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Clotrimazole Inhibits Hemoperoxidase of Plasmodium falciparum and Induces Oxidative Stress PROPOSED ANTIMALARIAL MECHANISM OF CLOTRIMAZOLE

The mechanism of antimalarial activity of clotrimazole was studied placing emphasis on its role in inhibiting hemoperoxidase for inducing oxidative stress in Plasmodium falciparum. Clotrimazole, in the presence of H2O2, causes irreversible inactivation of the enzyme, and the inactivation follows pseudo-first order kinetics, consistent with a mechanism-based (suicide) mode. The pseudo-first order kinetic constants are ki= 2.85 μm, kinact = 0.9 min-1, and t½ = 0.77 min. The one-electron oxidation product of clotrimazole has been identified by EPR spectroscopy as the 5,5′-dimethyl-1-pyrroline N-oxide (DMPO) adduct of the nitrogen-centered radical (aN = 15 G), and as DMPO protects against inactivation, this radical is involved in the inactivation process. Binding studies indicate that the clotrimazole oxidation product interacts at the heme moiety, and the heme-clotrimazole adduct has been dissociated from the inactivated enzyme and identified (m/z 1363) by mass analysis. We found that the inhibition of hemoperoxidase increases the accumulation of H2O2 in P. falciparum and causes oxidative stress. Furthermore, the inhibition of hemoperoxidase correlates well with the inhibition of parasite growth. The results described herein indicate that the antimalarial activity of clotrimazole might be due to the inhibition of hemoperoxidase and subsequent development of oxidative stress in P. falciparum.

EPR STUDY OF NANOSTRUCTURED ZINC FERRITE

Bulk zinc ferrite has been studied in the past. In the bulk form zinc ferrite crystallizes in the normal spinel structure with all the zinc ions occupying the tetrahedral and all the iron occupying the octahedral sites, respectively. But, nanosize zinc ferrite is believed to crystallize in a different way. It is now well established that in a nanosize zinc ferrite there is partial inversion in the cation occupancy, leading to some kind of magnetic ordering in this system much above its Neel temperature of 10 K. Hence, there is ample scope of maneuvering the electrical and magnetic properties of this ferrite. In the present study nanosize zinc ferrite was prepared by a chemical reaction involving the nitrates of Zn and Fe and using the citric acid as the host. The sintering of the precursor was done for 1 h at various temperatures ranging from 300°C to 1000°C. These samples were characterized by X-ray diffractometer (XRD), transmission electron microscopy (TEM), and electron paramagnetic resonance (EPR). The average particle sizes in these sintered samples measured by TEM are found to vary from ≈ 10 to 62 nm. The XRD measurements show the formation of single-phase spinel structure in all the samples. The X-band EPR spectrum of the precursor specimen at room temperature consists of two EPR signals: an intense signal at geff = 2.02 having peak-to-peak line width △HPP = 425 Gauss and other a weak signal at geff = 4.51 having an asymmetric line shape. As the samples are heat-treated at different temperatures, the EPR signal corresponding to the intense peak gets stabilized at geff ≈ 2.03, whereas the weak signal gets suppressed progressively. The spin–spin relaxation time in these samples have values ≈ 3 × 10-10s. The effect of sintering temperature on the properties of the nanostructured specimen of zinc ferrite and the underlying mechanism would be discussed.

Nuclear Localization and in Situ DNA Damage by Mycobacterium tuberculosis Nucleoside-diphosphate Kinase

Nucleoside-diphosphate kinase of Mycobacterium tuberculosis (mNdK) is a secretory protein, but the rationale behind secreting an enzyme involved in the maintenance of cellular pool of nucleoside triphosphates is not clearly understood. To elucidate the biological significance of mNdK secretion, we expressed mNdK fused to green fluorescent protein in HeLa and COS-1 cells. Interestingly, mNdK was detected in the nuclei of HeLa and COS-1 cells. Incubation of mNdK with nuclei isolated from HeLa and COS-1 cells led to in situ damage of chromosomal DNA. Surface plasmon resonance studies demonstrated that mNdK binds supercoiled plasmid DNA lacking apurinic/apyrimidinic sites with a dissociation constant of 30 ± 3.2 μm. Plasmid cleavage by mNdK was found to be dependent on the specific divalent metal ion and inhibited by a metal ion chelator. Moreover, the metal ion-dependent DNA cleavage by mNdK was mediated by superoxide radicals as detected by electron paramagnetic resonance. The cleavage reaction was inhibited under nitrogen atmosphere confirming the necessity of molecular oxygen for DNA cleavage. In view of the findings that mNdK is secreted by intracellular mycobacteria and damages the nuclear DNA, it can be postulated that mNdK may cause cell death that could help in the dissemination of the pathogen.

