Emerging insights into the structure and function of ionotropic glutamate delta receptors.

Glutamate delta-1 (GluD1) and delta-2 (GluD2) receptors belong to the orphan GluD subfamily of ionotropic glutamate receptors (iGluRs). GluDs were classified as ionotropic glutamate receptors based on their sequence similarity. Two decades after these GluDs were first cloned they are still considered "orphan" due to a lack of knowledge of the endogenous ligands that can activate them. Nevertheless, they are crucial for synapse formation, maturation and maintenance of CNS functions, and are implicated in multiple neuronal disorders, including schizophrenia, autism spectrum disorder and depressive disorders. Over the last decade significant discoveries have been made, include role of GluD receptors in mediating trans-synaptic interactions and their unique non-swapped architecture, which is distinct from other ionotropic glutamate receptors. Also, the prospect of GluD ionotropic activity being regulated by direct interaction with metabotropic glutamate receptors is exciting. These discoveries will likely drive the field in the future, providing direction to GluD research. LINKED ARTICLES: This article is part of a themed issue on Structure Guided Pharmacology of Membrane Proteins (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.14/issuetoc.

Role of actin cytoskeleton in the organization and function of ionotropic glutamate receptors.

Neural networks with precise connection are compulsory for learning and memory. Various cellular events occur during the genesis of dendritic spines to their maturation, synapse formation, stabilization of the synapse, and proper signal transmission. The cortical actin cytoskeleton and its multiple regulatory proteins are crucial for the above cellular events. The different types of ionotropic glutamate receptors (iGluRs) present on the postsynaptic density (PSD) are also essential for learning and memory. Interaction of the iGluRs in association of their auxiliary proteins with actin cytoskeleton regulated by actin-binding proteins (ABPs) are required for precise long-term potentiation (LTP) and long-term depression (LTD). There has been a quest to understand the mechanistic detail of synapse function involving these receptors with dynamic actin cytoskeleton. A major, emerging area of investigation is the relationship between ABPs and iGluRs in synapse development. In this review we have summarized the current understanding of iGluRs functioning with respect to the actin cytoskeleton, scaffolding proteins, and their regulators. The AMPA, NMDA, Delta and Kainate receptors need the stable underlying actin cytoskeleton to anchor through synaptic proteins for precise synapse formation. The different types of ABPs present in neurons play a critical role in dynamizing/stabilizing the actin cytoskeleton needed for iGluRs function.

Seven coordinate Co(ii) and six coordinate Ni(ii) complexes of an aromatic macrocyclic triamide ligand as paraCEST agents for MRI.

We are reporting Co(ii) and Ni(ii) complexes of a pyridine containing aromatic macrocyclic triamide ligand, 3,6,9,15-tetraazabicyclo(9.3.1)pentadeca-1(15),11,13-triene-3,6,9-triacetamide (TPTA), as paramagnetic chemical exchange saturation transfer (paraCEST) MRI contrast agents. The synthesis and characterization of TPTA and its complexes are reported. The solution chemistry and solid-state structure of Co(ii) and Ni(ii) complexes are studied. Crystallographic data show that the [Co(TPTA)]·Cl2·2H2O complex (seven-coordinate, all four N atoms of ring and three amide O atoms) has a distorted pentagonal bipyramidal geometry, however the [Ni(TPTA)Cl]·Cl·0.25H2O complex (six-coordinate, all four N atoms of the ring, one amide O and one chloride ion) adopts a distorted octahedral geometry. Notably the two pendent amide arms are not coordinated in the [Ni(TPTA)Cl]+ complex and one chloride ion fulfils its sixth coordination. The CEST effect of [Co(TPTA)]2+ and [Ni(TPTA)Cl]+ amide protons is observed at 57 ppm and 78 ppm downfield of the bulk water proton respectively in a buffer solution containing 20 mM N-(2-hydroxyethyl)piperazine-N'-ethanesulfonic acid and 100 mM NaCl at pH 7.4 at 37 °C on a 9.4 T NMR spectrometer. The effects of CEST intensity and exchange rate constant with variation of pH of the solution were studied. The CEST effect and exchange rate constant for the amide protons of the [Co(TPTA)]2+ complex have been monitored in HEPES buffer, fetal bovine serum (FBS), rabbit serum and 4% agarose gel (w/w). The stability of the [Co(TPTA)]2+ complex in aqueous solution towards oxidation was verified by cyclic voltammetry measurement. The stability of [Co(TPTA)]2+ has further been monitored in the presence of biologically relevant ions including HPO42-, CO32-, and Zn2+ and under acidic conditions.

