Novel oxazolidinone based compounds as inhibitors of aromatase and the use of the substrate-heme complex approach in the rationalisation of these compounds

The synthesis, biochemical evaluation and molecular modelling of a series of N-alkylated 4-(4(')-aminobenzyl)-2-oxazolidinones is described involving the derivatisation of the starting R- or S-enantiomer of 4-benzyl-2-oxazolidinones. The compounds were tested for human placental aromatase (AR) inhibition in vitro and were found, in general, to be more potent than the standard compound, aminoglutethimide (AG). The inhibitory activity of the compounds was rationalised through the use of the novel substrate-heme complex (SHC) approach and suggests that the S-enantiomer based compounds protrude beyond the C(13), C(17), and C(16) area of the steroid backbone, resulting in steric hindrance with the active site of AR and thus reduced inhibitory activity. The R-enantiomer based compounds do not protrude in the same area and as such are not thought to undergo any steric hindrance and in comparison to the S-enantiomer, possess greater inhibitory activity.     

Exogenous salicylic acid stimulates physiological and biochemical changes to improve growth, yield and active constituents of fennel essential oil

Fennel (Foeniculum vulgare Mill) is a high-value medicinal and essential oil bearing plant used extensively in pharmaceutical, food and cosmetic industries. A pot experiment was carried out in the natural conditions of net house to resolve whether the foliar application of salicylic acid (SA) might enhance the growth, yield and essential oil production of fennel. Plants were sprayed three times with SA. The first spray was carried out at 40?days after sowing (DAS); the second and third sprays were applied one and 2?weeks later, the plants were sprayed with deionised water (control) and different concentrations of SA (10^?5, 10^?4 and 10^?3?M). The foliar spray of SA at 10^?4?M significantly enhanced the vegetative growth (shoot and root lengths, fresh and dry weights), physiological and biochemical characteristics (chl ??a??, chl ??b??, total chlorophyll and carotenoids contents, nitrate reductase activity, carbonic anhydrase activity, leaf-N, -P and -K contents), yield characteristics (number of umbels and fruits, 1,000-seed weight and seed yield) and essential oil yield of fennel. GLC analysis revealed the significant increase in the components of essential oil, viz. trans-anethole (80.4?C84.7?%), methyl chavicol (2.3?C2.5?%) and fenchone (5.6?C7.9?%). It was concluded that foliar spray of SA at 10^?4?M might be employed for enhancing the plant growth as well as yield and quality of essential oil of fennel.     

Bio-synthesis and applications of silver nanoparticles onto cotton fabrics

Recently, biosynthesis of metal nanoparticles has drawn considerable attention due to environment-ecofriendly and sustainable methods. Herein, fungus Fusarium solani was selected as candidate for biosynthesis of silver nanoparticles (AgNPs). Factors affecting the biomass concentration, pH of the reaction medium, AgNO(3) concentration and the ratio of AgNO(3) to biomass concentration on the production of AgNPs were extensively studied. Optimum conditions for biosynthesis of AgNPs could be attained using biomass of F. solani (10g/100ml); AgNO(3) (0.078g/100ml); pH, 12; temperature, 25°C and duration, 24h. Under these conditions, the maximum concentration of well stabilized AgNPs obtained was 2000ppm with a mean diameter range of 8-15nm. Such solution is unequivocally feasible for industrial applications. A diluted solution containing 50ppm AgNPs was applied to cotton fabrics which imparts antibacterial activity to the fabric with 97% and 91% reduction of Staphylococcus aureus and Escherichia coli, respectively.     

Depolymerised carrageenan enhances physiological activities and menthol production in Mentha arvensis L.

Irradiated carrageenan (IC) could elicit plant growth promoting activities in plants. The effect of foliar spray of five concentrations of IC (20, 40, 60_, 80 and 100 mg L⁻¹) was studied on Mentha arvensis L. in terms of plant growth, physiological attributes, herbage yield and the content and yield of essential oil and its components. Un-irradiated carrageenan and deionized water had no effect on the attributes studied. GPC study revealed formation of low molecular weight fractions in irradiated samples containing less than 20,000 molecular weight oligomers which are responsible for plant growth promotion in this study. 80 mg L⁻¹ of IC was the most effective concentration which resulted in the highest values of growth attributes, herbage yield and the content and yield of essential oil and menthol content of the oil. It also improved the leaf-nutrient contents, photosynthetic rate and other physiological parameters. 100 mg L⁻¹ of IC did not further improve the attributes studied, but it was always better than the control.     