EPR study of vanadyl ion in CoO · PbO · B2O3 glasses

Abstract Glasses with composition xCoO · (0.4 - x)PbO · 0.6B2O3 containing 1.0 mol% and 2.0 mol% V2O5 have been prepared over the range O ≤ x ≤ 0.20. The electron paramagnetic resonance spectra of VO2+ of these glasses have been measured in the X-band (≈ 9.3 GHz) at room temperature (RT ≈ 300 K). Glasses with 1.0 mol% of V2O5 were prepared by melting at 1173 K and 1373 K. Spin Hamiltonian parameters g|, g⊥, A|, A⊥, dipolar hyperfine coupling parameter, P, and Fermi contact interaction parameter, K, have been calculated. It is found that these parameters are independent of the temperature of the melt. Values of g|, P decrease; value of K increases and value of g⊥, A|, A⊥ are constant when V2O5 is increased from 1.0 mol% to 2.0 mol% in the binary lead borate glass. g|, g⊥, A|, A⊥, P and K change from 1.922 ± 0.001 to 1.927 ± 0.001, 1.968 ± 0.001 to 1.973 ± 0.001, (166.9 ± 1.0) × 10−4 Cm−1 to (165.1 ± 1.0) × 10−4 Cm−1, (58.8 ± 1.0) × 10−4 Cm−1 to (62.6 ± 1.0) × 10−4 Cm−1, 117.6 × 10−4 Cm−1 to 111.2 × 10−4 Cm−1 and 0.7614 to 0.8270, respectively, showing that tetragonal distortion of the V4+O6 complex increases with increase in the CoO:PbO ratio. It is also found that the increase in CoO:PbO ratio results in an expansion of the 3dxy orbit of unpaired electrons in the vanadium ion and that the spin Hamiltonian parameters do not depend on the value of theoretical optical basicity.

ESR of vanadyl ions in borate glasses

Electron spin resonance (ESR) of VO 2+ in Li 2 O·RO·B 2 O 3 (where R = Ba, Ca and Mg) glasses have been studied. Spin Hamiltonian parameters, the dipolar hyperfine coupling parameter, and the Fermi contact interaction parameter have been calculated. It is observed that with a decrease in B 2 O 3 mol% there is an improvement in the octahedral symmetry of the V 4+ site. The theoretical value of optical basicity, Λ th , of these glasses has also been calculated. It is found that at constant mol% of Li 2 O there is a decreasc in A ∥ , A ⊥ and Δ g ∥ /Δ g ⊥ and an increase in P with increase in the value of Λ th , whereas at constant mol% of B 2 O 3 by varying modifier contents the spin Hamiltonian parameters are independent of Λ th .

EPR study of Vanadyl Ion in cadmium - maleate dihydrate single crystals

Abstract Electron paramagnetic resonance (EPR) of VO2+ doped in cadmium maleate dihydrate single crystal was studied in X-band frequencies (∼9.1 GHz) at room and liquid nitrogen temperatures. Spin Hamiltonian parameters and molecular orbital coefficients were calculated from the EPR and optical data. It is found that VO2+ enters the lattice interstitially and only one type of complex is identified. The EPR results indicate that the vanadyl complex possesses a C4V symmetry.

Electron paramagnetic resonance study of doped synthetic crystals of struvite and its zinc analogue

The electron paramagnetic resonance (EPR) technique has been used to study the Mn2+ paramagnetic impurity complexes in synthetic struvite (MgNH4PO4β6H2O) and the zinc isomorph (ZnNH4PO4β6H2O). EPR of VO2+ ion complexes in vanadyl doped crystals of the zinc isomorph of struvite has also been studied. Two differently oriented, but otherwise identical complexes of both Mn2+ ion and VO2+ ion are found in these crystals. The spin Hamiltonian parameters indicate a large orthorhombic distortion of the [Mn2+(H2O)6] octahedra and an axial symmetry of the vanadyl complexes. The results indicate that in both manganese and vanadyl complexes, the metal ions have covalent bonding with the ligands.

Electrical studies in some alkali titanates

Abstract D.C. electrical conductivity of Na2Ti3O7, NaKTi3O7, K2Ti4O9 and KRbTi4O9 pelletized samples has been studied in the temperature range between 400 K and 800 K. Dependence of loss tangent (tan δ) on temperature and frequency has been studied in detail for Na2Ti3O7 and NaKTi3O7. The results indicate possibility of ferroelectricity at higher temperatures.

EPR and impedance spectroscopic investigations on lithium bismuth borate glasses containing nickel and vanadium ions.

Glasses having composition 7NiO∙23Li2O∙20Bi2O3∙50B2O3, 7V2O5∙23Li2O∙20Bi2O3∙50B2O3 and x(2NiO∙V2O5)∙(30-x)Li2O∙50B2O3∙20Bi2O3 (with x=0, 2, 5, 7 & 10 mol%) prepared through melt-quench route are explored by analyzing density, impedance spectroscopy and electron paramagnetic resonance (EPR). It is found that both density and molar volume increase with an increase in substitution of 2NiO∙V2O5 in the base glass matrix. Different dielectric parameters viz. dielectric loss (ε), electrical modulus (M), loss tangent (tanδ) etc. are evaluated and their variations with frequency and temperature are analyzed which reveals that these glasses exhibit a non-Debye relaxation behavior. A phenomenal description of the capacitive behavior is obtained by considering the circuitry as a parallel combination of bulk resistance (Rb) and constant phase element (CPE). The conduction mechanism is found to follow Quantum Mechanical Tunneling (QMT) model. Spin Hamiltonian Parameters (SHPs) and covalency rates are calculated from the EPR spectra of vanadyl ion. The observed EPR spectra confirmed that V(4+) ion exists as vanadyl ion in the octahedral coordination with tetragonal compression.

Effect of vanadium and cobalt ions on electrical conductivity and EPR in sodium borate glasses

Abstract Glasses with composition xCoO · (0.3–x)Na2O · 0.70B2O3 have been prepared over the range 0 · x · 0.12 containing 1 mol%/2 mol% of V2O5. Electron paramagnetic resonance spectra of VO2+ of the glasses have been measured at X-band (v · 9.3 GHz) at room temperature. Spin Hamiltonian parameters of the VO2+ ions have been calculated. It is found that for x · 0.05 the octahedral symmetry is reduced when Na2O is replaced by CoO. d.c. conductivity of these samples has also been measured which shows that conductivity decreases and activation energy increases when Na2O is replaced by CoO.