a failure of ASA to suppress platelet aggregation. The consumption of antioxidant or antioxidant rich foods such as vitamin C, E, and polyphenols might impart anti-thrombotic and cardiovascular protective effects via their inhibition of platelet hyper-activation or aggregation similar to the action of aspirin. This review will discuss the risk of thrombosis in diabetes, what aspirin resistance means, and the effectiveness of antioxidant therapy in the prevention and possible treatment of atherothrombotic disorders.

Novel Combination Therapy Boosts the Host Immune System, Destroys Free Radicals and Targets the Critical Flaw in Chronic Pancreatic Disease

Aim: To investigate the role of combination therapy using the cytokines antagonist, pentoxifylline in combination with a novel powerful antioxidant derived from grape product in the treatment of pancreatic disease. Methods and Research Plan: We want to acknowledge that much of the groundwork has already been done demonstrating the positive effect of antioxidant therapy in pancreatic diseases including pancreatitis, chronic pancreatic disorders, fibrosis and even pancreatic cancer. It is also well accepted that pentoxifylline, originally described as a drug to aid blood circulation via actions on adenosine triphosphate, is also an effective and efficient inhibitor of platelet derived growth factor and other cytokines essential to the inflammatory and fibrotic processes. We have understood for several years that this immunopharmacological drug inhibits other key signalling molecules in the immune system, ultimately preventing the collagen synthesis and deposition which is critical in pancreatic, hepatic and intestinal fibrosis. Our aim is to combine these two forms of therapy in patients with chronic pancreatic disease while simultaneously optimizing conditions using as our basis the dramatic results that have already been reported widely in literature, by world class investigators. Results and Conclusion: Results to date are promising. Our results presented here clearly indicate that pentoxifylline will block a process in a relatively rare form of intestinal fibrosis called collagenous colitis. This was our proof of concept. In this very selective disease the critical step is collagen deposition. Collagen synthesis resulting in deposition is the key factor involved and has a direct effect on the outcome in these patients with collagenous colitis. We were able to show that pentoxifylline would effectively reduce collagen deposition in the colons of a group of relatively heterogeneous patients with their one consistent variable being biopsy proven colonic collagen deposition and an elevated FSI or fibrogenic stimulation index. Our results also clearly indicate that the reduction in colonic collagen deposition occurring with pentoxifylline therapy is accompanied by a measurable DII or drug inhibition index and that the FSI was predictive of which cohort of patients would respond to this drug. Pentoxifylline was an effective anti-fibrotic agent while having little if any side effect and working in a very effective way to reduce the signs and symptoms of the disease. Long before we were able to see the histological proof in colonic biopsies, patients who prior to treatment showed a predictive DII were already reporting beneficial effects on their symptoms and clinicians were reporting improvement in clinical signs. At time points during the treatment period, biopsies revealed that the collagen was diminishing and results also indicate that the rate of reduction of collagen deposition related to the chronicity of the disease itself. The combination of a novel antioxidant derived from grapes together with the drug pentoxifylline has the potential to be effective in treating chronic pancreatic disease and may prevent and likely will slow the course of pancreatic fibrosis and the ensuing pancreatic cancer [1-10].

Effect of N-Acetyl-L-Cysteine on Cysteine Redox Status in Patients with Thrombotic Thrombocytopenic Purpura: Protein Disulfide Bound Cysteine As a Biomarker of Oxidative Stress

