Detection of reactive oxygen and nitrogen species by electron paramagnetic resonance (EPR) technique

During the last decade there has been growing interest in physical-chemical oxidation processes and the behavior of free radicals in living systems. Radicals are known as intermediate species in a variety of biochemical reactions. Numerous techniques, assays and biomarkers have been used to measure reactive oxygen and nitrogen species (ROS and RNS), and to examine oxidative stress. However, many of these assays are not entirely satisfactory or are used inappropriately. The purpose of this chapter is to review current EPR (Electron Paramagnetic Resonance) spectroscopy methods for measuring ROS, RNS, and their secondary products, and to discuss the strengths and limitations of specific methodological approaches

Proteinopathy, oxidative stress and mitochondrial dysfunction: cross talk in alzheimer’s disease and parkinson’s disease

Alzheimer's disease and Parkinson's disease are two common neurodegenerative diseases of the elderly people that have devastating effects in terms of morbidity and mortality. The predominant form of the disease in either case is sporadic with uncertain etiology. The clinical features of Parkinson's disease are primarily motor deficits, while the patients of Alzheimer's disease present with dementia and cognitive impairment. Though neuronal death is a common element in both the disorders, the postmortem histopathology of the brain is very characteristic in each case and different from each other. In terms of molecular pathogenesis, however, both the diseases have a significant commonality, and proteinopathy (abnormal accumulation of misfolded proteins), mitochondrial dysfunction and oxidative stress are the cardinal features in either case. These three damage mechanisms work in concert, reinforcing each other to drive the pathology in the aging brain for both the diseases; very interestingly, the nature of interactions among these three damage mechanisms is very similar in both the diseases, and this review attempts to highlight these aspects. In the case of Alzheimer's disease, the peptide amyloid beta (A beta) is responsible for the proteinopathy, while alpha-synuclein plays a similar role in Parkinson's disease. The expression levels of these two proteins and their aggregation processes are modulated by reactive oxygen radicals and transition metal ions in a similar manner. In turn, these proteins - as oligomers or in aggregated forms - cause mitochondrial impairment by apparently following similar mechanisms. Understanding the common nature of these interactions may, therefore, help us to identify putative neuroprotective strategies that would be beneficial in both the clinical conditions

Redox control of multidrug resistance and Its possible modulation by antioxidants

Clinical efficacy of anticancer chemotherapies is dramatically hampered by multidrug resistance (MDR) dependent on inherited traits, acquired defence against toxins, and adaptive mechanisms mounting in tumours. There is overwhelming evidence that molecular events leading to MDR are regulated by redox mechanisms. For example, chemotherapeutics which overrun the first obstacle of redox-regulated cellular uptake channels (MDR1, MDR2, and MDR3) induce a concerted action of phase I/II metabolic enzymes with a temporal redox-regulated axis. This results in rapid metabolic transformation and elimination of a toxin. This metabolic axis is tightly interconnected with the inducible Nrf2-linked pathway, a key switch-on mechanism for upregulation of endogenous antioxidant enzymes and detoxifying systems. As a result, chemotherapeutics and cytotoxic by-products of their metabolism (ROS, hydroperoxides, and aldehydes) are inactivated and MDR occurs. On the other hand, tumour cells are capable of mounting an adaptive antioxidant response against ROS produced by chemotherapeutics and host immune cells. The multiple redox-dependent mechanisms involved in MDR prompted suggesting redox-active drugs (antioxidants and prooxidants) or inhibitors of inducible antioxidant defence as a novel approach to diminish MDR. Pitfalls and progress in this direction are discussed

Effect of oxidative stress on ABC transporters: contribution to epilepsy pharmacoresistance

Epilepsy is a neurological disorder affecting around 1%-2% of population worldwide and its treatment includes use of antiepileptic drugs to control seizures. Failure to respond to antiepileptic drug therapy is a major clinical problem and over expression of ATP-binding cassette transporters is considered one of the major reasons for pharmacoresistance. In this review, we have summarized the regulation of ABC transporters in response to oxidative stress due to disease and antiepileptic drugs. Further, ketogenic diet and antioxidants were examined for their role in pharmacoresistance. The understanding of signalling pathways and mechanism involved may help in identifying potential therapeutic targets and improving drug response

