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A series of dual stimuli responsive synthetic polymer bioconjugate chimeric materials, poly(N-isopropylacrylamide)55-block-poly(L-histidine)n [p(NIPAM)55-b-p(His)n] (n=50, 75, 100, 125), have been synthesized by employing reversible addition-fragmentation chain transfer polymerization of NIPAM, followed by ring-opening polymerization of α-amino acid N-carboxyanhydrides. The dual stimuli responsive properties of the resulting biocompatiable and membrenolytic p(NIPAM)55-b-p(His)n polymers are investigated for their use as a stimuli responsive drug carrier for tumor targeting. Highly uniform self-assembled micelles (∼55 nm) fabricated by p(NIPAM)55-b-p(His)n polymers display sharp thermal and pH responses in aqueous media. An anticancer drug, doxorubicin (Dox), is effectively encapsulated in the micelles and the controlled Dox release is investigated in different temperature and pH conditions. Antitumor effect of the released Dox is also assessed using the HepG2 human hepatocellular carcinoma cell lines. Dox molecules released from the [p(NIPAM)55-b-p(His)n] micelles remain biologically active and have stimuli responsive capability to kill cancer cells. The self-assembling ability of these hybrid materials into uniform micelles and their efficiency to encapsulate Dox makes them a promising drug carrier to cancer cells. The new chimeric materials thus display tunable properties that can make them useful for a molecular switching device and controlled drug delivery applications needing responses to temperature and pH for the improvement of cancer chemotherapy.

Targeting protein-protein interactions, such as the HIV-1 gp120-CD4 interface, has become a cutting-edge approach in the current drug discovery scenario. Many small molecules have been developed so far as inhibitors of the interaction between CD4 and HIV-1 gp120. However, due to a variety of reasons such as solubility, drug toxicity and drug resistance, these inhibitors have failed to prove clinically useful. As such, the identification of novel compounds that bind to protein-protein interactions is still a research area of considerable interest. Here, a structure-based virtual screening approach was successfully applied with the aim of identifying novel HIV-1 entry inhibitors targeting the Phe43 pocket of HIV-1 gp120. Several compounds able to inhibit viral replication in cell culture were identified, with the best agent endowed with an EC(50) value of 0.9 μM. Inactivity of all the identified hits toward a mutant (Met475Ile) strain strongly suggests that they interact in the Phe43 cavity of gp120, as intended. Remarkably, all of these small molecules have a chemical scaffold unrelated to any known class of entry inhibitors reported thus far. Overall, our strategy led to the identification of four novel chemical scaffolds that inhibit HIV-1 replication through the destabilization of the HIV-1 gp120-CD4 interface., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We approach a green method in the production of alkylaromatic ketones over hexagonally ordered mesoporous CrSBA-15 catalysts, which were used, in green routes, in the liquid-phase oxidation of alkylaromatics. A promising chemical treatment method was used with ammonium acetate solution to remove the toxic nature of non-framework chromium oxides deposited on the surface of calcined CrSBA-15(8), and the obtained green mesoporous CrSBA-15(8) catalyst was used to find its catalytic activity while the recyclability of mesoporous CrSBA-15 catalysts was also studied. Particularly, the mesoporous CrSBA-15 catalysts synthesized with a variety of chromium contents were extensively used in the production of acetophenone (AP=O) with various reaction parameters. On the basis of all catalytic results, the mesoporous CrSBA-15(8) catalyst produced a higher selectivity of alkylaromatic ketones (76-100%) as compared to other CrSBA-15 catalysts and was found to be a highly active, recyclable and promising heterogeneous catalyst for selective synthesis of alkylaromatic ketones.

