Restore Redox Balance Research Articles

Neuroinflammation, oxidative stress and their interplay in neuropathic pain: Focus on specialized pro-resolving mediators and NADPH oxidase inhibitors as potential therapeutic strategies

Neuropathic pain (NP) is a chronic condition that results from a lesion or disease of the nervous system, greatly impacting patients’ quality of life. Current pharmacotherapy options deliver inadequate and/or insufficient responses and thus a significant unmet clinical need remains for alternative treatments in NP. Neuroinflammation, oxidative stress and their reciprocal relationship are critically involved in NP pathophysiology. In this context, new pharmacological approaches, aiming at enhancing the resolution phase of inflammation and/or restoring redox balance by targeting specific reactive oxygen species (ROS) sources, are emerging as potential therapeutic strategies for NP, with improved efficacy and safety profiles. Several reports have demonstrated that administration of exogenous specialized pro-resolving mediators (SPMs) ameliorates NP pathophysiology. Likewise, deletion or inhibition of the ROS-generating enzyme NADPH oxidase (NOX), particularly its isoforms 2 and 4, results in beneficial effects in NP models. Notably, SPMs also modulate oxidative stress and NOX also regulates neuroinflammation. By targeting neuroinflammatory and oxidative pathways, both SPMs analogues and isoform-specific NOX inhibitors are promising therapeutic strategies for NP.

Hot-processed virgin coconut oil abrogates cisplatin-induced nephrotoxicity by restoring redox balance in rats compared to fermentation-processed virgin coconut oil

Virgin coconut oil (VCO) is a functional food oil prepared from fresh coconut kernel either by hot-processed (HPVCO) or fermentation-processed (FPVCO). The FPVCO has been widely explored for its pharmacological efficacy; while HPVCO, which has traditional uses, is less explored. The present study compared the phenolic content and nephroprotective effect of both these oils in male Wistar rats. In vitro antioxidant activity was estimated in terms of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, ferric reducing antioxidant power and ex vivo lipid peroxidation inhibition. In in vivo models, the rats were pretreated orally with of FPVCO or HPVCO (doses 2 and 4 mL/kg) for seven days and nephrotoxicity was induced by the single intraperitoneal injection of cisplatin (10 mg/kg). The results indicated significantly higher polyphenol content in HPVCO (400.3 ± 5.8 µg/mL) than that of FPVCO (255.5 ± 5.8 µg/mL). Corroborating with the increased levels of polyphenols, the in vitro antioxidant potential was significantly higher in the HPVCO. Further, pretreatment with these VCO preparations protected the rats against the cisplatin-induced nephrotoxicity, with higher extent by HPVCO. The renal function markers like urea, creatinine and total bilirubin were significantly reduced (p < 0.05) with HPVCO pretreatment. Apart from the nephroprotective effects, HPVCO also abrogated the cisplatin-induced myelosuppression and hepatotoxicity. The restoration of hepato-renal function by the pretreatment of HPVCO was well corroborated with the improvement in functional antioxidants and subsequent reduction in renal lipid peroxidation. Supporting these observations, renal histology revealed reduced glomerular/tubular congestion and necrosis. Thus, the study concludes that HPVCO may be better functional food than FPVCO.

Drug targeting CYP2E1 for the treatment of early-stage alcoholic steatohepatitis.

Alcoholic steatohepatitis (ASH)-the inflammation of fatty liver-is caused by chronic alcohol consumption and represents one of the leading chronic liver diseases in Western Countries. ASH can lead to organ dysfunction or progress to hepatocellular carcinoma (HCC). Long-term alcohol abstinence reduces this probability and is the prerequisite for liver transplantation-the only effective therapy option at present. Elevated enzymatic activity of cytochrome P450 2E1 (CYP2E1) is known to be critically responsible for the development of ASH due to excessively high levels of reactive oxygen species (ROS) during metabolization of ethanol. Up to now, no rational drug discovery process was successfully initiated to target CYP2E1 for the treatment of ASH. In this study, we applied a rational drug design concept to develop drug candidates (NCE) including preclinical studies. A new class of drug candidates was generated successfully. Two of the most promising small compounds named 12-Imidazolyl-1-dodecanol (abbr.: I-ol) and 1-Imidazolyldodecane (abbr.: I-an) were selected at the end of this process of drug discovery and developability. These new ω-imidazolyl-alkyl derivatives act as strong chimeric CYP2E1 inhibitors at a nanomolar range. They restore redox balance, reduce inflammation process as well as the fat content in the liver and rescue the physiological liver architecture of rats consuming continuously a high amount of alcohol. Due to its oral application and therapeutic superiority over an off-label use of the hepatoprotector ursodeoxycholic acid (UDCA), this new class of inhibitors marks the first rational, pharmaceutical concept in long-term treatment of ASH.

