Novel thyroid hormone analogues, enzyme inhibitors and mimetics, and their action.

Thyroid hormones (THs) play key roles in modulating the overall metabolism of the body, protein synthesis, fat metabolism, neuronal and bone growth, and cardiovascular as well as renal functions. In this review, we discuss on the thyroid hormone synthesis and activation, thyroid hormone receptors (TRs) and mechanism of action, applications of thyroid hormone analogues, particularly the compounds that are selective ligands for TRβ receptors, or enzyme inhibitors for the treatment of thyroidal disorders with a specific focus on thyroid peroxidase and iodothyronine deiodinases. We also discuss on the development of small-molecule deiodinase mimetics and their mechanism of deiodination, as these compounds have the potential to regulate the thyroid hormone levels.

Synthetic (p)ppGpp Analogue Is an Inhibitor of Stringent Response in Mycobacteria.

Bacteria elicit an adaptive response against hostile conditions such as starvation and other kinds of stresses. Their ability to survive such conditions depends, in part, on stringent response pathways. (p)ppGpp, considered to be the master regulator of the stringent response, is a novel target for inhibiting the survival of bacteria.

Biochemical and structural studies of Mycobacterium smegmatis MutT1, a sanitization enzyme with unusual modes of association.

Mycobacterium smegmatis MutT1, which is made up of a Nudix domain (domain 1) and a histidine phosphatase domain (domain 2), efficiently hydrolyses 8-oxo-GTP and 8-oxo-dGTP to the corresponding nucleoside diphosphates and phosphate in the presence of magnesium ions. Domain 1 alone hydrolyses nucleoside triphosphates less efficiently. Under high concentrations and over long periods, the full-length enzyme as well as domain 1 catalyses the hydrolysis of the nucleoside triphosphates to the respective nucleoside monophosphates and pyrophosphate.

Formation of Pentosidine Cross-Linking in Myoglobin by Glyoxal: Detection of Fluorescent Advanced Glycation End Product.

Glyoxal, a reactive α-oxoaldehyde, increases in diabetic condition and reacts with proteins to form advanced glycation end products (AGEs) following Maillard-like reaction. Considering the significance of protein modification by glyoxal-derived AGEs, we investigated the in vitro effect of glyoxal (200 μM) on the monomeric heme protein myoglobin (Mb) (100 μM) after incubation for one week at 25 °C. Glyoxal-treated Mb exhibited increased absorbance around the Soret region, decreased α-helicity and thermal stability compared to control Mb.

Covariation and phenotypic integration in chemical communication displays: biosynthetic constraints and eco-evolutionary implications.

Chemical communication is ubiquitous. The identification of conserved structural elements in visual and acoustic communication is well established, but comparable information on chemical communication displays (CCDs) is lacking. We assessed the phenotypic integration of CCDs in a meta-analysis to characterize patterns of covariation in CCDs and identified functional or biosynthetically constrained modules.

Rapid sensing of melamine in milk by interference green synthesis of silver nanoparticles.

A highly sensitive, selective, and rapid interference green synthesis based determination of potential milk adulterant melamine has been reported here. Melamine is a nitrogenous compound added to milk for mimicking proteins, consumption of which leads to kidney stones and renal failures. Melamine interacts with ascorbic acid (AA) through strong hydrogen-bonding interactions, thus resulting in an interference/interruption in the formation of silver (Ag) nanoparticles which was confirmed by UV-Vis spectroscopy and Transmission Electron Microscopy (TEM).

Identification of a novel epitope in the C terminus of hepatitis C virus-E2 protein that induces potent and cross-reactive neutralizing antibodies.

Hepatitis C virus (HCV) is a leading cause of chronic viral hepatitis, but an effective vaccine is still not available to prevent infection. Use of neutralizing antibodies could be a potential therapeutic option. In this study, the presence of anti-HCV antibodies in HCV-infected patients was assessed from 50 patients and the presence of neutralizing antibodies was examined using 'hepatitis C virus-like particles'.

Enzyme activity of α-chymotrypsin: Deactivation by gold nano-cluster and reactivation by glutathione.

Effect of gold nanoclusters (Au-NCs) on the circular dichroism (CD) spectra and enzymatic activity of α-chymotrypsin (ChT) (towards hydrolysis of a substrate, N-succinyl-l-phenylalanine p-nitroanilide) are studied. The CD spectra indicate that on binding to Au-NC, ChT is completely unfolded, resulting in nearly zero ellipticity. α-chymotrypsin (ChT) coated gold nano-clusters exhibit almost no enzymatic activity.

Radical Approach to the Chiral Quaternary Center in Asperaculin A: Synthesis of 9-Deoxyasperaculin A.

Diastereoselective approaches toward the synthesis of a marine-derived sesquiterpenoid fungal metabolite, asperaculin A, are delineated, combining step economy and simplicity. Two distinct lactonization sequences from a common intermediate led to the first synthesis of 9-deoxyasperaculin A, a novel dioxa[5.5.