In vitro interaction of 5‐aminoorotic acid and its gallium(III) complex with superoxide radical, generated by two model systems

Increased levels of the superoxide radical are associated with oxidative damage to healthy tissues and with elimination of malignant cells in a living body. It is desirable that a chemotherapeutic combines pro‐oxidant behavior around and inside tumors with antioxidant action near healthy cells. A complex consisting of a pro‐oxidant cation and antioxidant ligands could be a potential anticancer agent. Ga(III) salts are known anticancer substances, and 5‐aminoorotic acid (HAOA) is a ligand with antioxidant properties. The in vitro effects of HAOA and its complex with Ga(III) (gallium(III) 5‐aminoorotate (GaAOA)) on the in vitro accumulation of superoxide and other free radicals were estimated. Model systems such as potassium superoxide (KO2), xanthine/xanthine oxidase (X/XO), and rat blood serum were utilized. Data suggested better antioxidant effect of GaAOA compared to HAOA. Evidently, all three ligands of GaAOA participated in the scavenging of superoxide. The effects in rat blood serum were more nuanced, considering the chemical and biochemical complexity of this model system. It was observed that the free‐radical‐scavenging action of both compounds investigated may be manifested via both hydrogen donation and electron transfer pathways. It was proposed that the radical‐scavenging activities (RSAs) of HAOA and its complex with Ga(III) may be due to a complex process, depending on the concentration, and on the environment, nature, and size of the free radical. The electron transfer pathway was considered as more probable in comparison to hydrogen donation in the scavenging of superoxide by 5‐aminoorotic acid and its gallium(III) complex

Novel 5-oxo-hexahydroquinoline derivatives: design, synthesis, in vitro P-glycoprotein-mediated multidrug resistance reversal profile and molecular dynamics simulation study

Overexpression of the efflux pump P-glycoprotein (P-gp) is one of the important mechanisms of multidrug resistance (MDR) in many tumor cells. In this study, 26 novel 5-oxo-hexahydroquinoline derivatives containing different nitrophenyl moieties at C-4 and various carboxamide substituents at C-3 were designed, synthesized and evaluated for their ability to inhibit P-gp by measuring the amount of rhodamine 123 (Rh123) accumulation in uterine sarcoma cells that overexpress P-gp (MES-SA/Dx5) using flow cytometry. The effect of compounds with highest MDR reversal activities was further evaluated by measuring the alterations of MES-SA/Dx5 cells' sensitivity to doxorubicin (DXR) using MTT assay. The results of both biological assays indicated that compounds bearing 2-nitrophenyl at C-4 position and compounds with 4-chlorophenyl carboxamide at C-3 demonstrated the highest activities in resistant cells, while they were devoid of any effect in parental nonresistant MES-SA cells. One of the active derivatives, 5c, significantly increased intracellular Rh123 at 100 mu M, and it also significantly reduced the IC50 of DXR by 70.1% and 88.7% at 10 and 25 mu M, respectively, in MES-SA/Dx5 cells. The toxicity of synthesized compounds against HEK293 as a noncancer cell line was also investigated. All tested derivatives except for 2c compound showed no cytotoxicity. A molecular dynamics simulation study was also performed to investigate the possible binding site of 5c in complex with human P-gp, which showed that this compound formed 11 average H-bonds with Ser909, Thr911, Arg547, Arg543 and Ser474 residues of P-gp. A good agreement was found between the results of the computational and experimental studies. The findings of this study show that some 5-oxo-hexahydroquinoline derivatives could serve as promising candidates for the discovery of new agents for P-gp-mediated MDR reversal