Geraniol ameliorates diabetic nephropathy via interference with miRNA-21/PTEN/Akt/mTORC1 pathway in rats.

Deregulatedactivity of protein kinase B/mammalian target of rapamycin complex-1 (Akt/mTORC1) incites crucial pathological characteristics of diabetic nephropathy. The acyclic monoterpene geraniol has been recently reported to possess antidiabetic effects; however, its potential renoprotective effect in diabetes has not yet been elucidated. This study aimed to assess the possible modulatory effect of geraniol on the Akt/mTORC1 pathway in diabetes-induced nephropathy in rats compared to the standard antidiabetic drug gliclazide. Geraniol and gliclazide was administered daily to diabetic rats for 6weeks starting on the 3rd-day post diabetes induction by streptozotocin (STZ). Geraniol amended the deteriorated renal function (serum creatinine; blood urea nitrogen). It exerted a remarkable antihyperglycemic effect that is comparable to that of gliclazide and suppressed the fibrotic marker, transforming growth factor-β. Geraniol restored redox balance and inhibited lipid peroxidation by reducing nicotine amide adenine dinucleotide phosphate oxidase and enhancing the antioxidant enzyme, superoxide dismutase. These beneficial effects were associated with a robust downregulation of miRNA-21 and consequently, reversion of tumor suppressor protein phosphatase and tension homolog (PTEN)/Akt/mTORC1 cue and its downstream proteins required for mesangial cell proliferation and matrix protein synthesis. The current study indicates that geraniol interfered with miRNA-21/ PTEN/AKT/mTORC1 pathway signaling that contributes largely to the progression of mesangial expansion and extracellular matrix deposition in diabetic nephropathy.

High-dose biotin restores redox balance, energy and lipid homeostasis, and axonal health in a model of adrenoleukodystrophy.

Biotin is an essential cofactor for carboxylases that regulates the energy metabolism. Recently, high-dose pharmaceutical-grade biotin (MD1003) was shown to improve clinical parameters in a subset of patients with chronic progressive multiple sclerosis. To gain insight into the mechanisms of action, we investigated the efficacy of high-dose biotin in a genetic model of chronic axonopathy caused by oxidative damage and bioenergetic failure, the Abcd1- mouse model of adrenomyeloneuropathy. High-dose biotin restored redox homeostasis driven by NRF-2, mitochondria biogenesis and ATP levels, and reversed axonal demise and locomotor impairment. Moreover, we uncovered a concerted dysregulation of the transcriptional program for lipid synthesis and degradation in the spinal cord likely driven by aberrant SREBP-1c/mTORC1signaling. This resulted in increased triglyceride levels and lipid droplets in motor neurons. High-dose biotin normalized the hyperactivation of mTORC1, thus restoring lipid homeostasis. These results shed light into the mechanism of action of high-dose biotin of relevance for neurodegenerative and metabolic disorders.

Effects of dietary quercetin on the antioxidative status and cecal microbiota in broiler chickens fed with oxidized oil

This study was conducted to evaluate the effects of quercetin on the antioxidant ability, intestinal barrier functions, and cecal microbiota in broiler chickens fed with oxidized soya oil. Four hundred eighty male Arbor Acres broilers were randomly assigned to 5 treatments, each involving 8 cages (12 birds per cage). The treatment groups were as follows: the control group, birds fed with basal diets containing oxidized oil, and birds fed with basal diets containing oxidized oil and supplemented with 200 ppm of quercetin, 400 ppm of quercetin, and 800 ppm of quercetin. The results showed that dietary supplementation with quercetin at a dose of 400 ppm or 800 ppm alleviated the increased serum malondialdehyde (MDA) level induced by oxidized oil on day 11 (P = 0.005) and reversed the increased MDA level in the mucosa on day 11 (P = 0.021). Quercetin significantly upregulated the transcription of nuclear factor erythroid 2–related factor 2 (Nrf2) and its downstream genes such as catalase (P < 0.001), superoxide dismutase 1 (P < 0.001), glutathione peroxidase 2 (P = 0.018), heme oxygenase-1 (HO-1) (P = 0.0), and thioredoxin (P = 0.002) and reversed the mRNA expression of HO-1 (P = 0.007) in the ileal mucosa. Tight junction protein 1 was only downregulated by oxidized oil (P = 0.013). In addition, quercetin (800 ppm) alleviated the decreased mRNA expression of mucin 2 (MUC2), which contributed to the intestinal chemical barrier (P = 0.039). The supplemental dose of 400 ppm of quercetin was able to promote Lactobacillus in the cecum, which enhanced the gastrointestinal tract health. In summary, these results indicated that quercetin ameliorated the oxidized oil–induced oxidative stress by upregulating the transcription of Nrf2 and its downstream genes to restore redox balance and reinforced the intestinal barrier via higher expression and secretion of MUC2 and facilitating the growth of Lactobacillus in the cecum. Therefore, quercetin could be a potential feed additive that can be applied in poultry production for amelioration of oxidative stress caused by oxidized oil and preventing the potential invasion of exogenous pathogens.

