Further structure–activity relationships study of substituted dithiolethiones as glutathione-inducing neuroprotective agents

Background

Parkinson’s disease is a neurodegenerative disorder associated with oxidative stress and glutathione depletion. The induction of cellular glutathione levels by exogenous molecules is a promising neuroprotective approach to limit the oxidative damage that characterizes Parkinson’s disease pathophysiology. Dithiolethiones, a class of sulfur-containing heterocyclic molecules, are known to increase cellular levels of glutathione; however, limited information is available regarding the influence of dithiolethione structure on activity. Herein, we report the design, synthesis, and pharmacological evaluation of a further series of dithiolethiones in the SH-SY5Y neuroblastoma cell line.

Results

Our structure–activity relationships data show that dithiolethione electronic properties, given as Hammett σ_p constants, influence glutathione induction activity and compound toxicity. The most active glutathione inducer identified, 6a, dose-dependently protected cells from 6-hydroxydopamine toxicity. Furthermore, the protective effects of 6a were abrogated by the inhibitor of glutathione synthesis, buthionine sulfoximine, confirming the importance of glutathione in the protective activities of 6a.

Conclusions

The results of this study further delineate the relationship between dithiolethione chemical structure and glutathione induction. The neuroprotective properties of analog 6a suggest a role for dithiolethiones as potential antiparkinsonian agents.

     

Spectroscopic probing of bile salt-albumin interaction

Interaction of the bile salts, sodium cholate and sodium deoxy cholate with albumin has been probed by fluorescence and circular dichroism studies. Both covalently and non-covalently labeled protein have been used to follow the aggregation of bile salts in presence of protein and to study bile salt-protein interactions in general. Time resolved studies, in agreement with steady-state fluorescence and circular dichroism studies, indicate alteration of protein secondary structure due to positive co-operative effects in bile salt binding to protein. These studies also indicate that covalent labeling may not always be good for studying proteins as it causes alteration of protein secondary structure.     

pH‐Dependent Nitrotyrosine Formation in Ribonuclease A is Enhanced in the Presence of Polyethylene Glycol (PEG)

Protein nitration can occur as a result of peroxynitrite‐mediated oxidative stress. Excess production of peroxynitrite (PN) within the cellular medium can cause oxidative damage to biomolecules. The in vitro nitration of Ribonuclease A (RNase A) results in nitrotyrosine (NT) formation with a strong dependence on the pH of the medium. In order to mimic the cellular environment in this study, PN‐mediated RNase A nitration has been carried out in a crowded medium. The degree of nitration is higher at pH 7.4 (physiological pH) compared to pH 6.0 (tumor cell pH). The extent of nitration increases significantly when PN is added to RNase A in the presence of crowding agents PEG 400 and PEG 6000. PEG has been found to stabilize PN over a prolonged period, thereby increasing the degree of nitration. NT formation in RNase A also results in a significant loss in enzymatic activity.     

A review on iron chelators as potential therapeutic agents for the treatment of Alzheimer’s and Parkinson’s diseases

Iron plays a vital role in several cellular functions due to its unique physiochemical properties. Iron concentration increases in the brain with age due to multiple factors. Excessive amount of iron can lead to formation of reactive oxygen species. Neurodegenerative disorders are characterized by iron supplemented increase in oxidative stress and cellular damage. There is an urgent need of novel therapies which should not only provide symptomatic relief but also be able to modulate iron accumulation in the brain. Therefore, the development of novel iron chelators as neuroprotective agents for the treatment of neurodegeneration is an emerging trend. Several iron chelators including 8-hydroxyquinoline derivatives, dopaminergic agonists and natural products are under preclinical and clinical investigations for the treatment of neurodegenerative disorders.

     

Local Mechanical Behavior of Steel Exposed to Nonlinear Harmonic Oscillation

The local mechanical behavior of fatigued steel specimens was probed using nanoindentation. High-carbon steel cantilevers were exposed to nonlinear harmonic oscillation. The indentation modulus on the beam surface and plastic work during indentation decreased as a function of cycles, which was attributed to grain fragmentation and reorientation as well as the continuous reduction in inherent energy dissipation capacity of the material. X-ray diffraction, electron backscatter diffraction, and atomic force microscopy were used to characterize this microstructural evolution during early stages of the beam fatigue life, which altered 1) the local mechanical properties and 2) the global structural dynamic response. The results provide insight into fatigue damage precursors and provides a framework for connecting materials evolution with nonlinear structural dynamics.     

