Synthesis, biological evaluation, and molecular docking of N-{3-[3-(9-methyl-9H-carbazol-3-yl)-acryloyl]-phenyl}-benzamide/amide derivatives as xanthine oxidase and tyrosinase inhibitors

Claisen-Schmidt condensation of 3-formyl-9-methylcarbazole with various amides of 3-aminoacetophenone afforded N-{3-[3-(9-methyl-9H-carbazol-3-yl)-acryloyl]-phenyl}-benzamide/amide derivatives. All compounds were investigated for their in vitro xanthine oxidase (XO), tyrosinase and melanin production inhibitory activity. Most of the target compounds had more potent XO inhibitory activity than the standard drug (IC(50)=4.3-5.6μM). Interestingly, compound 7q bearing cyclopropyl ring was found to be the most potent inhibitor of XO (IC(50)=4.3μM). Molecular modelling study gave an insight into its binding modes with XO. Compounds 7a, 7d, 7e, 7g, and 7k were found to be potent inhibitors of tyrosinase (IC(50)=14.01-17.52μM). These results suggest the possible use of these compounds for the design and development of novel XO and tyrosinase inhibitors.     

Host plant interactions of the corn planthopper, Peregrinus maidis Ashm. (Homoptera: Delphacidae) in maize and sorghum agroecosystems

The corn planthopper, Peregrinus maidis (Ashmead) (Homoptera: Delphacidae) causes serious economic losses in corn and sorghum. The insect occurs mostly at humid low elevations in the tropics and coastal areas of subtropical and temperate regions of all continents, the Caribbean Islands, and islands in the Atlantic, Indian, and Pacific Oceans. This review provides a detailed compilation on the chronological progress made in basic and strategic aspects of research on the interactions between P. maidis and various host plants. The nature of damage by P. maidis and its economic impact, ecobiology in relation to host diversity, abiotic, and seasonal interactions; and life tables and alary polymorphism are discussed. Host plant resistance studies indicate that very few sources of resistance to P. maidis have been identified in maize, sorghum, or pearl millet, warranting a need to standardize rapid and reliable screening methods. The behavioral responses vis-à-vis mechanisms of resistance show the predominance of antixenosis for colonization and/or oviposition with variable degrees of antibiosis affecting life cycle parameters of P. maidis on maize and sorghum. The role of morphological traits, physiological mechanisms, and biochemical factors governing resistance are described. Population dynamics based on density-dependent and density-independent interactions are also discussed. In addition, aspects of P. maidis on chemical control, biological control, and trophobiosis interactions are listed. Future thrusts on research approaches are also discussed. Genetic engineering techniques involving lectin genes in the development of transgenic plants, and the molecular mapping of genes conferring resistance to both P. maidis and its transmitted virus diseases may stimulate further research and lead to better understanding of P. maidis—host plant interactions. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

NOTCH1 up-regulation and signaling involved in Mycobacterium bovis BCG-induced SOCS3 expression in macrophages

Suppressor of cytokine signaling (SOCS) 3 is a critical negative regulator of cytokine signaling and is induced by Mycobacterium bovis Bacille Calmette-Guérin (M. bovis BCG) in mouse macrophages. However, little is known about the early receptor proximal signaling mechanisms underlying mycobacteria-mediated induction of SOCS3. We demonstrate here for the first time that M. bovis BCG up-regulates NOTCH1 and activates the NOTCH1 signaling pathway, leading to the expression of SOCS3. We show that perturbing Notch signaling in infected macrophages results in the marked reduction in the expression of SOCS3. Furthermore, enforced expression of the Notch1 intracellular domain in RAW 264.7 macrophages induces the expression of SOCS3, which can be further potentiated by M. bovis BCG. The perturbation of Toll-like receptor (TLR) 2 signaling resulted in marked reduction in SOCS3 levels and expression of the NOTCH1 target gene, Hes1. The down-regulation of MyD88 resulted in a significant decrease in SOCS3 expression, implicating the role of the TLR2-MyD88 axis in M. bovis BCG-triggered signaling. However, the SOCS3 inducing ability of M. bovis BCG remains unaltered also upon infection of macrophages from TLR4-defective C3H/HeJ mice. More importantly, signaling perturbation data suggest the involvement of cross-talk among members of the phosphoinositide 3-kinase and mitogen-activated protein kinase cascades with NOTCH1 signaling in SOCS3 expression. Furthermore, SOCS3 expression requires the NOTCH1-mediated recruitment of Suppressor of Hairless (CSL) and nuclear factor-kappaB to the Socs3 promoter. Overall, these results implicate NOTCH1 signaling during inducible expression of SOCS3 following infection of macrophages with an intracellular bacillus-like M. bovis BCG.     

Studies on the efficiency of different extraction procedures on the anti microbial activity of selected medicinal plants

Many doubts still persist even today when it comes to selection of the solvents for extracting the active constituents from various Indian medicinal plants. This study was aimed at assessing and establishing the best solvent for extracting the active constituents from 10 plant extracts. Thin layer chromatography (TLC) was used to separate and establish the active constituents present in each of the medicinal plants. Active constituents from each plant were extracted by using three different solvent systems namely diethyl ether, chloroform and hexane and were tested against three species of gram negative and three species of gram positive bacteria (Escherichia coli, Pseudomonas aureginosa, Streptococcus pneumoniae, Aeromonas hydrophila, Staphylococcus aereus, Bacillus cereus) by means of agar well diffusion assay. Studies on the antioxidant activity studies were also carried out for these plant extracts by using Diphenylpicryl-hydrazyl (DPPH) method. For the antimicrobial activity, the study revealed that among the selected plants, Azadiracta indica, Pongamia pinnata, Aloe barbadensis had the maximum antibacterial activity. Among the extraction procedures diethyl ether was found to be the best solvent that could be used for the extraction procedure. On the antioxidant activity part, Coleus amboinicus and Calotropis procera were found to have high antioxidant activity of 91.64% and 88.72% respectively and the further results are reported and discussed.     