KEAP1, a cysteine-based sensor and a drug target for the prevention and treatment of chronic disease.

Redox imbalance and persistent inflammation are the underlying causes of most chronic diseases. Mammalian cells have evolved elaborate mechanisms for restoring redox homeostasis and resolving acute inflammatory responses. One prominent mechanism is that of inducing the expression of antioxidant, anti-inflammatory and other cytoprotective proteins, while also suppressing the production of pro-inflammatory mediators, through the activation of transcription factor nuclear factor-erythroid 2 p45-related factor 2 (NRF2). At homeostatic conditions, NRF2 is a short-lived protein, which avidly binds to Kelch-like ECH-associated protein 1 (KEAP1). KEAP1 functions as (i) a substrate adaptor for a Cullin 3 (CUL3)-based E3 ubiquitin ligase that targets NRF2 for ubiquitination and proteasomal degradation, and (ii) a cysteine-based sensor for a myriad of physiological and pharmacological NRF2 activators. Here, we review the intricate molecular mechanisms by which KEAP1 senses electrophiles and oxidants. Chemical modification of specific cysteine sensors of KEAP1 results in loss of NRF2-repressor function and alterations in the expression of NRF2-target genes that encode large networks of diverse proteins, which collectively restore redox balance and resolve inflammation, thus ensuring a comprehensive cytoprotection. We focus on the cyclic cyanoenones, the most potent NRF2 activators, some of which are currently in clinical trials for various pathologies characterized by redox imbalance and inflammation.

Applications of nanomaterials for scavenging reactive oxygen species in the treatment of central nervous system diseases.

Reactive oxygen species (ROS) are the key signaling molecules in many physiological processes and play an important role in the development and function of the central nervous system (CNS). However, the process of CNS diseases is often accompanied by excessive production of ROS, which will induce oxidative stress, aggravate the pathological changes of the diseases, and cause neuroinflammation and loss of neurons. Therefore, it is beneficial for the treatment of CNS diseases and the recovery of the nerve function to eliminate the excessive ROS formed during the pathological changes of the CNS. Although several antioxidants have been proved to restore redox balance, their disappointing clinical performance has predicted less optimistic prospects in antioxidant therapy for ROS-associated CNS diseases. In recent years, nanomaterials with ROS-scavenging ability have been considered as promising substances to alleviate oxidative stress in CNS diseases because of their excellent ROS scavenging effect and biodistribution. This review article aims to elucidate the ROS scavenging mechanisms of various nanomaterials, introduce the reasons for ROS generation in CNS diseases, and review the applications of nanomaterials in scavenging ROS in CNS diseases reported in recent years.

Safety and Efficacy of Omaveloxolone in Friedreich's Ataxia (MOXIe Study): A Multicentre, Randomised, Double-Blind, Placebo-Controlled Trial

