Both N- and C-terminal domains of galectin-9 are capable of inducing HIV reactivation despite mediating differential immunomodulatory functionalities

BackgroundThe shock-and-kill strategy for HIV cure requires the reactivation of latent HIV followed by the killing of the reactivated cellular reservoir. Galectin-9, an immunomodulatory protein, is shown to induce HIV reactivation as well as contribute to non-AIDS- and AIDS-defining events. The protein is prone to cleavage by inflammatory proteases at its linker region separating the N- and C-terminal carbohydrate-binding domains (N- and C-CRDs) which differ in their binding specificities. It is important to study the activity of its cleaved as well as uncleaved forms in mediating HIV reactivation and immunomodulation in order to understand their role in HIV pathogenesis and their further utilization for the shock-and-kill strategy.MethodologyThe PBMCs of HIV patients on virally suppressive ART (n = 11) were stimulated using 350 nM of the full-length protein and N- and C-CRDs of Gal-9. HIV reactivation was determined by analyzing gag RNA copies using qPCR using isolated CD4 cells and intracellular P24 staining of PBMCs by flow cytometry. Cytokine responses induced by the full-length protein and N- and C-CRDs of Gal-9 were also assessed by flow cytometry, Luminex, and gene expression assays. Changes in T helper cell gene expression pattern after the stimulation were also determined by real-time PCR array.ResultsBoth N- and C-CRDs of galectin-9 induced HIV reactivation in addition to the full-length galectin-9 protein. The two domains elicited higher cytokine responses than the full-length protein, possibly capable of mediating higher perturbations in the immune system if used for HIV reactivation. N-CRD was found to induce the development of Treg cells, whereas C-CRD inhibited the induction of Treg cells. Despite this, both domains elicited IL-10 secretory response although targeting different CD4 cell phenotypes.ConclusionN- and C-CRDs were found to induce HIV reactivation similar to that of the full-length protein, indicating their possible usefulness in the shock-and-kill strategy. The study indicated an anti-inflammatory role of N-CRD versus the proinflammatory properties of C-CRD of galectin-9 in HIV infection

Synthesis and QSAR analysis of oxazolo/thiazolo pyrimidine derivatives as potential antibacterial agents

Development of new antibacterial agents is increasingly important due to the resistance of microbes to the known antibacterial drugs. A series of benzylidene oxazolo/thiazolo (3,2-a)-pyrimidine-6- carboxamides were synthesized by condensing 2-oxo/thioxo-1,2,3,4-tetrahydropyrimidine carboxamides with various aromatic aldehydes. The structures of newly synthesized compounds were characterized by IR and NMR spectral data. All the compounds were screened for their antibacterial activity against Gram-positive and Gram-negative bacteria and MIC values were determined by serial dilution method. The 2D-QSAR studies were performed on VLife MDS software. QSAR equation revealed that selected physicochemical parameters such as Alignment Independent, Electrostatic and 2PathCount have correlation with antibacterial activity. Among synthesized benzylidene oxazolo or thiazolo (3,2-a) pyrimidine-6- carboxamide derivatives, compounds containing electron withdrawing polar group at para position of 5- phenyl ring and electron withdrawing non-polar group at para position of 2-benzylidene moiety of thiazolopyrimidine nucleus are better antibacterials.Colegio de Farmacéuticos de la Provincia de Buenos Aire

QSAR analysis of structurally similar antitubercular isatin analogues

A series of structurally similar isatin analogues with antitubercular activity have been subjected for 2D and 3D QSAR analysis using V life MDS 3.5 software. The compounds were divided into training and test set of 44 and 11 each. Best QSAR models were selected on the basis of various statistical parameters like square correlation coefficient (2 ), cross validated square correlation coefficient (q2 ), standard error of estimation (SE) and sequential Fischer test (F). QSAR studies reveals that new isatin analogues with less bulky substitution on nitrogen of first position and at third position electropositive side chain of optimum four atoms length whose terminal atom is substituted with aromatic system bearing polar group may be better antitubercular agents.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Synthesis, spectroscopy, thermal and X-structure studies of a seven coordinated hydrated Ca(II)-<i>para</i>-nitrobenzoate complex showing mono and bidentate carboxylate ligation^ψ

2392-2399The reaction of CaCo3 with 4-nitrobenzoic acid (4-nhaH) results in the formation of a seven coordinated Ca (II) complex [Ca(H2O)4(4-nba)2] 1, (4-nba being 4-nitrobenzoate). The compound has been characterized by elemental analysis, IR and UV-Vis spectra and its structure determined. The complex can be dehydrated to the corresponding anhydrous Ca(II)bis-4-nitrobenzoate Ca(4-nba)2 2, and the anhydrous complex thus formed can he rehydrated as evidenced by IR spectra. The structure of 1 exhibits both monodentate and bidentate carboxylate ligation of the 4-nitrobenzoate ligand. The coordination by the O atom from four water molecules completes the heptacoordination around Ca(II). The free O atoms of the monodentate 4-nba and one of the coordinated O atom of the bidentate 4-nba in 1 are linked via H-bonding to one of the coordinated waters of a neighbouring Ca(II) resulting in the formation of psuedo dimers. The dimers thus formed are further linked with the aid of II bonds, along a as well as b resulting in the formation of an intricate supramolecular network

On the distorted {NiN₆} octahedron in hexakis(imidazole)nickel(II) bis(4-nitrobenzoate) dihydrate