Regularity criterion for solutions of the three-dimensional Cahn-Hilliard-Navier-Stokes equations and associated computations.

We consider the three-dimensional (3D) Cahn-Hilliard equations coupled to, and driven by, the forced, incompressible 3D Navier-Stokes equations. The combination, known as the Cahn-Hilliard-Navier-Stokes (CHNS) equations, is used in statistical mechanics to model the motion of a binary fluid. The potential development of singularities (blow-up) in the contours of the order parameter ϕ is an open problem.

Boron Precursor-Dependent Evolution of Differently Emitting Carbon Dots.

Attention has been directed toward electron-deficient boron doping in carbon dots (CDs) with the expectation of revealing new photophysical aspects in accordance with varying amounts of boron content. It has been emphatically shown that boron uptake in CDs varies with different boron precursors evolving altered emissive CDs. Boron doping in CDs causes definite surface defect due to the generation of electron-deficient states.

Functional characterization of recombinant major envelope protein (rB2L) of orf virus.

Orf, or contagious ecthyma, a highly contagious transboundary disease of sheep and goats, is caused by a double-stranded DNA virus (ORFV) belonging to the genus Parapoxvirus of the family Poxviridae. The ORFV genome encodes the major envelope proteins B2L and F1L, which have been found to be highly immunogenic and have multiple functional characteristics. In order to investigate the functional properties of the B2L protein, in this study, the B2L gene of ORFV strain 59/05, encoding recombinant mature B2L (aa M-D), was produced as a fusion protein in Escherichia coli.

Attenuation of Mycobacterium species through direct and macrophage mediated pathway by unsymmetrical diaryl urea.

Tuberculosis is a major threat for mankind and the emergence of resistance strain of Mycobacterium tuberculosis (Mtb) against first line antibiotics makes it lethal for human civilization. In this study, we have synthesized different diaryl urea derivatives targeting the inhibition of mycolic acid biosynthesis. Among the 39 synthesized molecules, compounds 46, 57, 58 and 86 showed MIC values ≤ 10 μg/ml against H37Rv and mc6030 strains.

Design, synthesis, and characterization of (1-(4-aryl)- 1H-1,2,3-triazol-4-yl)methyl, substituted phenyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates against Mycobacterium tuberculosis.

The novel (1-(4-aryl)-1H-1,2,3-triazol-4-yl)methyl, substituted phenyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives were synthesized by the click reaction of the dihydropyrimidinones, bearing a terminal alkynyl group, with various substituted aryl azides at room temperature using a catalytic amount of Cu(OAc)2 and sodium ascorbate in a 1:2 ratio of acetone and water as a solvent. The newly synthesized compounds were characterized by a number of spectroscopic techniques, such as infrared, liquid chromatography-mass spectrometry, (1)H, and (13)C nuclear magnetic resonance along with single crystal X-ray diffraction. The current procedure for the synthesis of 1,2,3-triazole hybrids with dihydropyrimidinones is appropriate for the synthesis of a library of analogs 7a-l and the method accessible here is operationally simple and has excellent yields.

Inhibition of Mycobacterium tuberculosis dihydrodipicolinate synthase by alpha-ketopimelic acid and its other structural analogues.

The Mycobacterium tuberculosis dihydrodipicolinate synthase (Mtb-dapA) is an essential gene. Mtb-DapA catalyzes the aldol condensation between pyruvate and L-aspartate-beta-semialdehyde (ASA) to yield dihydrodipicolinate. In this work we tested the inhibitory effects of structural analogues of pyruvate on recombinant Mtb-DapA (Mtb-rDapA) using a coupled assay with recombinant dihydrodipicolinate reductase (Mtb-rDapB).

Photorelease and Cellular Delivery of Mitocurcumin from Its Cytotoxic Cobalt(III) Complex in Visible Light.

Ternary cobalt(III) complexes of curcumin (Hcur) and mitocurcumin [Hmitocur, a dicationic bis(triphenylphosphonium) derivative of curcumin] having a tetradentate phenolate-based ligand (H2L), namely, [Co(cur)(L)] (1) and [Co(mitocur)(L)]Cl2 (2), were prepared and structurally characterized, and their photoinduced cytotoxicity was studied. The diamagnetic cobalt(III) complexes show an irreversible Co(III)-Co(II) redox response and a quasireversible curcuminoid-based reduction near -1.45 and -1.

Evidence for the involvement of neuropeptide Y in the antidepressant effect of imipramine in type 2 diabetes.

Depression is a major comorbidity factor of diabetes and the outcome of one disorder influences the other. Our aim is to scrutinize the link between the two, if any. Since neuropeptide Y (NPY) system plays an important role in regulating central glucose sensing mechanisms, and also depression-related behavior, we test the involvement of NPY in the modulation of depression in type 2 diabetic mice.