Background: Friedreich’s ataxia (FRDA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function, restores redox balance, and reduces inflammation in a variety of neurological disease models, including FRDA. We aimed to investigate the safety and efficacy of omaveloxolone in patients with FRDA. Methods: We conducted an international, multicentre, double-blind, randomised, placebo-controlled parallel-group, registrational phase 2 trial at 11 clinical institutions in the United States, Europe, and Australia. Eligible patients, 16 to 40 years of age with genetically confirmed FRDA and baseline modified Friedreich’s Ataxia Rating Scale (mFARS) scores between 20 and 80, were randomised 1:1 to receive placebo or 150 mg per day of omaveloxolone. The primary outcome was change from baseline in the mFARS score in those treated with omaveloxolone as compared with those treated with placebo at 48 weeks. Findings: Between October 20, 2017 and November 5, 2018, 155 patients were screened and 103 were randomly assigned to receive omaveloxolone (n=51) or placebo (n=52), with 40 omaveloxolone patients and 42 placebo patients analysed in the full analysis set. Changes from baseline in mFARS scores in omaveloxolone (‒1·55 ± 0·69 [95% CI: ‒2·93, ‒0·18]) and placebo (0·85 ± 0·64 [95% CI: ‒0·43, 2·13]) patients showed a difference between treatment groups of ‒2·40 ± 0·96 ([95% CI: ‒4·31, ‒0·5]; p=0·014). Transient reversible increases in aminotransferase levels were observed with omaveloxolone that were not associated with increases in total bilirubin or other signs of liver injury. Headache, nausea, and fatigue were also more common among patients receiving omaveloxolone. Interpretation: In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It is therefore a potential therapeutic agent in FRDA. Trial Registration: This trial is registered with ClinicalTrials.gov (NCT02255435) and EudraCT (2015-002762-23). Funding: Funded by Reata Pharmaceuticals. Declaration of Interests: Dr. Delatycki reports other from Reata Pharmaceuticals, during the conduct of the study. Dr. Boesch reports grants from EFACTS consortium, grants from NICOFA E-rare (FWF I 3352-B28), other from Abvie, Ipsen, Grunenthal, outside the submitted work. Dr Hoyle reports other from Reata Pharmaceuticals, during the conduct of the study; personal fees from Reata Pharmaceuticals, outside the submitted work. Dr. Mariotti reports grants from Reata Pharmaceuticals, during the conduct of the study. Dr. Mathews reports grants from Reata Pharmaceuticals, during the conduct of the study; grants from Takeda, grants from Friedreich Ataxia Research Alliance (FARA), outside the submitted work. Dr. Perlman has nothing to disclose. Dr. Subramony reports grants from Reata Pharmaceuticals, during the conduct of the study; grants from Biohaven Pharmaceuticals, grants from Takeda Pharmaceuticals, grants from Acceleron Pharmaceuticals, personal fees from Reata Pharmaceuticals, personal fees from Stealth, personal fees from Avexis, personal fees from Dyne therapeutics, outside the submitted work. Dr. Wilmot report no conflicts or relevant disclosures. Dr Zesiewicz has received personal compensation for serving on the advisory boards of Boston Scientific; Reata Pharmaceuticals, Inc; and Steminent Biotherapeutics; has received personal compensation as senior editor for Neurodegenerative Disease Management and as a consultant for Steminent Biotherapeutics; has received royalty payments as co-inventor of varenicline for treating imbalance (patent number 9,463,190) and nonataxic imbalance (patent number 9,782,404); has received research/grant support as principal investigator/ investigator for studies from AbbVie Inc; Biogen; Biohaven Pharmaceutics; Boston Scientific; Bukwang Pharmaceuticals Co, Ltd; Cala Health, Inc; Cavion; Friedreich’s Ataxia Research Alliance; Houston Methodist Research Institute; National Institutes of Health (READISCA U01); Retrotope Inc; and Takeda Development Center Americas, Inc. Dr Lynch receives grants from Reata, Takeda, Chondrial, the NIH, FDA MDA and FARA. Drs. Chin, Meyer, O’Grady, and Goldsberry report other from Reata Pharmaceuticals, outside the submitted work. Ethics Approval Statement: The trial was conducted at 11 clinical institutions in the United States, Europe, and Australia, and was approved by Institutional Review Boards or Independent Ethics Committees associated with the individual study sites.

Therapeutic Applications of Cysteamine and Cystamine in Neurodegenerative and Neuropsychiatric Diseases.

