Proteomic profiling of high glucose primed monocytes identifies cyclophilin A as a potential secretory marker of inflammation in type 2 diabetes

Hyperglycemia is widely recognized to be a potent stimulator of monocyte activity, which is a crucial event in the pathogenesis of atherosclerosis. We analyzed the monocyte proteome for potential markers that would enhance the ability to screen for early inflammatory status in Type 2 diabetes mellitus (T2DM), using proteomic technologies. Monocytic cells (THP-1) were primed with high glucose (HG), their protein profiles were analyzed using 2DE and the downregulated differentially expressed spots were identified using MALDI TOF/MS. We selected five proteins that were secretory in function with the help of bioinformatic programs. A predominantly downregulated protein identified as cyclophilin A (sequence coverage 98%) was further validated by immunoblotting experiments. The cellular mRNA levels of cyclophilin A in various HG-primed cells were studied using qRT-PCR assays and it was observed to decrease in a dose-dependent manner. LC-ESI-MS was used to identify this protein in the conditioned media of HG-primed cells and confirmed by Western blotting as well as ELISA. Cyclophilin A was also detected in the plasma of patients with diabetes. We conclude that cyclophilin A is secreted by monocytes in response to HG. Given the paracrine and autocrine actions of cyclophilin A, the secreted immunophilin could be significant for progression of atherosclerosis in type 2 diabetes. Our study also provides evidence that analysis of monocyte secretome is a viable strategy for identifying candidate plasma markers in diabetes.

Pricing credit derivatives

The financial crisis set off by the default of Lehman Brothers in 2008 leading to disastrous consequences for the global economy has focused attention on regulation and pricing issues related to credit derivatives. Credit risk refers to the potential losses that can arise due to the changes in the credit quality of financial instruments. These changes could be due to changes in the ratings, market price (spread) or default on contractual obligations. Credit derivatives are financial instruments designed to mitigate the adverse impact that may arise due to credit risks. However, they also allow the investors to take up purely speculative positions. In this article we provide a succinct introduction to the notions of credit risk, the credit derivatives market and describe some of the important credit derivative products. There are two approaches to pricing credit derivatives, namely the structural and the reduced form or intensity-based models. A crucial aspect of the modelling that we touch upon briefly in this article is the problem of calibration of these models. We hope to convey through this article the challenges that are inherent in credit risk modelling, the elegant mathematics and concepts that underlie some of the models and the importance of understanding the limitations of the models.

Stabilization and Structural Alteration of the G-Quadruplex DNA Made from the Human Telomeric Repeat Mediated by Troger's Base Based Novel Benzimidazole Derivatives

Ligand-induced stabilization of the G-quadruplex DNA structure derived from the single-stranded 3'-overhang of the telomeric DNA is an attractive strategy for the inhibition of the telomerase activity. The agents that can induce/stabilize a DNA sequence into a G-quadruplex structure are therefore potential anticancer drugs. Herein we present the first report of the interactions of two novel bisbenzimidazoles (TBBz1 and TBBz2) based on Troger's base skeleton with the G-quadruplex DNA (G4DNA). These Troger's base molecules stabilize the G4DNA derived from a human telomeric sequence. Evidence of their strong interaction with the G4DNA has been obtained from CD spectroscopy, thermal denaturation, and UV-vis titration studies. These ligands also possess significantly higher affinity toward the G4DNA over the duplex DNA. The above results obtained are in excellent agreement with the biological activity, measured in vitro using a modified TRAP assay. Furthermore, the ligands are selectively more cytotoxic toward the cancerous cells than the corresponding noncancerous cells. Computational studies suggested that the adaptive scaffold might allow these ligands to occupy not only the G-quartet planes but also the grooves of the G4DNA.