The Role of the NRF2 Pathway in Maintaining and Improving Cognitive Function

Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a redox-sensitive transcription factor that binds to the antioxidant response element consensus sequence, decreasing reactive oxygen species and regulating the transcription of a wide array of genes, including antioxidant and detoxifying enzymes, regulating genes involved in mitochondrial function and biogenesis. Moreover, NRF2 has been shown to directly regulate the expression of anti-inflammatory mediators reducing the expression of pro-inflammatory cytokines. In recent years, attention has turned to the role NRF2 plays in the brain in different diseases such Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and others. This review focused on the evidence, derived in vitro, in vivo and from clinical trials, supporting a role for NRF2 activation in maintaining and improving cognitive function and how its activation can be used to elicit neuroprotection and lead to cognitive enhancement. The review also brings a critical discussion concerning the possible prophylactic and/or therapeutic use of NRF2 activators in treating cognitive impairment-related conditions

A Perspective on Nrf2 Signaling Pathway for Neuroinflammation: A Potential Therapeutic Target in Alzheimer's and Parkinson's Diseases

Neuroinflammation plays a pivotal role in Alzheimer's disease (AD) and Parkinson's disease (PD), the leading causes of dementia. These neurological disorders are characterized by the accumulation of misfolded proteins such as amyloid-ß (Aß), tau protein and α-synuclein, contributing to mitochondrial fragmentation, oxidative stress, and neuroinflammation. Misfolded proteins activate microglia, which induces neuroinflammation, expression of pro-inflammatory cytokines and subsequently facilitates synaptic damage and neuronal loss. So far, all the proposed drugs were based on the inhibition of protein aggregation and were failed in clinical trials. Therefore, the treatment options of dementia are still a challenging issue. Thus, it is worthwhile to study alternative therapeutic strategies. In this context, there is increasing data on the pivotal role of transcription factor NF- E2 p45-related factor 2 (Nrf2) on the redox homeostasis and anti-inflammatory functions in neurodegenerative disorders. Interestingly, Nrf2 signaling pathway has shown upregulation of antioxidant genes, inhibition of microglia-mediated inflammation, and improved mitochondrial function in neurodegenerative diseases, suggesting Nrf2 activation could be a novel therapeutic approach to target pathogenesis. The present review will examine the correlation between Nrf2 signaling with neuroinflammation in AD and PD

A Pivotal Role of Nrf2 in Neurodegenerative Disorders: A New Way for Therapeutic Strategies

Clinical and preclinical research indicates that neurodegenerative diseases are characterized by excess levels of oxidative stress (OS) biomarkers and by lower levels of antioxidant protection in the brain and peripheral tissues. Dysregulations in the oxidant/antioxidant balance are known to be a major factor in the pathogenesis of neurodegenerative diseases and involve mitochondrial dysfunction, protein misfolding, and neuroinflammation, all events that lead to the proteostatic collapse of neuronal cells and their loss. Nuclear factor-E2-related factor 2 (Nrf2) is a short-lived protein that works as a transcription factor and is related to the expression of many cytoprotective genes involved in xenobiotic metabolism and antioxidant responses. A major emerging function of Nrf2 from studies over the past decade is its role in resistance to OS. Nrf2 is a key regulator of OS defense and research supports a protective and defending role of Nrf2 against neurodegenerative conditions. This review describes the influence of Nrf2 on OS and in what way Nrf2 regulates antioxidant defense for neurodegenerative conditions. Furthermore, we evaluate recent research and evidence for a beneficial and potential role of specific Nrf2 activator compounds as therapeutic agents

Kondo Effect in Fermi Systems with a Gap: A Renormalization Group Study

We present the results of a Wilson Renormalization Group study of the single-impurity Kondo and Anderson models in a system with a gap in the conduction electron spectrum. The behavior of the impurity susceptibility and the zero-frequency response function, $T>$ are discussed in the cases with and without particle-hole symmetry. In addition, for the asymmetric Anderson model the correlation functions, $<\vec S \cdot\vec \sigma (0)>$,$$, and$$ are computed.Comment: 10 pages, 10 figure