We demonstrate a much green synthesis method for highly selective synthesis of 6,8-di-t-butylated flavan (6,8-DTBF) by liquid phase alkylation of 2,4-di-t-butylphenol (2,4-DTBP) with cinnamyl alcohol (Cin-OH) over mesoporous Zn-Al-MCM-41 catalysts synthesized under direct basic hydrothermal method. The main alkylated product, 6,8-DTBF is importantly used as an intermediate in the manufacture of biosynthetic organic compounds. The recyclable mesoporous Zn-Al-MCM-41 catalysts have also been reused in this reaction to study their catalytic activities. The influences of various reaction parameters such as temperature, time, ratios of reactant (2,4-DTBP-to-Cin-OH) have been extensively investigated for the synthesis of 6,8-DTBF. In addition, dimethyl sulfoxide (DMSO) has also been used as a solvent in this catalytic reaction. The mesoporous Zn-Al-MCM-41(75) gives excellent catalytic activity with 6,8-DTBF selectivity (86.0%) and 2,4-DTBP conversion (63.1%), and these catalytic results have also compared with that obtained using other mesoporous and microporous catalysts. On the basis of catalytic activity obtained by using the all catalysts, the Zn-Al-MCM-41(75) catalyst is found to be a highly active, recyclable and eco-friendly heterogeneous catalyst in the liquid-phase alkylation of 2,4-DTBP.

The discrepancy between the X-ray and NMR structures of Mycobacterium tuberculosis peptidyl-tRNA hydrolase in relation to the functionally important plasticity of the molecule led to molecular dynamics simulations. The X-ray and the NMR studies along with the simulations indicated an inverse correlation between crowding and molecular volume. A detailed comparison of proteins for which X-ray and the NMR structures appears to confirm this correlation. In consonance with the reported results of the investigations in cellular compartments and aqueous solution, the comparison indicates that the crowding results in compaction of the molecule as well as change in its shape, which could specifically involve regions of the molecule important in function. Crowding could thus influence the action of proteins through modulation of the functionally important plasticity of the molecule.

Diabetes, obesity, and cancer affect upward of 15% of the world's population. Interestingly, all three diseases juxtapose dysregulated intracellular signaling with altered metabolic state. Exactly which genetic factors define stable metabolic set points in vivo remains poorly understood. Here, we show that hedgehog signaling rewires cellular metabolism. We identify a cilium-dependent Smo-Ca(2+)-Ampk axis that triggers rapid Warburg-like metabolic reprogramming within minutes of activation and is required for proper metabolic selectivity and flexibility. We show that Smo modulators can uncouple the Smo-Ampk axis from canonical signaling and identify cyclopamine as one of a new class of "selective partial agonists," capable of concomitant inhibition of canonical and activation of noncanonical hedgehog signaling. Intriguingly, activation of the Smo-Ampk axis in vivo drives robust insulin-independent glucose uptake in muscle and brown adipose tissue. These data identify multiple noncanonical endpoints that are pivotal for rational design of hedgehog modulators and provide a new therapeutic avenue for obesity and diabetes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Well hexagonally ordered NbSBA-15 catalysts synthesized by an efficient hydrothermal method were used, for the first time, for the selective synthesis of vitamin K(3) by liquid-phase oxidation of 2-methyl-1-naphthol (2MN1-OH) under various reaction conditions. The recyclable NbSBA-15 catalysts were also reused to find their catalytic activities. To investigate the leaching of non-framework niobium species on the surface of silica networks, the results of original and recyclable NbSBA-15 catalysts were correlated and compared. To find an optimum condition for the selective synthesis of vitamin K(3), the washed NbSBA-15(2.2pH) was extensively used in this reaction with various reaction parameters such as temperature, time and ratios of reactant (2M1N-OH to H(2)O(2)), and the obtained results were also demonstrated. Additionally, the liquid-phase oxidation of 2M1N-OH was carried out with different solvents to find the best solvent with a good catalytic activity. Based on the all catalytic studies, the vitamin K(3) selectivity (97.3%) is higher in NbSBA-15(2.2pH) than that of other NbSBA-15 catalysts, and the NbSBA-15(2.2pH) is found to be a highly active and eco-friendly heterogeneous catalyst for the selective synthesis of vitamin K(3).