Deoxythiosugar Derivatives with Furano, Pyrano, and Septano Motifs from L-Gulono-1,4-lactone and D-Glycero-D-gulo-heptono-1,4-lactone

A short synthesis of thiosugar derivatives mimicking furanose, pyranose, and septanose structures has been achieved starting from L-gulono-1,4-lactone and D-glucoheptono-1,4-lactone. Different strategies used in the synthesis are: (1) a nucleophilic displacement and Michael addition; (2) epoxide ring opening and Michael addition; (3) epoxide ring opening and nucleophilic displacement process; and (4) double nucleophilic displacement. All of these reactions used benzyltriethylammonium tetrathiomolybdate, (BnEt3N)(2)MoS4 as the sulfur-transfer reagent.

Fluoranthene based derivatives for detection of trace explosive Nitroaromatics

A series of fluoranthene derivatives (F1-F5) varied with nature and type of substituents were synthesized via Diels-Alder reaction followed by in situ decarbonylation. The solid state structures have been established through single crystal X-ray diffraction (XRD). The presence of extended conjugation and having two alkyloxy chains on phenyl rings induces flexibility to orient opposite to each other and interacts with another fluoranthene unit with weak pi-pi interactions and show unique supramolecular arrangements. The envisaged photophysical and DFT studies demonstrated that HOMO-LUMO levels were effectively tuned by different substituents with an optical band gap from 3.44 to 3.88 eV provoked to examine as sensitive fluorescent chemosensors for the detection of nitroaromatic compounds (NACs). The sensitivity toward the detection of NACs was evaluated through fluorescence quenching in solution (aqueous and non-aqueous) and solid state (vapor and contact mode). Fluorescence studies demonstrated that electron transfer occurs from the electron rich fluoranthene fluorophores to the electron deficient NACs by the dominant static quenching mechanism and the quenching process is reversible. It was found that the detection sensitivity increases with extent of conjugation on fluoranthene unit. The contact mode approach using thin layer silica chromatographic plates exhibits a femtogram (1.15 fg/cm(2)) detection limit for trinitrotoluene (TNT) and picric acid (PA), while the solution state fluorescence quenching shows for PA detection at the 2-20 ppb level. The sensing performance of fluoranthene thin films to NACs in aqueous solution reveals that fluorophores are highly selective towards the detection of PA. The smart performances of thin film fluorophores with high photostability have great advantage than those of conjugated polymers with superior sensitive detection of PA in groundwater.

Crystal structures and binding studies of atovaquone and its derivatives with cytochrome bc(1): a molecular basis for drug design

Crystal structure of trans-atovaquone (antimalarial drug), its polymorph and its stereoisomer (cis) along with five other derivatives with different functional groups have been analyzed. Based on the conformational features of these compounds and the characteristics of the nature of intermolecular interactions, valuable insights into the atomistic details of protein-inhibitor interactions have been derived by docking studies. Atovaquone and its derivatives pack in the crystal lattice using intermolecular O-H center dot center dot center dot O hydrogen bond dimer motifs supported by surrogate weak interactions including C-H center dot center dot center dot O and C-H center dot center dot center dot Cl hydrogen bonds. The docking results of these molecules with cytochrome bc(1) show preferences to form N-H center dot center dot center dot O, O-H center dot center dot center dot O and O-H center dot center dot center dot Cl hydrogen bonds. The involvement of halogen atoms in the binding pocket appears to be significant and is contrary to the theoretically predicted mechanism of protein-ligand docking reported earlier based on mimicking experimental binding results of stigmatellin with cytochrome bc(1). The significance of subtle energy factors controlled by weak intermolecular interactions appears to play a major role in drug binding.

Non-Enzymatic Electroanalysis of Glucose on Electrodeposited Au-PEDOT Dendrites

Electrodeposition of Au on poly (3,4-ethylenedioxythiophene) (PEDOT) coated carbon paper electrode results in the formation of a stable 3-D urchin-like morphology. Au-PEDOT/C electrode exhibits higher surface area, greater catalytic activity, higher sensitivity and lower detection limit for glucose analysis in an alkaline medium than Au/C electrode. Au-PEDOT/C electrode exhibits a linear current response in glucose concentration ranging up to 10 mu M with sensitivity of 515 mu A cm(-2) mu M-1 (on the basis of geometric area) and a low detection limit of 0.03 mu M with signal to noise ratio of 3. Thus, the PEDOT under-layer improves the property of Au for glucose analysis. (c) 2013 The Electrochemical Society.