Sub-50 fs excited state dynamics of 6-chloroguanine upon deep ultraviolet excitation.

The photophysical properties of natural nucleobases and their respective nucleotides are ascribed to the sub-picosecond lifetime of their first singlet states in the UV-B region (260-350 nm). Electronic transitions of the ππ* type, which are stronger than those in the UV-B region, lie at the red edge of the UV-C range (100-260 nm) in all isolated nucleobases. The lowest energetic excited states in the UV-B region of nucleobases have been investigated using a plethora of experimental and theoretical methods in gas and solution phases.

N7-(carboxymethyl)guanine-Lithium Crystalline Complex: A Bioinspired Solid Electrolyte.

Electrochemical device with components having direct significance to biological life processes is a potent futuristic strategy for the realization of all-round green and sustainable development. We present here synthesis design, structural analysis and ion transport of a novel solid organic electrolyte (G7Li), a compound reminiscent of ion channels, derived from regioisomeric N7-guanine-carboxylate conjugate and Li-ions. G7Li, with it's in-built supply of Li(+)-ions, exhibited remarkably high lithium-ion transference number (= 0.

Carbon-Nanotube-Mediated Electrochemical Transition in a Redox-Active Supramolecular Hydrogel Derived from Viologen and an l-Alanine-Based Amphiphile.

A two-component hydrogelator (16-A)2 -V(2+) , comprising an l-alanine-based amphiphile (16-A) and a redox-active viologen based partner (V(2+) ), is reported. The formation the hydrogel depended, not only on the acid-to-amine stoichiometric ratio, but on the choice of the l-amino acid group and also on the hydrocarbon chain length of the amphiphilic component. The redox responsive property and the electrochemical behavior of this two-component system were further examined by step-wise chemical and electrochemical reduction of the viologen nucleus (V(2+) /V(+) and V(+) /V(0) ).

Exquisite Modulation of the Active Site of Methanocaldococcus jannaschii Adenylosuccinate Synthetase in Forward Reaction Complexes.

In enzymes that conduct complex reactions involving several substrates and chemical transformations, the active site must reorganize at each step to complement the transition state of that chemical step. Adenylosuccinate synthetase (ADSS) utilizes a molecule each of guanosine 5'-monophosphate (GTP) and aspartate to convert inosine 5'-monophosphate (IMP) into succinyl adenosine 5'-monophosphate (sAMP) through several kinetic intermediates. Here we followed catalysis by ADSS through high-resolution vibrational spectral fingerprints of each substrate and intermediate involved in the forward reaction.

Insulin-like growth factor binding protein-2 regulates β-catenin signaling pathway in glioma cells and contributes to poor patient prognosis.

Background: Upregulation of insulin-like growth factor binding protein 2 (IGFBP-2) is often associated with aggressiveness of glioblastoma (GBM) and contributes to poor prognosis for GBM patients. In view of the regulation of β-catenin by IGFBP-2 in breast cancer and the crucial role of β-catenin pathway in glioma invasion, proliferation and maintenance of glioma stem cells, the mechanism of regulation of β-catenin by IGFBP-2, and its role in GBM prognosis was studied.

Methods: Regulation of the β-catenin pathway was studied by immunocytochemistry, Western blot analysis, luciferase assays, and real-time RT-PCR.

Approach to Merosesquiterpenes via Lewis Acid Catalyzed Nazarov-Type Cyclization: Total Synthesis of Akaol A.

A Lewis acid catalyzed Nazarov-type cyclization of arylvinylcarbinol has been developed for the asymmetric synthesis of carbotetracyclic core of merosesquiterpenes. The reaction works only in the presence of 2 mol % of Sn(OTf)2 and Bi(OTf)3 in dichloroethane under elevated temperature. The methodology offers the synthesis of a variety of enantioenriched arylvinylcarbinols from commercially available (3aR)-sclareolide 9 in six steps with an eventual concise total synthesis of marine sesquiterpene quinol, akaol A (1a).

C1, a highly potent novel curcumin derivative, binds to tubulin, disrupts microtubule network and induces apoptosis.

We have synthesized a curcumin derivative, 4-{5-(4-hydroxy-3-methoxy-phenyl)-2-[3-(4-hydroxy-3-methoxy-phenyl)-acryloyl]-3-oxo-penta-1,4-dienyl}-piperidine-1-carboxylic acid tert-butyl ester (C1) that displays much stronger antiproliferative activity against various types of cancer cells including multidrug resistance cells than curcumin. C1 depolymerized both interphase and mitotic microtubules in MCF-7 cells and also inhibited the reassembly of microtubules in these cells. C1 inhibited the polymerization of purified tubulin, disrupted the lattice structure of microtubules and suppressed their GTPase activity in vitro The compound bound to tubulin with a dissociation constant of 2.