POC1A Truncation Mutation Causes a Ciliopathy in Humans Characterized by Primordial Dwarfism

Primordial dwarfism (PD) is a phenotype characterized by profound growth retardation that is prenatal in onset. Significant strides have been made in the last few years toward improved understanding of the molecular underpinning of the limited growth that characterizes the embryonic and postnatal development of PD individuals. These include impaired mitotic mechanics, abnormal IGF2 expression, perturbed DNA-damage response, defective spliceosomal machinery, and abnormal replication licensing. In three families affected by a distinct form of PD, we identified a founder truncating mutation in POC1A. This gene is one of two vertebrate paralogs of POC1, which encodes one of the most abundant proteins in the Chlamydomonas centriole proteome. Cells derived from the index individual have abnormal mitotic mechanics with multipolar spindles, in addition to clearly impaired ciliogenesis. siRNA knockdown of POC1A in fibroblast cells recapitulates this ciliogenesis defect. Our findings highlight a human ciliopathy syndrome caused by deficiency of a major centriolar protein.     

The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors

Variously substituted indolin-2-ones were synthesized and evaluated for activity against KDR, Flt-1, FGFR-1 and PDGFR. Extension at the 5-position of the oxindole ring with ethyl piperidine (compound 7i) proved to be the most beneficial for attaining both biochemical and cellular potencies. Further optimization of 7i to balance biochemical and cellular potencies with favorable ADME/ PK properties led to the identification of 8h, a compound with a clean CYP profile, acceptable pharmacokinetic and toxicity profiles, and robust efficacy in multiple xenograft tumor models.     

Mesenchymal stem cells conditioned with glucose depletion augments their ability to repair-infarcted myocardium

Mesenchymal stem cells (MSCs) are an attractive candidate for autologous cell therapy, but their ability to repair damaged myocardium is severely compromised with advanced age. Development of viable autologous cell therapy for treatment of heart failure in the elderly requires the need to address MSC ageing. In this study, MSCs from young (2 months) and aged (24 months) C57BL/6 mice were characterized for gene expression of IGF‐1, FGF‐2, VEGF, SIRT‐1, AKT, p16^INK4a, p21 and p53 along with measurements of population doubling (PD), superoxide dismutase (SOD) activity and apoptosis. Aged MSCs displayed senescent features compared with cells isolated from young animals and therefore were pre‐conditioned with glucose depletion to enhance age affected function. Pre‐conditioning of aged MSCs led to an increase in expression of IGF‐1, AKT and SIRT‐1 concomitant with enhanced viability, proliferation and delayed senescence. To determine the myocardial repair capability of pre‐conditioned aged MSCs, myocardial infarction (MI) was induced in 24 months old C57BL/6 wild type mice and GFP expressing untreated and pre‐conditioned aged MSCs were transplanted. Hearts transplanted with pre‐conditioned aged MSCs showed increased expression of paracrine factors, such as IGF‐1, FGF‐2, VEGF and SDF‐1α. This was associated with significantly improved cardiac performance as measured by dp/dt_max, dp/dt_min, LVEDP and LVDP, declined left ventricle (LV) fibrosis and apoptosis as measured by Masson's Trichrome and TUNEL assays, respectively, after 30 days of transplantation. In conclusion, pre‐conditioning of aged MSCs with glucose depletion can enhance proliferation, delay senescence and restore the ability of aged cells to repair senescent infarcted myocardium.     

Selective Cu2+ binding, redox silencing, and cytoprotective effects of the small heat shock proteins alphaA- and alphaB-crystallin

Oxidative stress and Cu²⁺ have been implicated in several neurodegenerative diseases and in cataract. Oxidative stress, as well as Cu²⁺, is also known to induce the expression of the small heat shock proteins α-crystallins. However, the role of α-crystallins in oxidative stress and in Cu²⁺-mediated processes is not clearly understood. We demonstrate using fluorescence and isothermal titration calorimetry that α-crystallins (αA- and αB-crystallin and its phosphorylation mimic, 3DαB-crystallin) bind Cu²⁺ with close to picomolar range affinity. The presence of other tested divalent cations such as Zn²⁺, Mg²⁺, and Ca²⁺ does not affect Cu²⁺ binding, indicating selectivity of the Cu²⁺-binding site(s) in α-crystallins. Cu²⁺ binding induces structural changes and increase in the hydrodynamic radii of α-crystallins. Cu²⁺ binding increases the stability of α-crystallins towards guanidinium chloride-induced unfolding. Chaperone activity of αA-crystallin increases significantly upon Cu²⁺ binding. α-Crystallins rescue amyloid beta peptide, Aβ_1-40, from Cu²⁺-induced aggregation in vitro. α-Crystallins inhibit Cu²⁺-induced oxidation of ascorbate and, hence, prevent the generation of reactive oxygen species. Interestingly, α-synuclein, a Cu²⁺-binding protein, does not inhibit this oxidation process significantly. We find that the Cu²⁺-sequestering (or redox-silencing) property of α-crystallins confers cytoprotection. To the best of our knowledge, this is the first study to reveal high affinity (close to picomolar) for Cu²⁺ binding and redox silencing of Cu²⁺ by any heat shock protein. Thus, our study ascribes a novel functional role to α-crystallins in Cu²⁺ homeostasis and helps in understanding their protective role in neurodegenerative diseases and cataract.