Induction of Supramolecular Chirality in the Self-Assemblies of Lipophilic Pyrimidine Derivatives by Choice of the Amino Acid-Based Chiral Spacer

A new family of supramolecular organogelators, based on chiral amino acid derivatives of 2,4,6-trichloro-pyrimidine-5-carbaldehyde, has been synthesized. L-alanine was incorporated as a spacer between the pyrimidine core and long hydrocarbon tails to compare the effect of chirality and hydrogen bonding to that of the achiral analogue. The role of aromatic moiety on the chiral spacer was also investigated by introducing L-phenyl alanine moieties. The presence of intermolecular hydrogen-bonding leading to the chiral self-assembly was probed by concentration-dependent FTIR and UV/Vis spectroscopies, in addition to circular dichroism (CD) studies. Temperature and concentration-dependent CD spectroscopy ascribed to the formation of -sheet-type H-bonded networks. The morphology and the arrangements of the molecules in the freeze-dried gels were examined by scanning electron microscopy (SEM), transmission electron microscopy (TEM), atomic force microscopy (AFM), and X-ray diffraction (XRD) techniques. Calculation of the length of each molecular system by energy minimization in its extended conformation and comparison with the small-angle XRD pattern reveals that this class of gelator molecules adopts a lamellar organization. Polarized optical microscopy (POM) and differential scanning calorimetry (DSC) indicate that the solid state phase behavior of these molecules is totally dependent on the choice of their amino acid spacers. Structure-induced aggregation properties based on the H-bonding motifs and the packing of the molecule in three dimensions leading to gelation was elucidated by rheological studies. However, viscoelasticity was shown to depend only marginally on the H-bonding interactions; rather it depends on the packing of the gelators to a greater extent.

High catalytic activity of Au-PEDOT nanoflowers toward electrooxidation of glucose

Electrochemically deposited porous film of poly(3,4-ethylenedioxythiophene) (PEDOT) on carbon paper current collector is used as the substrate for electrochemical deposition of Au. PEDOT facilitates the formation of Au nanoflowers with an enhanced electrochemical active surface area, when compared with sub-micron size Au particles deposited on bare carbon paper electrode. Owing to enhanced surface area of Au nanoflowers, the Au-PEDOT/C electrode shows greater activity than Au/C electrode toward electrooxidation of glucose in 0.5 M NaOH electrolyte. Cyclic voltammetry studies show that the peak current density increases with increase in concentrations of glucose and NaOH in the electrolyte. H-1-NMR spectroscopy data indicates that sodium formate and gluconate are the primary products of electrooxidation of glucose on Au-PEDOT/C electrode. Repetitive cyclic voltametry and amperometry studies suggest that the electrochemical stability of Au-PEDOT/C electrode is higher than that of Au/C electrode. Thus, electrochemically deposited nanostructured Au on PEDOT/C is an efficient catalyst for direct glucose oxidation in alkaline media. (C) 2013 The Electrochemical Society. All rights reserved.

In vitro and in silico biological studies of novel thiazolo3,2-a]pyrimidine-6-carboxylate derivatives

In the present study, we report the synthesis, characterization of new series of thiazolo3,2-a]pyrimidine-6-carboxylate derivatives 3a-f and 4a-f. The newly synthesized compounds were screened for in vitro antimicrobial and antiviral activities. The probable mode of action of these active compounds was determined through in silico docking study by docking the receptor methionyl-tRNA synthetase and human inosine-5'-monophosphate dehydrogenase (IMPDH) for antibacterial and antiviral activities, respectively. Among the compounds, 4c exhibited excellent in vitro antimicrobial activity against all tested strains with binding and docking energies -35.6 and -12.4 kcal/mol, respectively. The antiviral studies were carried out for the selected compounds in which 4a exhibited 73.69 and 54.42 % of inhibition of buffalopox and camelpox viruses, respectively. Furthermore, compound 4a showed minimum docking and binding energy along with the maximum hydrogen/hydrophobic interaction with IMPDH. The study contributes towards identification and screening of potential antimicrobial and antiviral agent's against the pathogens.