The X-ray structures of new crystal forms of peptidyl-tRNA hydrolase from M. tuberculosis reported here and the results of previous X-ray studies of the enzyme from different sources provide a picture of the functionally relevant plasticity of the protein molecule. The new X-ray results confirm the connection deduced previously between the closure of the lid at the peptide-binding site and the opening of the gate that separates the peptide-binding and tRNA-binding sites. The plasticity of the molecule indicated by X-ray structures is in general agreement with that deduced from the available solution NMR results. The correlation between the lid and the gate movements is not, however, observed in the NMR structure.

Salmonella enterica serovar Enteritidis (S. Enteritidis) is a major food-borne pathogen. From a transposon insertion mutant library created previously using S. Enteritidis 10/02, one of the mutants was identified to have a 50% lethal dose (LD(50) ) at least 100 times that of the parental strain in young chicks, with an attenuation in a poorly studied gene encoding a component of pyruvate dehydrogenase, namely the aceE gene. Evaluation of the in vitro virulence characteristics of the ΔaceE∷kan mutant revealed that it was less able to invade epithelial cells, less resistant to reactive oxygen intermediate, less able to survive within a chicken macrophage cell line and had a retarded growth rate compared with the parental strain. Young chicks vaccinated with 2 × 10(9) CFU of the ΔaceE∷kan mutant were protected from the subsequent challenge of the parental strain, with the mutant colonized in the liver and spleen in a shorter time than the group infected with the parental strain. In addition, compared with the parental strain, the ΔaceE∷kan mutant did not cause persistent eggshell contamination of vaccinated hens., (© 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.)

The design, synthesis and biological evaluation of a novel series of isoindoline-based hydroxamates is described. Several analogs were shown to inhibit HDAC1 with IC(50) values in the low nanomolar range and inhibit cellular proliferation of HCT116 human colon cancer cells in the sub-micromolar range. The cellular potency of compound 17e was found to have greater in vitro anti-proliferative activity than several compounds in late stage clinical trials for the treatment of cancer. The in vitro safety profiles of selected compounds were assessed and shown to be suitable for further lead optimization., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

A series of vanadia-doped iron-oxide-pillared clays (V/Fe-PILCs) with various amounts of vanadia were prepared and their performance for the selective catalytic oxidation of H(2)S was investigated. V/Fe-PILCs were characterized using X-ray diffraction (XRD), surface area- and pore volume measurements, chemical analysis, Fourier-transform infrared (FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), and temperature-programmed reduction by H(2) (H(2)-TPR). V/Fe-PILCs showed better catalytic performance than Fe-PILC without any significant SO(2) emissions. The H(2)S conversion over V/Fe-PILCs increased with increasing vanadia content up to 7 wt.%. However, it decreased at higher vanadia loading due to the decrease in surface area and the formation of the crystalline V(2)O(5) phase. The presence of water vapor in the reactant mixture resulted in a decrease of H(2)S conversion.

The ORF3 protein of porcine circovirus type 2 (PCV2) causes apoptosis in virus-infected cells and is not essential for virus replication. The ORF3 protein plays an important role in the pathogenesis of the PCV2 infection in mouse models and SPF piglets. The ORF3 protein interacts with the porcine homologue of Pirh2 (pPirh2), a p53-induced ubiquitin-protein E3 ligase, which regulates p53 ubiquitination. Here, we present our study analyzing the details of the molecular interaction between these three factors. Our experiments, in vitro and in vivo, show that ORF3 protein competes with p53 in binding to pPirh2. The amino acid residues 20 to 65 of the ORF3 protein are essential in this competitive interaction of ORF3 protein with pPirh2 over p53. The interaction of ORF3 protein with pPirh2 also leads to an alteration in the physiological cellular localization of pPirh2 and a significant reduction in the stability of pPirh2. These events contribute to the deregulation of p53 by pPirh2, leading to increased p53 levels and apoptosis of the infected cells., (Copyright 2009 Elsevier Inc. All rights reserved.)

