Molecular docking analysis of calcium channel blockers with ALR2 and RAGE.

A metabolic condition called diabetes mellitus is linked to a number of substantial challenges. Advanced Glycation End Products (AGEs) and Aldose reductase (ALR2) are crucial in the slow development of several secondary complications. Selected calcium channel blockers (CCB's-1, 4-dihydropyridines) were docked against ALR2 (PDB code: 1Z3N) and RAGE (PDB code: 3CJJ) in the current study. We report that 1, 4-dihydropyridine compounds, particularly Benidipine, bind to the active sites with good efficiency. Thus, 1,4 dihydropyridine derivatives can be considered for further confirmation in drug discovery.

Inorganic nanorods direct neuronal differentiation of bone marrow-derived mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are multipotent cells and are considered a potential source for tissue and organ repair due to their self-renewal, proliferation, and differentiation abilities. However, in most cases, MSCs are needed to be stimulated with external growth factors to promote their proliferation and differentiation. Over the past decade, it has been demonstrated that nanomaterials could facilitate MSC proliferation and differentiation, and excellent efforts are carried out to investigate their possible modulating pattern and mechanisms for MSC differentiation. Europium hydroxide (EuIII(OH)3) nanorods (EHN) are well-researched for their biomimicking properties and act as a substitute for growth factors that induce cell proliferation, migration, and differentiation. In the current study, the human MSCs were chosen as anin vitromodel for evaluating the role of EHN in modulating the differentiation process of MSCs into neuronal and glial lineages. The characterization of MSCs and differentiated neuronal cells observed by flow cytometry, confocal, and gene marker expression studies supported our hypothesis that the EHNs are pro-angiogenic and pro-neurogenic. Finally, altogether our results suggest that EHNs have the potential to play an essential part in developing novel treatment strategies for neurodegenerative diseases and spinal cord injuries based on the nanomedicine approach.

Historical changes in trace metals and hydrocarbons in nearshore sediments, Alaskan Beaufort Sea, prior and subsequent to petroleum-related industrial development: part II. Hydrocarbons.

Composition and concentration of hydrocarbons (normal and isoprenoid alkanes, triterpenoids, steranes, and PAHs) in nearshore surface sediments from Elson Lagoon (EL), Colville Delta-Prudhoe Bay (CDPB) and Beaufort Lagoon (BL), Alaskan Beaufort Sea, were assessed for spatio-temporal variability. Principal component analysis of the molecules/biomarkers concentrations delineated CDPB and BL samples into two groups, and cluster analysis identified three station groups in CDPB. Overall there was no geographic distribution pattern in the groups. The diversities between groups and individual samples are attributed to differences in n-alkanes and PAHs contents, which are influenced predominantly by sediment granulometry and sitespecific fluvial input. The predominant hydrocarbon source is biogenic, mainly terrigenous, with hardly any contribution from natural oil seeps, oil drill effluents and/or refined crude. The terrigenous source is corroborated by δ(13)C, δ(15)N, and OC/N of sediment organic matter. Time interval (1976-1977, 1984 and 1997) changes in hydrocarbon compositions and concentrations in CDPB are not significant.

Historical changes in trace metals and hydrocarbons in nearshore sediments, Alaskan Beaufort Sea, prior and subsequent to petroleum-related industrial development: Part I. Trace metals.

Concentrations of Fe, As, Ba, Cd, Cu, Cr, Pb, Mn, Ni, Sn, V and Zn in mud (<63µm size), and total and methyl Hg in gross sediment are reported for Arctic Alaska nearshore. Multivariate-PCA analysis discriminated seven station clusters defined by differences in metal concentrations, attributed to regional variations in granulometry and, as in Elson Lagoon, to focused atmospheric fluxes of contaminants from Eurasia. In Colville Delta-Prudhoe Bay, V increase was noted in 1985 and 1997 compared to 1977, and Ba increase from 1985 to 1997. Presumably the source of increased V is the local gas flaring plant, and the elevated Ba is due to barite accumulation from oil drilling effluents. In Prudhoe Bay, concentration spikes of metals in ∼1988 presumably reflect enhanced metals deposition following maximum oil drilling in 1980s. In summary, the Alaskan Arctic nearshore has remained generally free of metal contamination despite petroleum-related activities in past 40 years.

Impact of selenium on the leukotriene B4 synthesis pathway during isoproterenol-induced myocardial infarction in experimental rats.

Selenium (Se), an essential micronutrient, exerts its biological functions through selenoproteins. There are evidences that show Se to have an impact on the course and outcome of a number of etiologically inflammatory diseases. Leukotriene B(4) (LTB(4)) is an inflammatory mediator, and its production is mediated through two specific enzymes--lipooxygenase (LOX) and leukotriene A(4) hydrolase (LTA(4)H). We examined the effect of Se on LTB(4) synthesis during isoproterenol (ISP)-induced myocardial infarction (MI) in rats. Rats were divided as: control, ISP, Se, and Se + ISP. Sodium selenite was administered at dose of 8 µg/100 g/day. ISP was injected subcutaneously twice (10 mg/100 g body weight). The rats pretreated with Se had increased concentration of phospholipids and enhanced biosynthetic enzymes compared with that of ISP. The activities of phospholipases decreased on Se treatment. The level of calcium was increased in ISP group whereas, on Se treatment, it was near normal levels. Activities of LOX and expression of LTA(4)H were down-regulated in the case of Se-pretreated rats. Our study shows the anti-inflammatory mechanism of selenium during MI.