Two new Aromatic Glycosides from a Soil Bacterium Burkholderia gladioli OR1.

Two new aromatic glycosides, named as gladioside I (1) and II (2) were isolated from the culture broth of a soil bacterium, Burkholderia gladioli OR1. Both 1 and 2 contained one unit each of rhamnose and 3-O-methyl xylose and differed from each other in the aglycone part. Compound 1 contained an aromatic aldehyde and compound 2 contained a styrylcarbamate unit as the aglycone part. The structures of 1 and 2 were elucidated by detailed spectral analysis and chemical degradation.

Formulation and characterization of benzoyl peroxide gellified emulsions.

The present investigation was carried out with the objective of formulating a gellified emulsion of benzoyl peroxide, an anti-acne agent. The formulations were prepared using four different vegetable oils, viz. almond oil, jojoba oil, sesame oil, and wheat germ oil, owing to their emollient properties. The idea was to overcome the skin irritation and dryness caused by benzoyl peroxide, making the formulation more tolerable. The gellified emulsions were characterized for their homogeneity, rheology, spreadability, drug content, and stability. In vitro permeation studies were performed to check the drug permeation through rat skin. The formulations were evaluated for their antimicrobial activity, as well as their acute skin irritation potential. The results were compared with those obtained for the marketed formulation. Later, the histopathological examination of the skin treated with various formulations was carried out. Formulation F3 was found to have caused a very mild dysplastic change to the epidermis. On the other hand, the marketed formulation led to the greatest dysplastic change. Hence, it was concluded that formulation F3, containing sesame oil (6%w/w), was the optimized formulation. It exhibited the maximum drug release and anti-microbial activity, in addition to the least skin irritation potential.

Heat stable antimicrobial activity of Burkholderia gladioli OR1 against clinical drug resistant isolates.

BACKGROUND & OBJECTIVES: Drug resistant microbes are a serious challenge to human health. During the search for novel antibiotics/inhibitors from the agricultural soil, a bacterial colony was found to inhibit the growth of clinical isolates including Staphylococcus (resistant to amikacin, ciprofloxacin, clindamycin, clinafloxacin, erythromycin, gentamicin and methicillin) and Candida (resistant to fluconazole and itraconazole). The culture was identified as Burkholderia gladioli and produced at least five different antimicrobial compounds which were highly stable at high temperature (121 o C) and in the broad pH range (3.0-11.0). We report here the antimicrobial activity of B. gladioli against drug resistant bacterial pathogens. METHODS: The bacterial culture was identified using morphological, biochemical and 16S rRNA gene sequencing techniques. The antimicrobial activity of the identified organism against a range of microbial pathogens was checked by Kirby-Bauer's disc diffusion method. The antimicrobial compounds in the cell free supernatant were chloroform-extracted and separated by thin layer chromatography (TLC). RESULTS: B. gladioli OR1 exhibited broad spectrum antimicrobial activity against drug resistant clinical isolates belonging to various genera of bacteria (Staphylococcus, Enterobacter, Enterococcus, Acinetobacter and Citrobacter) and a fungus (Candida). Based on TLC profile and bioautography studies, the chloroform extract of B. gladioli OR1 consisted of at least three anti-staphylococcal and two anti-Candida metabolites. The antimicrobial activity was heat stable (121 o C/20 min) as well as pH stable (3.0-11.0). INTERPRETATION & CONCLUSIONS: The bacterial soil isolate, B. gladioli OR1 possessed the ability to kill various drug resistant bacteria and a fungus. This organism produced many antimicrobial metabolites which might have the potential to be used as antibiotics in future.