Current medications for neurodegenerative and neuropsychiatric diseases such as Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), and Schizophrenia mainly target disease symptoms. Thus, there is an urgent need to develop novel therapeutics that can delay, halt or reverse disease progression. AD, HD, PD, and schizophrenia are characterized by elevated oxidative and nitrosative stress, which play a central role in pathogenesis. Clinical trials utilizing antioxidants to counter disease progression have largely been unsuccessful. Most antioxidants are relatively non-specific and do not adequately target neuroprotective pathways. Accordingly, a search for agents that restore redox balance as well as halt or reverse neuronal loss is underway. The small molecules, cysteamine, the decarboxylated derivative of the amino acid cysteine, and cystamine, the oxidized form of cysteamine, respectively, mitigate oxidative stress and inflammation and upregulate neuroprotective pathways involving brain-derived neurotrophic factor (BDNF) and Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Cysteamine can traverse the blood brain barrier, a desirable characteristic of drugs targeting neurodegeneration. This review addresses recent developments in the use of these aminothiols to counter neurodegeneration and neuropsychiatric deficits.

Saturated Fatty Acid Activates T Cell Inflammation Through a Nicotinamide Nucleotide Transhydrogenase (NNT)-Dependent Mechanism.

Circulating fatty acids (FAs) increase with obesity and can drive mitochondrial damage and inflammation. Nicotinamide nucleotide transhydrogenase (NNT) is a mitochondrial protein that positively regulates nicotinamide adenine dinucleotide phosphate (NADPH), a key mediator of energy transduction and redox homeostasis. The role that NNT-regulated bioenergetics play in the inflammatory response of immune cells in obesity is untested. Our objective was to determine how free fatty acids (FFAs) regulate inflammation through impacts on mitochondria and redox homeostasis of peripheral blood mononuclear cells (PBMCs). PBMCs from lean subjects were activated with a T cell-specific stimulus in the presence or absence of generally pro-inflammatory palmitate and/or non-inflammatory oleate. Palmitate decreased immune cell expression of NNT, NADPH, and anti-oxidant glutathione, but increased reactive oxygen and proinflammatory Th17 cytokines. Oleate had no effect on these outcomes. Genetic inhibition of NNT recapitulated the effects of palmitate. PBMCs from obese (BMI >30) compared to lean subjects had lower NNT and glutathione expression, and higher Th17 cytokine expression, none of which were changed by exogenous palmitate. Our data identify NNT as a palmitate-regulated rheostat of redox balance that regulates immune cell function in obesity and suggest that dietary or therapeutic strategies aimed at increasing NNT expression may restore redox balance to ameliorate obesity-associated inflammation.

Metabolic remodelling of glucose, fatty acid and redox pathways in the heart of type 2 diabetic mice.

Hearts from type 2 diabetic animals display perturbations in excitation-contraction coupling, impairing myocyte contractility and delaying relaxation, along with altered substrate consumption patterns. Under high glucose and β-adrenergic stimulation conditions, palmitate can, at least in part, offset left ventricle (LV) dysfunction in hearts from diabetic mice, improving contractility and relaxation while restoring coronary perfusion pressure. Fluxome calculations of central catabolism in diabetic hearts show that, in the presence of palmitate, there is a metabolic remodelling involving tricarboxylic acid cycle, polyol and pentose phosphate pathways, leading to improved redox balance in cytoplasmic and mitochondrial compartments. Under high glucose and increased energy demand, the metabolic/fluxomic redirection leading to restored redox balance imparted by palmitate helps explain maintained LV function and may contribute to designing novel therapeutic approaches to prevent cardiac dysfunction in diabetic patients. Type-2 diabetes (T2DM) leads to reduced myocardial performance, and eventually heart failure. Excessive accumulation of lipids and glucose is central to T2DM cardiomyopathy. Previous data showed that palmitate (Palm) or glutathione preserved heart mitochondrial energy/redox balance under excess glucose, rescuing β-adrenergic-stimulated cardiac excitation-contraction coupling. However, the mechanisms underlying the accompanying improved contractile performance have been largely ignored. Herein we explore in intact heart under substrate excess the metabolic remodelling associated with cardiac function in diabetic db/db mice subjected to stress given by β-adrenergic stimulation with isoproterenol and high glucose compared to their non-diabetic controls (+/+, WT) under euglycaemic conditions. When perfused with Palm, T2DM hearts exhibited improved contractility/relaxation compared to WT, accompanied by extensive metabolic remodelling as demonstrated by metabolomics-fluxomics combined with bioinformatics and computational modelling. The T2DM heart metabolome showed significant differences in the abundance of metabolites in pathways related to glucose, lipids and redox metabolism. Using a validated computational model of heart's central catabolism, comprising glucose and fatty acid (FA) oxidation in cytoplasmic and mitochondrial compartments, we estimated that fluxes through glucose degradation pathways are ∼2-fold lower in heart from T2DM vs. WT under all conditions studied. Palm addition elicits improvement of the redox status via enhanced β-oxidation and decreased glucose uptake, leading to flux-redirection away from redox-consuming pathways (e.g. polyol) while maintaining the flux through redox-generating pathways together with glucose-FA 'shared fuelling' of oxidative phosphorylation. Thus, available FAs such as Palm may help improve function via enhanced redox balance in T2DM hearts during peaks of hyperglycaemia and increased workload.

