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Cucurbit[7]uril: A High-Affinity Host for Encapsulation of Amino Saccharides and Supramolecular Stabilization of Their a-Anomers in Water
No full textCucurbit[7]uril (CB[7]), an uncharged and watersoluble
macrocyclic host, binds protonated amino saccharides
(d-glucosamine, d-galactosamine, d-mannosamine and 6-
amino-6-deoxy-d-glucose) with excellent affinity (Ka=103 to
104m�1). The host–guest complexation was confirmed by NMR
spectroscopy, isothermal titration calorimetry (ITC), and
MALDI-TOF mass spectral analyses. NMR analyses revealed
that the amino saccharides, except d-mannosamine, are bound
as a-anomers within the CB[7] cavity. ITC analyses reveal that CB[7] has excellent affinity for binding amino saccharides in water. The maximum affinity was observed for d-galactosamine hydrochloride (Ka=1.6 � 104m�1). Such a strong affinity for any saccharide in water using a synthetic receptor is unprecedented, as is the supramolecular stabilization of an aanomer by the host
Quercetin Improves Behavioral Deficiencies, Restores Astrocytes and Microglia, and Reduces Serotonin Metabolism in 3-Nitropropionic Acid-Induced Rat Model of Huntington’s Disease
No full textHuntington’s disease (HD) is an autosomal dominant disorder, for which clinically available drugs offer only symptomatic relief. These prescription drugs are not free of side effects, and the patients usually suffer from anxiety and depression. We investigated quercetin,
a dietary flavonoid with free radical scavenging properties, for its beneficial potential if any, in 3-nitropropionic acid (3-NP)-induced HD in rats where both drugs were administered simultaneously
Metal free catalytic hydroboration of multiple bonds in methanol using N-heterocyclic carbenes under open atmosphere
No full textA facile method for the general synthesis of 2-arylmethylindoles has been developed through the reaction
of 2-(2-propynyl)aniline or 2-(2-propynyl)tosylanilide with aryl iodides in the presence of Pd(OAc)2, PPh3,
and DBU. 2-(2-Propynyl)tosylanilide is found to be reactive also towards electron deficient alkenes in the presence of Pd(OAc)2 and sodium iodide under an oxygen atmosphere, providing easy access to 2-vinylic indoles which possess exclusive E-stereochemistry in the side chain double bond. Operational simplicity,compatibility of the various functional groups, and ease of product formation are the hallmarks of these methods. A mechanism has been proposed to explain the product formation
Class II MHC/Peptide Interaction in Leishmania donovani Infection: Implications in Vaccine Design
No full textWe show that Leishmania donovani–infectedmacrophages (MFs) are capable of stimulatingMHC class II (MHC-II)–restricted T cells at 6 h of infection. At 48 h, infectedMFs (I-MFs) failed to stimulateMHC-II–restricted T cells but notMHC class I–restricted ones, in contrast to normalMFs. Such I-MFs could stimulate T cells at a higher Ag concentration, indicating that general Ag processing and trafficking of peptide–MHC-II complexes are not defective. Analysis of the kinetic parameters, like “kon” and “koff,” showed that
peptide–MHC-II complex formation is compromised in I-MFs comparedwith normal MFs. This indicates interference in loading of the cognate peptide to MHC-II, which may be due to the presence of a noncognate molecule. This notion received support from the finding that exposure of I-MFs to low pH or treatment with 2-(1-adamantyl)-ethanol, a molecule that favors peptide exchange, led to
T cell activation. When treated with 2-(1-adamantyl)-ethanol, splenocytes from 8 wk–infected BALB/c mice showed significantly higher antileishmanial T cell expansion in vitro compared with untreated controls. Hence, it is tempting to speculate that high, but not low, concentrations of cognate peptide may favor peptide exchange in I-MFs, leading to expansion of the antileishmanial T cell repertoire. The results suggest that a high Ag dose may overcome compromised T cell responses in visceral leishmaniasis, and this has an important implication in therapeutic vaccine desig
Elucidating the Role of WNT5A Signaling in Immune Response and Inflammation using Animal Model
No full textSeveral lines of evidence suggest that Wnt5a signaling in macrophages plays a significant role in the regulation of cytokine secretion. However, whether or how it also facilitates the coordination of immune response and inflammation that is concomitant with cytokine secretion is unclear at the cellular and molecular level. We are interested in analyzing the influence of Wnt5a signaling on macrophages, which comprise a crucial component of host immune surveillance and inflammation. Phagocytosis by macrophages is a crucial component of innate immune functions which if remains unregulated may enhance inflammation thus leading to pathological conditions. Thus we addressed if Wnt5a, a potential mediator of inflammation stimulates phagocytosis of exogenous antigens by macrophages, and analyzed its effects. In the current investigation we have demonstrated the escalating prevalence of Wnt5a expressing macrophages in the lymph nodes, with increasing inflammation. Our experimental findings, furthermore, reveal that Wnt5a stimulates phagocytosis and associated cell activation through Rac1-PI3 kinase and lipid raft dependent processes. Wnt5a mediated augmentation in phagocytosis is suppressed by blocking expression of the putative Wnt5a receptor Frizzled 5. Enhanced phagocytosis of bacteria by Wnt5a – Fz5 signaling is linked with an upsurge in pro-inflammatory cytokine secretion, but not with an increase in bacterial killing rate. Importantly, a small molecule inhibitor of Wnt production, IWP-2, which reduces secretion of functionally active Wnt5a, not only suppresses both phagocytosis and the secretion of proinflammatory