Reconstructing the ubiquitin network - cross-talk with other systems and identification of novel functions

Background  

The ubiquitin system (Ub-system) can be defined as the ensemble of components including Ub/ubiquitin-like proteins, their conjugation and deconjugation apparatus, binding partners and the proteasomal system. While several studies have concentrated on structure-function relationships and evolution of individual components of the Ub-system, a study of the system as a whole is largely lacking.     

Syncope: Assessment of risk and an approach to evaluation in the emergency department and urgent care clinic

Syncope is among the most frequent forms of transient loss of consciousness (TLOC), and is characterized by a relatively brief and self-limited loss of consciousness that by definition is triggered by transient cerebral hypoperfusion. Most often, syncope is caused by a temporary drop of systemic arterial pressure below that required to maintain cerebral function, but brief enough not to cause permanent structural brain injury. Currently, approximately one-third of syncope/collapse patients seen in the emergency department (ED) or urgent care clinic are admitted to hospital for evaluation. The primary objective of developing syncope/TLOC risk stratification schemes is to provide guidance regarding the immediate prognostic risk of syncope patients presenting to the ED or clinic; thereafter, based on that risk assessment physicians may be better equipped to determine which patients can be safely evaluated as outpatients, and which require hospital care. In general, the need for hospitalization is determined by several key issues: i) the patient''s immediate (usually considered 1 week to 1 month) mortality risk and risk for physical injury (e.g., falls risk), ii) the patient''s ability to care for him/herself, and iii) whether certain treatments inherently require in-hospital initiation (e.g., pacemaker implantation). However, at present no single risk assessment protocol appears to be satisfactory for universal application, and development of a consensus recommendation is an essential next step.     

Synthesis of new coumarin tethered isoxazolines as potential anticancer agents

A series of new coumarin tethered isoxazolines (7a-l) were synthesized and evaluated for their cytotoxic potency against human melanoma cancer cell line (UACC 903) as well as fibroblast normal cell line (FF2441). Preliminary results revealed that some of these coumarin tethered isoxazolines 7b, 7c, 7f and 7j exhibited significant antiproliferative effect against human melanoma cancer (UACC 903) with IC₅₀ values of 8.8, 10.5, 9.2 and 4.5?μM respectively. However, compound 7c was non-toxic to normal human cells at the tested concentration. Further, we have chosen compound 7c to check its efficacy in Ehrlich Ascites Carcinoma animal model in-vivo for its antitumor and antiangiogenic properties. Our lead compound significantly reduced the cell viability, body weight, ascites volume and downregulated the formation of neovasculature such as regression of tumor volume. The present study indicates the scope of developing into potent anticancer drug in near future.     

Depletion of intracellular zinc from neurons by use of an extracellular chelator in vivo and in vitro.

The membrane-impermeable chelator CaEDTA was introduced extracellularly among neurons in vivo and in vitro for the purpose of chelating extracellular Zn(2+). Unexpectedly, this treatment caused histochemically reactive Zn(2+) in intracellular compartments to drop rapidly. The same general result was seen with intravesicular Zn(2+), which fell after CaEDTA infusion into the lateral ventricle of the brain, with perikaryal Zn(2+) in Purkinje neurons (in vivo) and with cortical neurons (in vitro). These findings suggest either that the volume of zinc ion efflux and reuptake is higher than previously suspected or that EDTA can enter cells and vesicles. Caution is therefore warranted in attempting to manipulate extracellular or intracellular Zn(2+) selectively.     

Improvement of 1,3-propanediol oxidoreductase (DhaT) stability against 3-hydroxypropionaldehyde by substitution of cysteine residues

1,3-propanediol oxidoreductase (DhaT), which catalyzes the conversion of 3-hydroxypropionaldehyde (3-HPA) to 1,3-propanediol (1,3-PD) with the oxidation of NADH to NAD⁺, is a key enzyme in the production of 1,3-PD from glycerol. DhaT is known to be severely inactivated by its physiological substrate, 3-HPA, due to the reaction of 3-HPA with the thiol group of the cysteine residues. In this study, using site-directed mutagenesis, four cysteine residues in Klebsiella pneumoniae J2B DhaT were substituted to alanine, the amino acid commonly found in cysteine’s positions in other DhaT, individually and in combination. Among the total of 15 mutants developed, a double mutant (C28A_C107A) and a triple mutant (C28A_C93A_C107A) exhibited approximately 50 and 16% higher activity than the wild-type counterpart, respectively, after 1 h incubation with 10 mM 3-HPA. According to detailed kinetic studies, the double mutant had slightly better kinetic properties (V _max , K _cat , and K _m for both 3-HPA and NADH) than wild-type DhaT. This study shows that DhaT stability against 3-HPA can be increased by cysteine-residue removal, albeit to a limited extent.