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

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

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

Calculation of Optical Conductivity of YbB12_{12} using Realistic Tight-Binding Model

Based on the previously reported tight-binding model fitted to the LDA+U band calculation, optical conductivity of the prototypical Kondo insulator YbB$_{12}$ is calculated theoretically. Many-body effects are taken into account by the self-consistent second order perturbation theory. The gross shape of the optical conductivity observed in experiments are well described by the present calculation, including their temperature-dependences.Comment: 6 pages, 7 figures, use jpsj2.cls, to appear in J. Phys. Soc. Jpn. Vol.73, No.10 (2004

Optical conductivity of filled skutterudites

A simple tight-binding model is constructed for the description of the electronic structure of some Ce-based filled skutterudite compounds showing an energy gap or pseudogap behavior. Assuming band-diagonal electron interactions on this tight-binding model, the optical conductivity spectrum is calculated by applying the second-order self-consistent perturbation theory to treat the electron correlation. The correlation effect is found to be of great importance on the description of the temperature dependence of the optical conductivity. The rapid disappearance of an optical gap with increasing temperature is obtained as observed in the optical experiment for Ce-based filled-skutterudite compounds.Comment: 6 pages, 7 figures, use jpsj2.cls, to appear in J. Phys. Soc. Jpn. Vol.73, No.10 (2004

Indirect and direct energy gaps in the Kondo semiconductor YbB12

Optical conductivity [$\sigma(\omega)$] of the Kondo semiconductor YbB$_{12}$ has been measured over wide ranges of temperature ($T$=8$-$690 K) and photon energy ($\hbar \omega \geq$ 1.3 meV). The $\sigma(\omega)$ data reveal the entire crossover of YbB$_{12}$ from a metallic electronic structure at high $T$ into a semiconducting one at low $T$. Associated with the gap development in $\sigma(\omega)$, a clear onset is newly found at $\hbar\omega$=15 meV for $T \leq$ 20 K. The onset energy is identified as the gap width of YbB$_{12}$ appearing in $\sigma(\omega)$. This gap in \sigma(\omega)$is interpreted as the indirect gap, which has been predicted in the band model of Kondo semiconductor. On the other hand, the strong mid-infrared (mIR) peak observed in$\sigma(\omega)$ is interpreted as arising from the direct gap. The absorption coefficient around the onset and the mIR peak indeed show characteristic energy dependences expected for indirect and direct optical transitions in conventional semiconductors.Comment: 4 pages, 3 figures, submitted to J. Phys. Soc. Jp

Holographic constraints on Bjorken hydrodynamics at finite coupling

In large-N-c conformal field theories with classical holographic duals, inverse coupling constant corrections are obtained by considering higher-derivative terms in the corresponding gravity theory. In this work, we use type IIB supergravity and bottom-up Gauss-Bonnet gravity to study the dynamics of boost-invariant Bjorken hydrodynamics at finite coupling. We analyze the time-dependent decay properties of non-local observables (scalar two-point functions and Wilson loops) probing the different models of Bjorken flow and show that they can be expressed generically in terms of a few field theory parameters. In addition, our computations provide an analytically quanti fiable probe of the coupling-dependent validity of hydrodynamics at early times in a simple model of heavyion collisions, which is an observable closely analogous to the hydrodynamization time of a quark-gluon plasma. We find that to third order in the hydrodynamic expansion, the convergence of hydrodynamics is improved and that generically, as expected from field theory considerations and recent holographic results, the applicability of hydrodynamics is delayed as the field theory coupling decreases.Peer reviewe

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