Improving mitochondrial function with SS-31 reverses age-related redox stress and improves exercise tolerance in aged mice

Sarcopenia and exercise intolerance are major contributors to reduced quality of life in the elderly for which there are few effective treatments. We tested whether enhancing mitochondrial function and reducing mitochondrial oxidant production with SS-31 (elamipretide) could restore redox balance and improve skeletal muscle function in aged mice. Young (5 mo) and aged (26 mo) female C57BL/6Nia mice were treated for 8-weeks with 3 mg/kg/day SS-31. Mitochondrial function was assessed in vivo using 31P and optical spectroscopy. SS-31 reversed age-related decline in maximum mitochondrial ATP production (ATPmax) and coupling of oxidative phosphorylation (P/O). Despite the increased in vivo mitochondrial capacity, mitochondrial protein expression was either unchanged or reduced in the treated aged mice and respiration in permeabilized gastrocnemius (GAS) fibers was not different between the aged and aged+SS-31 mice. Treatment with SS-31 also restored redox homeostasis in the aged skeletal muscle. The glutathione redox status was more reduced and thiol redox proteomics indicated a robust reversal of cysteine S-glutathionylation post-translational modifications across the skeletal muscle proteome. The gastrocnemius in the age+SS-31 mice was more fatigue resistant with significantly greater mass compared to aged controls. This contributed to a significant increase in treadmill endurance compared to both pretreatment and untreated control values. These results demonstrate that the shift of redox homeostasis due to mitochondrial oxidant production in aged muscle is a key factor in energetic defects and exercise intolerance. Treatment with SS-31 restores redox homeostasis, improves mitochondrial quality, and increases exercise tolerance without an increase in mitochondrial content. Since elamipretide is currently in clinical trials these results indicate it may have direct translational value for improving exercise tolerance and quality of life in the elderly.

Sub-acute restraint stress progressively increases oxidative/nitrosative stress and inflammatory markers while transiently upregulating antioxidant gene expression in the rat hippocampus

We have previously demonstrated that acute stress decreases neuronal nitric oxide synthase (NOS) expression in the hippocampus despite increased concentrations of nitric oxide which may indicate feedback inhibition of neuronal NOS expression via inducible NOS-derived nitric oxide. Moreover, the hippocampus undergoes an initial oxidative/nitrosative insult that is rapidly followed by upregulation of protective antioxidants, including the zinc-binding metallothioneins, in order to counter this and restore redox balance following acute stress exposure. In the present study, we have utilized indicators of oxidative/nitrosative stress, members of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, antioxidant metallothioneins, and neuroinflammatory markers to observe the changes occurring in the hippocampus following short term repeated stress exposure. Male Wistar rats were subjected to control conditions or 6 h of restraint stress applied for 1, 2, or 3 days (n = 8 per group) after which the hippocampus was isolated for redox assays and relative gene expression. The hippocampus showed increased oxidative stress, transient dys-homeostasis of total zinc, and increased expression of the Nrf2 pathway members. Moreover, repeated stress increased nitrosative status, nitric oxide metabolites, and 3-nitrotyrosine, indicative of nitrosative stress in the hippocampus. However, levels of neuronal NOS decreased over all stress treatment groups, while increases were observed in inducible NOS and xanthine dehydrogenase. In addition to inducible NOS, mRNA expression of other inflammatory markers including interleukin-6 and interleukin-1β also increased even in the presence of increased anti-inflammatory glucocorticoids. Together, these results demonstrate that despite increases in antioxidant expression, sub-acute stress causes an inflammatory phenotype in the hippocampus by inducing oxidative/nitrosative stress, zinc dys-homeostasis, and the accumulation of nitrotyrosinated proteins which is likely driven by increased inducible NOS signaling.

Exercise and Redox Status Responses Following Alpha-Lipoic Acid Supplementation in G6PD Deficient Individuals.