Computation of energy interaction parameters as well as electric dipole intensity parameters for the absorption spectral study of the interaction of Pr(III) with l-phenylalanine, l-glycine, l-alanine and l-aspartic acid in the presence and absence of Ca2+ in organic solvents.

Studying the absorption difference and comparative absorption spectra of the interaction of Pr(III) and Nd(III) with l-phenylalanine, l-glycine, l-alanine and l-aspartic acid in the presence and absence of Ca(2+) in organic solvents, various energy interaction parameters like Slater-Condon (F(K)), Racah (E(k)), Lande factor (xi(4f)), nephelauxetic ratio (beta), bonding (b(1/2)), percentage-covalency (delta) have been evaluated applying partial and multiple regression analysis. The values of oscillator strength (P) and Judd-Ofelt electric dipole intensity parameter T(lambda) (lambda = 2, 4, 6) for different 4f-4f transitions have been computed. On analysis of the variation of the various energy interaction parameters as well as the changes in the oscillator strength (P) and T(lambda) values reveal the mode of binding with different ligands.

Calculation of electric dipole intensity parameter to explore some interaction between hard metal ions Pr(III) and Nd(III) with pi-electron density of butene-1,4 and butyne-1,4-diols in non-aqueous solutions: an absorption spectral study.

Pr(III) and Nd(III) are hard acceptors in HSAB (hard and soft acid base) sense and hence are known to exhibit practically a little affinity towards electrons. At the same time these metal ions show strong preference for oxygen donor chelating ligands. The ligands chosen for this study are structurally related diols, viz. butane-1,4, butene-1,4 and butyne-1,4-diols which form identical seven membered chelate ring by coordinating to metals in a bidentate manner through oxygen on 1 and 4 positions of the diol molecules. Complexation of these diols with Pr(III) and Nd(III) was carried out in DMF, CH3OH, CH3CN and their equimolar binary mixtures using comparative absorption spectrophotometry of 4f-4f transitions. The variation of oscillator strengths (P) of different 4f-4f bands as well as the magnitude and variation of Judd-Ofelt electric dipole intensity parameters (T lambda, lambda = 2, 4, 6) was discussed. They correlate the interaction between the metal 4f-orbitals of Pr(III) and Nd(III) with the pi-electron densities of the double and triple bonds present in butene-1,4 and butyne-1,4-diols, respectively. The value of empirical intensity parameter [T lambda(complex)/T lambda (aquo)] was calculated and its plot against oscillator strength (P) is drawn.

Comparison of energy interaction parameters for the complexation of Pr(III) with glutathione reduced (GSH) in absence and presence of Zn(II) in aqueous and aquated organic solvents using 4f-4f transition spectra as PROBE.

The coordination chemistry of glutathione reduced (GSH) is of great importance as it acts as excellent model system for the binding of metal ions. The GSH complexation with metal ions is involved in the toxicology of different metal ions. Its coordination behaviour for soft metal ions and hard metal ions is found different because of the structure of GSH and its different potential binding sites. In our work we have studied two chemically dissimilar metal ions viz. Pr(III), which prefer hard donor site like carboxylic groups and Zn(II) the soft metal ion which prefer peptide-NH and sulphydryl groups. The absorption difference and comparative absorption spectroscopy involving 4f-4f transitions of the heterobimetallic Complexation of GSH with Pr(III) and Zn(II) has been explored in aqueous and aquated organic solvents. The variation in the energy parameters like Slater-Condon (F(K)), Racah (E(K)) and Lande (xi(4f)), Nephelauxetic parameter (beta) and bonding parameter (b(1/2)) are computed to explain the nature of complexation.

Quinones and aromatic chemical compounds in particulate matter induce mitochondrial dysfunction: implications for ultrafine particle toxicity.