Porcine circovirus 2 (PCV2), open reading frame 3 (ORF3) codes a 105 amino acid protein that causes apoptosis of PCV2 infected cells. In infected cells, the ORF3 causes the accumulation of p53 by interacting with pPirh2 and possibly by disrupting the association of p53 and pPirh2 (J.Virol.81(2007)9560). Mutant PCV2 lacking the expression of ORF3 are infectious and replicate in cells in vitro, but do not cause apoptosis of the infected cells. The ORF3 of PCV2 has been shown to be involved in pathogenesis of the virus in mice model (J. Virol. 80(2006)5065). Here we report the experimental inoculation of ORF3 deficient PCV2 in its natural host, the piglets. The pathogenicity of the ORF3 deficient virus is attenuated in the piglets. The mutant virus did not cause any observable disease or perturbation of the lymphocyte count in the inoculated piglets and elicited an efficient immune response. When compared with the wildtype virus infection, the mutant virus infection was characterized by mild viremia and absence of pathological lesions. The findings highlight the role of ORF3 in the pathogenesis of PCV2 infection in its host.

The mesoporous MnSBA-15 materials with different n(Si)/n(Mn) ratios of 4, 8, 20, and 50 have been synthesized, for the first time, using manganese nitrate tetrahydrate and Pluronic 123 triblock polymer [(EO)20(PO)70(EO)20] by simply adjusting the molar ratio of water to hydrochloric acid (n(H2O)/n(HCl)) under direct hydrothermal conditions. For the effect of structural and textural properties with incorporation of manganese, the MnSBA-15 has been synthesized with different synthesis temperatures at the fixed molar ratios of n(Si)/n(Mn) = 4 and n(H2O)/n(HCl) = 295 in the synthesis gel. The hydrothermal and thermal stabilities of MnSBA-15 have also been investigated. The calcined MnSBA-15 materials prepared have been characterized by ICP-AES, XRD, N2 adsorption, ESR, FE-SEM, and TEM. The ICP-AES studies show a higher amount of manganese incorporation on the silica pore walls, as MnSBA-15 with a n(Si)/n(Mn) ratio up to 2.2 can be successfully prepared at a fixed n(H2O)/n(HCl) molar ratio of 295 by adjusting the ratios of n(Si)/n(Mn) in the synthesis gel. The structural and textural properties of calcined MnSBA-15 prepared can be found by the results of XRD and N2 adsorption. The investigation of ESR results clearly describe the effect of structure and Mn species coordination on the SBA-15 silica pore walls while the uniform pore diameter and rope-like hexagonal mesoporous structure of MnSBA-15 can be identified by TEM and FE-SEM images. With increasing synthesis temperature, an increase the unit cell parameter, pore size, and pore volume and a decrease the specific surface area and pore wall thickness of MnSBA-15 can be obviously noted by the results of XRD and N2 adsorption. The hexagonal MnSBA-15 materials prepared could be tested as catalysts in epoxidation of trans-stilbene to produce trans-stilbene oxide under various optimal conditions while their catalytic properties could also be compared to the results of MnMCM-41 and ZrMnMCM-41.

The structure and biochemical content of adult albino rat seminal vesicles, were studied, after administration of two different doses of eugenol for 10 days (0.2 and 0.3 mg/kg/day, i.m.). Marked decreases in the concentrations of nucleic acids, fructose and total protein as well as RNA/DNA ratio (61%) and protein/DNA ratio (27%) were observed. A remarkable increase in phospholipid concentration was noted with a corresponding decrease in neutral lipids. Histologically, eugenol treated animals showed degeneration of the secretory columnar cells and well developed myofibrillar connective tissues when compared to control animals.