N-Acetyl-L-Cysteine (NAC), an antioxidant drug, has been used to treat many diseases associated with oxidative stress. Nevertheless, its molecular mechanism of action in vivo remains to be understood. In an ongoing pilot study of NAC to treat thrombotic thrombocytopenic purpura (TTP), we found that NAC treatment following plasma exchange was safe in two TTP patients accompanying with rapid recovery. To explore whether the effectiveness of NAC is linked to plasma redox status, we developed a mass spectrometry based approach to measure cysteine (Cys) and Cys-containing disulfides including protein-bound cysteine (p-ss-Cys) in plasma, and measured these molecular species in plasma from patients with TTP before or after treatment with NAC. We propose that effect of NAC on p-ss-Cys may serve as an indicator for NAC action on redox sensitive proteins in plasma.Methods: Free thiols in plasma were blocked by N-ethylamaleimide (NEM), which also stops further disulfide exchange. NEM blocked thiols and small-molecule disulfides were extracted by methanol with isotopically-labeled internal standards and analyzed by liquid chromatography-tandem mass spectrometry with multiple reaction monitoring (LC-MS/MS-MRM). To determine total Cys including p-ss-Cys, we revaluated a parallel aliquot of plasma first reducing all disulfide-bound Cys with dithiothreitol (DTT) and then blocking the thiols with NEM before methanol extraction. Blood samples from TTP patients and normal donors were collected under protocols approved by IRB. Citrated Blood was collected daily from two patients with relapsed TTP before, during, andafter NAC treatment.Results: We first compared the concentrations of free-thiol Cys and Cys-containing disulfides in the plasma from two TTP patients before plasma exchange to plasma from normal donors. The concentrations of free-thiol Cys were in the low µM range and there were no significant differences between normal donor and TTP patients. However, the concentration of p-ss-Cys was greatly increased in the plasma from both TTP patients (337±33 µM) compared to normal heathy controls (181±27 µM, n=15). After plasma exchange prior to NAC infusion, the concentrations of p-ss-Cys in plasma from both patients decreased to the normal range. During a 4-day NAC treatment at doses of 300 mg/kg/day, p-ss-Cys further decreased to less than 80 µM in both TTP patients. The decreased p-ss-Cys was associated with increased the total free thiol concentration in patient plasma. Interestingly, we observed the lowest level of p-ss-Cys after the 3rd day of NAC treatment in patient 1, while it reached the lowest concentration after only one day of NAC treatment in patient 2. The different response to NAC treatment in the two patients may reflect that the patients are under different extent of oxidative stress.Conclusions: Our results suggest that TTP is associated with a high level of oxidative stress, as determined by accumulation of protein-bound Cys in plasma. NAC effectively reduces the disulfides that attach Cys to proteins, an effect that can be monitored by mass spectrometry. These results indicate that protein-ss-Cys can serve as a plasma biomarker for oxidative stress and effectiveness of antioxidant therapy. DisclosuresNo relevant conflicts of interest to declare.

Effects of Human Mesenchymal Stem Cells Transduced with Superoxide Dismutase on Imiquimod-Induced Psoriasis-Like Skin Inflammation in Mice

The immunomodulatory and anti-inflammatory properties of mesenchymal stem cells (MSCs) have been proposed in several autoimmune diseases and successfully tested in animal models, but their contribution to psoriasis and underlying pathways remains elusive. Likewise, an increased or prolonged presence of reactive oxygen species and aberrant antioxidant systems in skin are known to contribute to the development of psoriasis and therefore effective antioxidant therapy is highly required. We explored the feasibility of using extracellular superoxide dismutase (SOD3)-transduced allogeneic MSCs as a novel therapeutic approach in a mouse model of imiquimod (IMQ)-induced psoriasis-like inflammation and investigated the poorly understood underlying mechanism. In addition, the chronicity and late-phase response of inflammation were evaluated during continued activation of antigen receptors by applying a booster dose of IMQ. Subcutaneous injection of allogeneic SOD3-transduced MSCs significantly prevented psoriasis development in our IMQ-induced mouse model, likely through a suppression of proliferation and infiltration of various effector cells into skin with a concomitant modulated cytokine and chemokine expression and inhibition of signaling pathways such as toll-like receptor-7, nuclear factor-kappa B, p38 mitogen-activated kinase, and Janus kinase-signal transducer and activator of transcription, as well as adenosine receptor activation. Our data offer a novel therapeutic approach to chronic inflammatory skin diseases such as psoriasis by leveraging immunomodulatory effects of MSCs as well as SOD3 expression.

Antioxidants and vascular health.