Particulate pollutants cause adverse health effects through the generation of oxidative stress. A key question is whether these effects are mediated by the particles or their chemical compounds. In this article we show that aliphatic, aromatic, and polar organic compounds, fractionated from diesel exhaust particles (DEPs), exert differential toxic effects in RAW 264.7 cells. Cellular analyses showed that the quinone-enriched polar fraction was more potent than the polycyclic aromatic hydrocarbon (PAH)-enriched aromatic fraction in O2 .- generation, decrease of membrane potential (Delta-Psi m), loss of mitochondrial membrane mass, and induction of apoptosis. A major effect of the polar fraction was to promote cyclosporin A (CsA)-sensitive permeability transition pore (PTP) opening in isolated liver mitochondria. This opening effect is dependent on a direct effect on the PTP at low doses as well as on an effect on Delta-Psi m at high doses in calcium (Ca2+)-loaded mitochondria. The direct PTP effect was mimicked by redox-cycling DEP quinones. Although the aliphatic fraction failed to perturb mitochondrial function, the aromatic fraction increased the Ca2+ retention capacity at low doses and induced mitochondrial swelling and a decrease in Delta-Psi m at high doses. This swelling effect was mostly CsA insensitive and could be reproduced by a mixture of PAHs present in DEPs. These chemical effects on isolated mitochondria could be reproduced by intact DEPs as well as ambient ultrafine particles (UFPs). In contrast, commercial polystyrene nanoparticles failed to exert mitochondrial effects. These results suggest that DEP and UFP effects on the PTP and Delta-Psi m are mediated by adsorbed chemicals rather than the particles themselves.

Nrf2 is a key transcription factor that regulates antioxidant defense in macrophages and epithelial cells: protecting against the proinflammatory and oxidizing effects of diesel exhaust chemicals.

The proinflammatory effects of particulate pollutants, including diesel exhaust particles (DEP), are related to their content of redox cycling chemicals and their ability to generate oxidative stress in the respiratory tract. An antioxidant defense pathway, which involves phase II enzyme expression, protects against the pro-oxidative and proinflammatory effects of DEP. The expression of enzymes, including heme oxygenase-1 (HO-1) and GST, is dependent on the activity of a genetic antioxidant response element in their promoters. In this study we investigated the mechanism by which redox cycling organic chemicals, prepared from DEP, induce phase II enzyme expression as a protective response. We demonstrate that aromatic and polar DEP fractions, which are enriched in polycyclic aromatic hydrocarbons and quinones, respectively, induce the expression of HO-1, GST, and other phase II enzymes in macrophages and epithelial cells. We show that HO-1 expression is mediated through accumulation of the bZIP transcription factor, Nrf2, in the nucleus, and that Nrf2 gene targeting significantly weakens this response. Nrf2 accumulation and subsequent activation of the antioxidant response element is regulated by the proteasomal degradation of Nrf2. This pathway is sensitive to pro-oxidative and electrophilic DEP chemicals and is also activated by ambient ultrafine particles. We propose that Nrf2-mediated phase II enzyme expression protects against the proinflammatory effects of particulate pollutants in the setting of allergic inflammation and asthma.

Biological and clinical aspects of Lanthanide coordination compounds.

The coordinating chemistry of lanthanides, relevant to the biological, biochemical and medical aspects, makes a significant contribution to understanding the basis of application of lanthanides, particularly in biological and medical systems. The importance of the applications of lanthanides, as an excellent diagnostic and prognostic probe in clinical diagnostics, and an anticancer material, is remarkably increasing. Lanthanide complexes based X-ray contrast imaging and lanthanide chelates based contrast enhancing agents for magnetic resonance imaging (MRI) are being excessively used in radiological analysis in our body systems. The most important property of the chelating agents, in lanthanide chelate complex, is its ability to alter the behaviour of lanthanide ion with which it binds in biological systems, and the chelation markedly modifies the biodistribution and excretion profile of the lanthanide ions. The chelating agents, especially aminopoly carboxylic acids, being hydrophilic, increase the proportion of their complex excreted from complexed lanthanide ion form biological systems. Lanthanide polyamino carboxylate-chelate complexes are used as contrast enhancing agents for Magnetic Resonance Imaging. Conjugation of antibodies and other tissue specific molecules to lanthanide chelates has led to a new type of specific MRI contrast agents and their conjugated MRI contrast agents with improved relaxivity, functioning in the body similar to drugs. Many specific features of contrast agent assisted MRI make it particularly effective for musculoskeletal and cerebrospinal imaging. Lanthanide-chelate contrast agents are effectively used in clinical diagnostic investigations involving cerebrospinal diseases and in evaluation of central nervous system. Chelated lanthanide complexes shift reagent aided (23)Na NMR spectroscopic analysis is used in cellular, tissue and whole organ systems.

Determination of linear alkylbenzenes in fish tissue by gel permeation chromatography and gas chromatography-mass spectrometry.

A gel permeation chromatographic (GPC) procedure is described for separation of the long-chain linear alkylbenzenes (LABs) from fish muscle tissues. This technique was found to remove the matrix interference significantly and thereby improve the sensitivity of detection of LABs in the extracts. Gas chromatography-mass spectrometry (GC-MS) was then used to quantitate LABs in different species of fish and also fish from different locations on a transect from the outfalls from the Orange County Sanitation Districts, in the coastal waters of Southern California. The results are consistent with the proximity of the (sewage) source. The data, thus, show that LAB contents in fish tissues, especially that from white croaker (Genyonemus lineatus) are useful in assessing exposure to sewage residues in the marine waters. This method of concentrating LABs by GPC could be applicable to all other similar biological matrices.