G6PD deficiency renders cells more susceptible to oxidative insults, while antioxidant dietary supplementation could restore redox balance and ameliorate exercise-induced oxidative stress. To examine the effects of alpha-lipoic acid (ALA) supplementation on redox status indices in G6PD deficient individuals, eight male adults with G6PD deficiency (D) participated in this randomized double-blind placebo-controlled crossover trial. Participants were randomly assigned to receive ALA (600 mg/day) or placebo for 4 weeks separated by a 4-week washout period. Before and at the end of each treatment period, participants exercised following an exhaustive treadmill exercise protocol. Blood samples were obtained before (at rest), immediately after and 1h after exercise for later analysis of total antioxidant capacity (TAC), uric acid, bilirubin, thiobarbituric acid reactive substances (TBARS) and protein carbonyls (PC). ALA resulted in significantly increased resting TAC and bilirubin concentrations. Moreover, TAC increased immediately and 1h after exercise following both treatment periods, whereas bilirubin increased immediately after and 1h after exercise following only ALA. No significant change in uric acid, TBARS or PC was observed at any time point. ALA supplementation for 4 weeks may enhance antioxidant status in G6PD individuals; however, it does not affect redox responses to acute exercise until exhaustion or exercise performance.

Berberine ameliorates renal injury in a rat model of D‐galactose-induced aging through a PTEN/Akt-dependent mechanism

This study aimed to investigate the protective effects of berberine (BBR) against D-galactose (D-gal)-induced renal aging in rats, pointing to its ability to modulate phosphatase and tensin homolog deleted on chromosome ten (PTEN)/Akt signalling, and to attenuate oxidative stress, inflammation and apoptosis. Renal aging was induced by subcutaneous injection of D-gal for six consecutive weeks along with simultaneous oral administration of BBR and compared to control rats and rats received individual doses of either drug. BBR treatment significantly reduced the serum levels of urea and creatinine, retrieved the alterations in kidney histopathology, and restored redox balance evidenced by alleviations of the level of malondialdehyde, 8-hydroxy-2′-deoxyguanosine and activating heme oxygenase-1 enzyme. Moreover, it markedly reduced the serum levels of pro-inflammatory mediators, along with down-regulation of PTEN expression, enhanced Akt activity, as well as significantly higher immunostaining of the anti-apoptotic marker (Bcl-2). These findings hold a great promise for the use of BBR as a protecting agent against renal aging.

Redox imbalance stress in diabetes mellitus: Role of the polyol pathway.

In diabetes mellitus, the polyol pathway is highly active and consumes approximately 30% glucose in the body. This pathway contains 2 reactions catalyzed by aldose reductase (AR) and sorbitol dehydrogenase, respectively. AR reduces glucose to sorbitol at the expense of NADPH, while sorbitol dehydrogenase converts sorbitol to fructose at the expense of NAD +, leading to NADH production. Consumption of NADPH, accumulation of sorbitol, and generation of fructose and NADH have all been implicated in the pathogenesis of diabetes and its complications. In this review, the roles of this pathway in NADH/NAD + redox imbalance stress and oxidative stress in diabetes are highlighted. A potential intervention using nicotinamide riboside to restore redox balance as an approach to fighting diabetes is also discussed.

Oroxylum indicum root bark extract prevents doxorubicin-induced cardiac damage by restoring redox balance

BackgroundOroxylum indicum Vent., a Dasamula plant used in Ayurveda possesses antioxidant properties. ObjectivesTo evaluate the cardioprotective effect of 70% methanolic extract of O. indicum Vent. root bark (OIM) against doxorubicin induced cardiomyopathy in female Sprague Dawley rats. Materials and methodsCardiotoxicity was induced by intra-peritoneal injection of doxorubicin 30 mg/kg body weight (b.w.) for 4 consecutive days after a ten-day pre-treatment of animals with OIM at 200 mg/kg b.w. and 400 mg/kg b.w (p.o.). Drug treatment continued up to day 14. Probucol, orally administered at a dose of 20 mg/kg b.w. served as standard. ECG was recorded. The animals were sacrificed on day 15 and comparative analysis of serum marker levels of creatine phosphokinase (CPK), lactate dehydrogenase (LDH), Serum Glutamate Oxaloacetate Transaminase (SGOT), Serum Glutamate Pyruvate Transaminase (SGPT), tissue antioxidant status based on Superoxide Dismutase (SOD), Glutathione Peroxidase (GPx), reduced Glutathione (GSH) and lipid peroxidation (LPO) was carried out. Histopathological examination was carried out using hematoxylin–eosin staining. ResultsECG records of OIM treated animals showed normal pattern, in comparison to the control with ST depression and arrhythmia in cardiogram. Tissue antioxidant profile (SOD, GSH and GPx) was significantly (p < 0.01) elevated in the cardiac tissue of treated group in dose-dependent manner; lipid peroxidation level was found to decrease with treatment. Comparative analysis of serum markers – CPK, LDH, SGOT and SGPT – among untreated control, standard and extract treated groups revealed that OIM extract at 400 mg/kg b.w. dose significantly reduced the levels (p < 0.01). Histological analysis revealed normal myocardial architecture in OIM treated groups. HPTLC fingerprint of OIM revealed 8 bands and detected the presence of chrysin, apigenin and quercetin. ConclusionO. indicum root bark shows marked cardio-protective activity, possibly due to the presence of antioxidant compounds acting synergistically.