Oxygen free radicals and other reactive oxygen species (ROS) are common products of normal aerobic cellular metabolism, but high levels of ROS lead to oxidative stress and cellular damage. Increased production of ROS favors vascular dysfunction, inducing altered vascular permeability and inflammation, accompanied by the loss of vascular modulatory function, the imbalance between vasorelaxation and vasoconstriction, and the aberrant expression of inflammatory adhesion molecules. Inflammatory stimuli promote oxidative stress generated from the increased activity of mitochondrial nicotinamide adenine dinucleotide phosphate oxidase, particularly of the Nox4 isoform, with the consequent impairment of mitochondrial β-oxidation. Vascular dysfunction due to the increase in Nox4 activity and ROS overproduction leads to the progression of cardiovascular diseases, diabetes, inflammatory bowel disease, and neurological disorders. Considerable research into the development of effective antioxidant therapies using natural derivatives or new synthetic molecules has been conducted. Antioxidants may prevent cellular damage by reducing ROS overproduction or interfering in reactions that involve ROS. Vitamin E and ascorbic acid are well known as natural antioxidants that counteract lipid peroxidative damage by scavenging oxygen-derived free radicals, thus restoring vascular function. Recently, preliminary studies on natural antioxidants such as goji berries, thymus, rosemary, green tea ginseng, and garlic have been conducted for their efficacy in preventing vascular damage. N-acetyl-cysteine and propionyl-L-carnitine are synthetic compounds that regulate ROS production by replacing endogenous antioxidants in both endothelial and smooth muscle cells. In this review, we consider the molecular mechanisms underlying the generation of oxidative stress-induced vascular dysfunction as well as the beneficial effects of antioxidant therapies.

Prooxidant and antioxidant properties of salicylaldehyde isonicotinoyl hydrazone iron chelators in HepG2 cells

BackgroundSalicylaldehyde isonicotinoyl hydrazone (SIH) is an iron chelator of the aroylhydrazone class that displays antioxidant or prooxidant effects in different mammalian cell lines. Because the liver is the major site of iron storage, elucidating the effect of SIH on hepatic oxidative metabolism is critical for designing effective hepatic antioxidant therapies. MethodsHepatocyte-like HepG2 cells were exposed to SIH or to analogs showing greater stability, such as N′-[1-(2-Hydroxyphenyl)ethyliden]isonicotinoyl hydrazide (HAPI), or devoid of iron chelating properties, such as benzaldehyde isonicotinoyl hydrazone (BIH), and toxicity, oxidative stress and antioxidant (glutathione) metabolism were evaluated. ResultsAutoxidation of Fe2+in vitro increased in the presence of SIH or HAPI (but not BIH), an effect partially blocked by Fe2+ chelation. Incubation of HepG2 cells with SIH or HAPI (but not BIH) was non-toxic and increased reactive oxygen species (ROS) levels, activated the transcription factor Nrf2, induced the catalytic subunit of γ-glutamate cysteine ligase (Gclc), and increased glutathione concentration. Fe2+ chelation decreased ROS and inhibited Nrf2 activation, and Nrf2 knock-down inhibited the induction of Gclc in the presence of HAPI. Inhibition of γ-glutamate cysteine ligase enzymatic activity inhibited the increase in glutathione caused by HAPI, and increased oxidative stress. ConclusionsSIH iron chelators display both prooxidant (increasing the autoxidation rate of Fe2+) and antioxidant (activating Nrf2 signaling) effects. General significanceActivation by SIH iron chelators of a hormetic antioxidant response contributes to their antioxidant properties and modulates the anti- and pro-oxidant balance.

Mitochondria-targeted antioxidants.

Redox homeostasis is maintained by the antioxidant defense system, which is responsible for eliminating a wide range of oxidants, including reactive oxygen species (ROS), lipid peroxides, and metals. Mitochondria-localized antioxidants are widely studied because the mitochondria, the major producers of intracellular ROS, have been linked to the cause of aging and other chronic diseases. Mitochondria-targeted antioxidants have shown great potential because they cross the mitochondrial phospholipid bilayer and eliminate ROS at the heart of the source. Growing evidence has identified mitochondria-targeted antioxidants, such as MitoQ and tiron, as potentially effective antioxidant therapies against the damage caused by enhanced ROS generation. This literature review summarizes the current knowledge on mitochondria-targeted antioxidants and their contribution to the body's antioxidant defense system. In addition to addressing the concerns surrounding current antioxidant strategies, including difficulties in targeting antioxidant treatment to sites of pathologic oxidative damage, we discuss promising therapeutic agents and new strategic approaches.