Synthesis, Antioxidant, and Cytotoxic Activities of N-Azole Substituted Thiomorpholine Derivatives

A new class of N-azole substituted thiomorpholine derivatives were prepared and their antioxidant and cytotoxic activities were studied. The methyl substituted oxazolyl thiomorpholine dioxide 9b exhibited radical scavenging activity greater than the standard ascorbic acid. On the other hand, the thiazolyl thiomorpholine 10c having a chloro substituent on the aromatic ring was identified as a remarkable lead molecule for cytotoxic activity against A549 and HeLa cells, with IC50 values of 10.1 and 30.0 mu M, respectively.

Post-absorptive glucose lowering in normal healthy individuals: An epidemiological observation

Post-absorptive glucose lowering (PALG) is observed in individuals with glucose intolerance and in healthy individuals. We report a prevalence of about 23% among healthy Asian Indians. Individuals with PALG are characterized by leaner phenotype, low body fat percentage, increased insulin sensitivity and higher fasting glucose levels. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Role of Vertex Index in Substructure Identification and Activity Prediction: A Study on Antitubercular Activity of a Series of Acid Alkyl Ester Derivatives

Tuberculosis (TB) is a life threatening disease caused due to infection from Mycobacterium tuberculosis (Mtb). That most of the TB strains have become resistant to various existing drugs, development of effective novel drug candidates to combat this disease is a need of the day. In spite of intensive research world-wide, the success rate of discovering a new anti-TB drug is very poor. Therefore, novel drug discovery methods have to be tried. We have used a rule based computational method that utilizes a vertex index, named `distance exponent index (D-x)' (taken x = -4 here) for predicting anti-TB activity of a series of acid alkyl ester derivatives. The method is meant to identify activity related substructures from a series a compounds and predict activity of a compound on that basis. The high degree of successful prediction in the present study suggests that the said method may be useful in discovering effective anti-TB compound. It is also apparent that substructural approaches may be leveraged for wide purposes in computer-aided drug design.

3 `-Amino-5 `-carboxymethy1-3 `,5 `-dideoxy nucleosides for the synthesis of fully amide-linked RNA mimics

A convenient protocol is developed for the synthesis of 3 `-N-(fluorenylmethoxycarbonyl)-amino]-5 `-carboxymethyl derivatives of all four natural ribonucleosides from cheap chiral pool compound glucose. Synthesis of fully amide-linked RNA analogues of small oligonucleotides containing, for the first time, all four nucleoside amino acids using standard solid phase Fmoc-chemistry is described. (C) 2014 Elsevier Ltd. All rights reserved.

Regioselective Deiodination of Iodothyronamines, Endogenous Thyroid Hormone Derivatives, by Deiodinase Mimics

Iodothyronine deiodinases (IDs) are mammalian selenoenzymes that play an important role in the activation and inactivation pound of thyroid hormones. It is known that iodothyronamines (TnAMs), produced by the decarboxylation of thyroid hormones, act as substrates for deiodinases. To understand whether decarboxylation alters the rate and/or regioselectivity of deiodination by using synthetic deiodinase mimics, we studied the deiodination of different iodothyronamines. The triiodo derivative 3,3',5-triiodothyronamine (T3AM) is deiodinated at the inner ring by naphthyl-based deiodinase mimics, which is similar to the deiodination of 3,3',5-triiodothyronine (T3). However, T3AM under-goes much slower deiodination than T3. Detailed experimental and theoretical investigations suggest that T3AM forms a weaker halogen bond with selenium donors than T3. Kinetic studies and single-crystal X-ray structures of T3 and T3AM reveal that intermolecular I center dot center dot center dot I interactions may play an important role in deiodination. The formation of hydrogen- and halogen-bonding assemblies, which leads to the formation of a dimeric species of T3 in solution, facilitates the interactions between the selenium and iodine atoms. In contrast, T3AM, which does not have I center dot center dot I interactions, undergoes much slower deiodination.