Effects of Curcumin on Autophagy and Nrf2 signaling pathway in a Rat Model of High fructose diet induced Steatohepatitis

Increased fructose consumption predisposes to nonalcoholic steatohepatitis (NASH).There no effective treatment to be used as the second line when lifestyle modification is insufficient .So, the aim of this study was to evaluate the effect of Curcumin on some biochemical markers in fructose induced NASH . Sixty male albino rats were divided randomly and equally into three groups. Group I (control group). Group II (NASH group), received 70% fructose for 5 weeks .Group III (curcumin treated NASH group), fed as group II followed by daily administration of curcumin at a dose of 50 mg/kg orally for 6 weeks. Blood samples were collected to measure lipid profile, and liver enzymes activities . Liver tissues samples were collected for estimation of mRNA expression levels of nuclear factor E2-related factor-2 (Nrf2) using quantitative real-time PCR ,levels of Beclin 1, AMPK, IL6 and Nrf2 DNA-binding activity by ELISA method, and oxidative stress markers malondialdehyde (MDA), superoxide dismutase (SOD) ,GSH spectrophotometrically. NASH was confirmed by histopathology as well as increased activity of liver enzymes and marked dyslipidemia .Curcumin ameliorated biochemical disturbance in NASH by upregulating autophagy process through increasing Beclin 1, increasing AMPK and hampered IL6 levels in the liver . It also restored redox balance as evident by suppressing MDA formation and preservation of intracellular antioxidants status via increasing GSH, activating SOD and Nrf2 signaling pathway. Results suggested that curcumin has an effective role in counteracting both abnormalities in autophagy process and redox balance, supporting the potential utility of this natural product in effective treatment of NASH.

All-Trans Retinoic Acid Ameliorates Arsenic-Induced Oxidative Stress and Apoptosis in the Rat Uterus by Modulating MAPK Signaling Proteins.

Exposure to arsenic leads to inhibition of the anti-oxidant defense mechanism of the body. Reactive oxygen species generated in response to arsenic causes reproductive failures in exposed females and also acts as an inducer of apoptosis. As a prospective remedial agent, all-trans retinoic acid (ATRA) was assessed for reversing arsenic-induced oxidative stress and apoptosis. Rats exposed to arsenic for 28 days were allowed to recover naturally or were treated simultaneously with ATRA for 28 days or up to 56 days. Production of H2 O2 was detected using 2',7'-dichlorfluorescein diacetate (DCFCA) by flow cytometry. Catalase, superoxide dismutase, glutathione, ALT, and AST were estimated by biochemical assays and Western blot analyses. Detection of apoptosis was performed using annexin V-FITC/propidium iodide. Expressions of p53, p21, cleaved caspase 3, JNK/pJNK, and ERK/pERK levels were estimated using Western blot analysis. Elemental arsenic deposition in the rat uterus and liver was estimated by atomic absorption spectrophotometry. Our results confirmed that ATRA ameliorated sodium arsenite-induced ROS generation, restored redox balance, and prevented apoptosis. Concomitant recovery was observed to be more prominent for ATRA-treated rats as compared to the rats that were allowed to recover naturally for 56 days. Tissue arsenic deposition was significantly reduced in the uterus upon continuous ATRA treatment. The results revealed that ATRA reversed arsenic-induced free radical generation, activated the anti-oxidant defence system, and subsequently repressed p53-dependent apoptosis through inhibition of the MAPK signaling components. J. Cell. Biochem. 118: 3796-3809, 2017. © 2017 Wiley Periodicals, Inc.