cytokines, but also accelerates the bacterial killing rate within a limited time frame
A novel chromo- and fluorogenic dual sensor for Mg2+ and Zn2+ with cell imaging possibilities and DFT studies
No full textA diformyl-p-cresol (DFC)-8-aminoquinoline based dual signaling probe was found to exhibit colorimetric
and fluorogenic properties on selective binding towards Mg2+ and Zn2+. Turn-on fluorescent enhancements (FE) as high as 40 fold and 53 fold in 9 : 1 MeCN/water (v/v) at pH 7.2 in HEPES buffer for Mg2+ and Zn2+, respectively, were observed. The binding constants determined from the fluorescence titration data are: K ¼ (1.52 � 0.21) � 105 M�1 and (9.34 � 4.0) � 103 M�2 at n ¼ 1 and 0.5, for Mg2+ and
Zn2+, respectively. The L : M binding ratios were also determined by Job's method, which support the
above findings. This is further substantiated by HRMS analysis. Due to solubility in mixed organo-aqueous
solvents as well as cell permeability it could be used for the in vitro/in vivo cell imaging of Mg2+ and Zn2+
ions with no or negligible cytotoxicity. This probe could be made selective towards Mg2+ over Zn2+ in the presence of TPEN, both under intra- and extracellular conditions and is superior to other Mg2+ probes which suffer from selectivity of Mg2+ over Ca2+ or Zn2+. Furthermore the dissociation constant (Kd ¼ 6.60 mM) of the Mg2+-(DFC-8-AQ) complex is far lower than the so far reported Mg2+ probes which fall in the mM rang
Targeting Proteins with Toxic Azo Dyes: A Microcalorimetric Characterization of the Interaction of the Food Colorant Amaranth with Serum Proteins
No full textThe interaction of amaranth with two homologous serum albumins from human and bovine (HSA and BSA) was
studied by microcalorimetry. The binding stoichiometry for the complexation of amaranth to both BSA and HSA was around 1, and the equilibrium constants were (5.79 ± 0.07) × 105 and (1.76 ± 0.05) × 105 M−1, respectively. The binding reaction to HSA at 298.15 K was driven by a large negative enthalpic contribution and a small but positive entropic contribution, while to BSA, it was entirely enthalpy-driven and the entropic contribution was unfavorable. Parsing of the standard molar Gibbs energy revealed that the complexation was dominated by non-polyelectrolytic forces. Temperature-dependent isothermal titration calorimetry
studies revealed that the enthalpic contribution increased and the entropic contribution decreased with the rise in the
temperature but the Gibbs energy change remained almost unaltered. Differential scanning calorimetry results revealed that the binding reaction stabilized the serum albumins significantly against thermal unfoldin
Anomalous altered expressions of downstream gene-targets in TP53-miRNA pathways in head and neck cancer
No full textThe prevalence of head and neck squamous cell carcinoma, HNSCC, continues to grow. Change in the expression of TP53 in HNSCC affects its downstream miRNAs and their gene targets, anomalously altering the expressions of the five genes, MEIS1, AGTR1, DTL, TYMS and BAK1. These expression alterations follow the repression of TP53 that upregulates miRNA-107, miRNA- 215, miRNA-34 b/c and miRNA-125b,
but downregulates miRNA-155. The above five so far unreported genes are the targets of these miRNAs. Meta-analyses of microarray and RNA-Seq data followed by qRT-PCR validation unravel these new ones in HNSCC. The regulatory roles of TP53 on miRNA-155 and miRNA-125b differentiate the expressions of AGTR1 and BAK1in HNSCC vis-a`-vis other carcinogenesis. Expression changes alter cell cycle regulation, angiogenic and blood cell formation, and apoptotic modes in affliction. Pathway analyses establish the resulting systems-level functional and mechanistic insights into the etiology of HNSCC
Specific Sequence of a Beta Turn in Human La Protein May Contribute to Species Specificity of Hepatitis C Virus
No full textHuman La protein is known to be an essential host factor for translation and replication of hepatitis C virus (HCV) RNA. Previously,we have demonstrated that residues responsible for interaction of human La protein with the HCV internal ribosomal entry site (IRES)around the initiator AUG within stem-loop IV form a�-turn in the RNA recognition motif (RRM) structure. In this study, sequence
alignment and mutagenesis suggest that the HCVRNA-interacting�-turn is conserved only in humans and chimpanzees, the species primarily known to be infected by HCV. A 7-mer peptide corresponding to the HCV RNA-interacting region of human La inhibits HCV translation, whereas another peptide corresponding to the mouse La sequence was unable to do so. Furthermore, IRES-mediated
translation was found to be significantly high in the presence of recombinant human La protein in vitro in rabbit reticulocyte lysate. We observed enhanced replication with HCV sub genomic and full-length replicons upon overexpression of either human La protein or a chimeric mouse La protein harboring a human La�-turn sequence in mouse cells. Taken together, our results raise the possibility of creating an immune competent HCV mouse model using human-specific cell entry factors and a humanized form of La protei
PPh3·HBr-DMSO Mediated Expedient Synthesis of g-Substituted b,g-Unsaturated a-Ketomethylthioesters and a-Bromo Enals: Application to the Synthesis of 2-Methylsulfanyl-3(2H)-furanones
No full textAn efficient chemoselective general procedure for the synthesis of g-substituted b,g-unsaturated a-ketomethylthioesters from a,b-unsaturated ketones has been
achieved through an unprecedented PPh3·HBr-DMSO mediated oxidative bromination and Kornblum oxidation sequence. The newly developed reagent system serves admirably for the synthesis of a-bromoenals from enals. Furthermore, AuCl3-catalyzed efficient access to 3(2H)-furanones from the above intermediates under extremely mild conditions are described