Design, analysis and optimization of silicon-on-insulator photonic crystal dual band wavelength demultiplexer

A highly efficient photonic crystal dual band wavelength demultiplexer (DBWD) using silicon-on-insulator (SOI) substrates is proposed for demultiplexing two optical communication wavelengths, 1.31 μm and 1.55 μm. Demultiplexing of two wavelength channels is obtained by modifying the propagation properties of guided modes in two arms of Y type photonic crystal structure. Propagation characteristics of proposed DBWD are analyzed utilizing 3D finite difference time domain (FDTD) method. Enhancement in spectral response is further obtained by optimizing the Y junction of demultiplexer giving rise to high transmission and extinction ratio for the wavelengths, 1.31 μm and 1.55 μm. Hence it validates the efficiency of proposed optimized DBWD design for separating two optical communication wavelengths, 1.31 μm and 1.55 μm. Tolerance analysis was also performed to check the effect of variation of air hole radius, etch depth and refractive index on the transmission characteristics of the proposed design of SOI based photonic crystal DBWD.     

Radiation response behaviour of Al codoped germano-silicate SM fiber at high radiation dose

Radiation response behaviour of Ge + Al doped SM fiber fabricated by the solution doping process has been studied at room temperature with respect to 1310 nm transmission wavelength under three different dose rates of 200, 400 and 600 Rad/min to compare with that of standard Er doped as well as Ge doped SM fibers. Their radiation sensitivity has been observed with variation of dose rates, transmission wavelength along with their recovery nature. Radiation response behaviour of Al doped SM fiber is found to be slightly non-linear in nature with very low dose rate dependency. No saturation level was found upto 13 Krad cumulative dose. Thermobleaching as well as photobleaching phenomena have also been studied. Gamma irradiated Al doped preform shows an absorption peak at around 300 nm due to generation of Al (E′) defect center and gets annihilated after thermobleaching process. Gamma irradiated Al doped SM fiber shows prominent photobleaching effect on their optical attenuation with respect to the 850 nm transmission wavelength. From ESR study resonance signals for Al³⁺ related radiation-induced defect centers are not clearly observed in this study. A very weak hyperfine pattern has been observed for gamma irradiated Al doped preform sample. The high radiation sensitivity along with linear response behaviour, low recovery and almost dose rate independence behaviour of the material system of Ge + Al codoped SM core optical fiber under gamma radiation shows their potential for application as fiber optic radiation sensor in comparison to the universal standard erbium doped SM fiber.     

Surface modification of polyacrylonitrile fiber for immobilization of antibodies and detection of analyte

Pendent nitrile groups of multifilamentous polyacrylonitrile (PAN) fibers were reduced to amino groups using lithium aluminum hydride for different time of reduction and amine content was estimated by performing acid-base titrations. Attenuated total reflection-fourier transform infrared spectroscopy (ATR-FTIR) and Differential Scanning Calorimetry (DSC) were used for the characterization of the generated amino groups and thermal properties of the reduced fibers, respectively. The surface morphology of the fibers after reduction and immobilization was characterized using Scanning Electron Microscope (SEM). The newly formed amino groups of the fibers were activated by using glutaraldehyde for the covalent linking of Goat anti-Rabbit IgG-HRP (GAR-HRP) antibody enzyme conjugate. Modified PAN fibers were evaluated as a matrix for sandwich ELISA by using Goat anti-Rabbit antibody (GAR-IgG), Rabbit anti-Goat (RAG-IgG) as analyte and enzyme conjugate GAR-HRP. The fibers reduced for 24 h were able to detect the analyte RAG-IgG at a concentration as low as 3.75 ng mL⁻¹ with 12% skimmed milk as blocking reagent for the optimized concentration of primary antibody GAR-IgG 3 μg mL⁻¹ and peroxidase conjugate GAR-HRP dilution of 8000 fold. The sensitivity, specificity and reproducibility of the developed immunoassay was further established with antibodies present in human blood using Rabbit anti-Human (RAH-IgG) antibody and the corresponding HRP enzyme conjugate. As low as 0.1 μL of human blood was sufficient to perform the assay with the modified fibers.