181-188The reaction of [Ni(H₂O)₆]Cl₂ with the sodium salt of 4-nitrobenzoic acid (4-nbaH) in the presence of imidazole results in the formation of the title compound hexakis(imidazole)nickel(II) bis(4-nitrobenzoate) dihydrate (1). Compound (1) is dehydrated to hexakis(imidazole)nickel(II) bis(4-nitrobenzoate) (2) by heating at 100oC. Both compounds are characterized by elemental analysis, infrared spectra, X-ray powder pattern and thermal studies. The title compound [Ni(Im)₆](4-nba)₂.2H₂O (1) crystallizes in the centrosymmetric triclinic space group P₁⁻ with the Ni(II) situated on an inversion center. The structure of (1) consists of a distorted octahedral hexakis(imidazole)nickel(II) cation, a free uncoordinated 4-nba anion and a lattice water with half of the molecule accounting for the asymmetric unit. In the complex cation the central metal is bonded to six neutral terminal Im ligands. The distortion of the {NiN6}octahedron in (1) is discussed in terms of the difference between the longest and shortest Ni-N bonds. A comparative study of several [Ni(Im)6]2+ compounds in different structural environments is described. In the crystal structure, the cation, anion and lattice water are linked by three types of H-bonding interactions comprising two O-H•••O, three N-H•••O and three C-H•••O interactions. Each hexacoordinated Ni(II) complex cation is linked to eight symmetry related 4-nba anions and four different lattice water molecules via N-H•••O and C-H•••O interactions, while each 4-nba anion is H-bonded to four complex cations and two symmetry related lattice water molecules. Pairs of [Ni(Im)₆]²⁺ cations and 4-nba anions are linked to lattice water molecules via O-H•••O and C-H•••O interactions. As a result of the hydrogen bonding interactions, the cations and anions are organized into alternating layers

Tyrosinase Inhibitory Activity, 3D QSAR, and Molecular Docking Study of 2,5-Disubstituted-1,3,4-Oxadiazoles

In continuation with our research program, in search of potent enzyme tyrosinase inhibitor, a series of synthesized 2,5-disubstituted 1,3,4-oxadiazoles have been evaluated for enzyme tyrosinase inhibitory activity. Subsequently, 3D QSAR and docking studies were performed to find optimum structural requirements for potent enzyme tyrosinase inhibitor from this series. The synthesized 20 compounds of 2,5-disubstituted-1,3,4-oxadiazole series were screened for mushroom tyrosinase inhibitory activity at various concentrations by enzyme inhibition assay. The percentage enzyme inhibition was calculated by recording absorbance at 492 nm with microplate reader. 3D QSAR and docking studies were performed using VLife MDS 3.5 software. In the series 2,5-disubstituted-1,3,4-oxadiazoles enzyme tyrosinase inhibitory activity was found to be dose dependent with maximum activity for compounds 4c, 4h, 4m, and 4r. 3D QSAR and docking studies revealed that more electropositive and less bulky substituents if placed on 1,3,4-oxadiazole nucleus may result in better tyrosinase inhibitory activity in the series

Bio-functionalized carbon dots for signaling immuno-reaction of carcinoembryonic antigen in an electrochemical biosensor for cancer biomarker detection

Abstract Early diagnosis of cancer demands sensitive and accurate detection of cancer biomarkers in blood. Carbon dots (CDs) bio-functionalization with antibodies, peptides or aptamers have played significant role in cancer diagnosis and targeted cancer therapy. Herein, a biosensor for detection of cancer biomarker carcinoembryonic antigen (CEA) in blood serum has been designed using CDs bio-functionalized with HRP-conjugated CEA antibody (CUCDs@CEAAb2) as detection probe. CDs were synthesized by upscaling of cow urine, a nitrogen rich biomass waste, by hydrothermal method. Detection probe based on CDs resulted in 3.5 times higher sensitivity as compared to conventional electrochemical sandwich immunoassay. To further improve the sensor performance, hyper-branched polyethylenimine grafted poly amino aniline (PEI-g-PAANI) was used as the sensing interface, which enabled immobilization of higher amount of capture antibody. Detection of CEA in human blood serum coupled with wide linear range (0.5–50 ng/ml), good specificity, stability, reproducibility and low detection limit (10 pg/ml) signified the excellence of CUCDs based CEA immunosensor. CUCDs exhibited excitation wavelength dependent fluorescence property and showed strong blue emission under UV irradiation. MTT assay indicated that the material is not toxic towards human dental pulp stem cells (hDPSCs) and MG63 osteosarcoma cells (cell viability > 90%). The present study demonstrates a methodology for valorization of animal waste to a cost-effective carbon based functional nanomaterial for clinical detection of cancer biomarkers

Targeting PPAR-gamma to design and synthesize antidiabetic thiazolidines

A series of thiazolidine derivatives were designed by docking into PPAR-γ active site. The structure of target was obtained from the protein data bank (PDB ID P37231). A library of 200 molecules was prepared on random basis. Molecular docking studies were performed using VLife MDS 4.3 software. After molecular docking studies, the 4-substituted-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid N-[4-(2,4-dioxo-thiazolidin-5- ylidenemethyl)-phenyl]-hydrazides (4a-4h) were selected for synthesis. The progress of reaction and purity of the synthesized compounds were monitored by TLC and melting point. Structures of title compounds were confirmed by elemental analysis, IR, 1H NMR and mass spectral data. The antidiabetic activity of title compounds was performed using the Wistar rats by alloxan-induced method. The compounds have shown antidiabetic activity comparable with the standard drug pioglitazone. These findings suggest that potent antidiabetics can be generated by substituting nonpolar, electron withdrawing substituents at the fourth position of pyrimidine skeleton and hydrogen bond acceptor at the nitrogen of the thiazolidine nucleus, to inhibit peroxisome proliferator-activated receptor-γ