Antivirulence Isoquinolone Mannosides: Optimization of the Biaryl Aglycone for FimH Lectin Binding Affinity and Efficacy in the Treatment of Chronic UTI

Uropathogenic E. coli (UPEC) employ the mannose‐binding adhesin FimH to colonize the bladder epithelium during urinary tract infection (UTI). Previously reported FimH antagonists exhibit good potency and efficacy, but low bioavailability and a short half‐life in vivo. In a rational design strategy, we obtained an X‐ray structure of lead mannosides and then designed mannosides with improved drug‐like properties. We show that cyclizing the carboxamide onto the biphenyl B‐ring aglycone of biphenyl mannosides into a fused heterocyclic ring, generates new biaryl mannosides such as isoquinolone 22 (2‐methyl‐4‐(1‐oxo‐1,2‐dihydroisoquinolin‐7‐yl)phenyl α‐d ‐mannopyranoside) with enhanced potency and in vivo efficacy resulting from increased oral bioavailability. N‐Substitution of the isoquinolone aglycone with various functionalities produced a new potent subseries of FimH antagonists. All analogues of the subseries have higher FimH binding affinity than unsubstituted lead 22 , as determined by thermal shift differential scanning fluorimetry assay. Mannosides with pyridyl substitution on the isoquinolone group inhibit bacteria‐mediated hemagglutination and prevent biofilm formation by UPEC with single‐digit nanomolar potency, which is unprecedented for any FimH antagonists or any other antivirulence compounds reported to date.     

Novel organic–inorganic composite material as a cation exchanger from a triterpenoidal system of dammar gum: synthesis,characterization and application

A pioneer study has been conducted to synthesize novel hydrogel starting from a non-cellulosic raw material, gum dammar-a triterpenoidal system, and then converting this hydrogel into an organic–inorganic composite zirconium-based ion exchanger. Gum dammar was cross-linked with polyacrylamide zirconium (IV) iodo-oxalate [Gd-cl-poly(AAm)-Zr (IV) iodo-oxalate] by incorporating inorganic precipitates into the polymeric mixture. The polymeric mixture was synthesized using gum dammar (Gd), acrylamide (AAm), N, N′-methylene-bis-acrylamide (MBA) and potassium persulphate (KPS). The reaction conditions for synthesis of hydrogel and ion exchanger such as time (120 min), temperature (70 °C), solvent (4 mL), concentration of monomer (12.97 × 10^?3 mol/L), initiator (1.48 × 10^?4 mol/L), cross-linker (4.22 × 10^?4 mol/L) and ratio of zirconium oxychloride (0.1 M), potassium iodate (0.1 M) and oxalic acid (0.1 M) in ratio 2:3:2 were optimized to obtain maximum ion exchange capacity (2.02 meq/g). The morphology and structure of hydrogel and ion exchanger were studied using FTIR, SEM, XRD and TGA/DTA/DTG. The SEM study was followed by energy dispersive spectroscopy for elemental analysis. The ion exchanger was quite stable in various acids and bases at low concentration but it completely dissolved in acids and bases at high concentrations. Distribution studies showed that the synthesized ion exchanger had high selectivity for Pb²⁺ ions. Thus, the polymeric-inorganic hybrid material showed integration of both inorganic and organic characteristics within the composite material.     

Analysis of Sub-Threshold Adiabatic Logic Model Using Junctionless MOSFET for Low Power Application

Silicon - In this paper Junctionless Double Gate MOSFET based Efficient Charge Recovery Logic (JL-ECRL) circuits have been driven in sub-threshold regime for the first time in literature to...     

Comparison of Particle Number Counts Measured with an Ink Jet Aerosol Generator and an Aerodynamic Particle Sizer

Aerodynamic particle sizer (APS) users typically calibrate the particle sizing capabilities, but not the counting efficiency upon which aerosol concentration results are based. Herein, comparisons were made between the counts provided by an ink jet aerosol generator (IJAG) with those measured by an APS. Near-monodisperse (geometric standard deviation of about 1.06) liquid or solid aerosols in the size range of 0.95 to 13.3 μm aerodynamic diameter (AD) generated with an IJAG were released into the inner inlet-tube of the APS in a manner that rendered APS wall and aspiration losses negligible. For most experiments, the IJAG generated 75 particles/s, which rate was maintained by the IJAG system through control of electrical pulses applied to its ink jet cartridge. For particles in the size range of 2–13.3 μm AD, the ratio of relative detection efficiency (ratio of the number of particles counted by the APS to the number reported as generated by the IJAG) was 99.3 ± 1.4%; however, for test particles between 0.95 and 2 μm AD, the relative detection efficiency was somewhat lower, but the drop off was less than about 2%. This slight drop off is likely associated with the light scattering detection approach and corresponding counting algorithm of the APS. Tests were conducted where the IJAG produced 7.0 μm AD particles at rates of 1 to 500 s^-1 and the results showed essentially a 1:1 correspondence between IJAG and APS counts. The presence of smaller-sized background particles did not affect the measured APS counts of larger-sized challenge particles.

Copyright 2014 American Association for Aerosol Research     

Development of topical gel containing aceclofenac-crospovidone solid dispersion by “Quality by Design (QbD)” approach

This article describes the development, optimization, and evaluation of Carbopol 940 topical gel containing aceclofenac-crospovidone (1:4) solid dispersion using “Quality by Design (QbD)” approach based on 2³ factorial design. The effect of crospovidone, tri-ethanolamine, and ethyl alcohol amount on the drug permeation profile of the topical gel containing aceclofenac-crospovidone solid dispersion was optimized by 2³ factorial design. The optimized gel showed improved permeation profile with cumulative drug permeation of 26.262 ± 2.157%, and permeation flux of 0.059 ± 0.011 μg/cm²/h. These gels were characterized by pH, viscosity, gel strength and FTIR study. The in vivo anti-inflammatory activity of the optimized gel was evaluated in rats using carrageenan-induced rat-paw oedema model and found excellent anti-inflammatory comparable with a marketed gel without producing any skin irritation.     

Gas holdup in tapered bubble column using pseudoplastic non-Newtonian liquids

Experimental studies on the gas holdup in two tapered bubble columns using non-Newtonian pseudoplastic liquid have been reported. The effects of different variables such as gas flow rate, liquid viscosity, bed height, and orifice diameter of sieve plate on gas holdup have been investigated. An empirical correlation has been developed for the prediction of the gas holdup as a function of various measurable parameters of the system. The correlation is statistically acceptable.     

The dependence of the photocatalytic activity of TiO2/carbon nanotubes nanocomposites on the modification of the carbon nanotubes

Nanostructural TiO₂/modified multi-wall carbon nanotubes photocatalysts were prepared by hydrolysis of Ti(iso-OC₃H₇)₄ providing chemical bonding of anatase TiO₂ nanoparticles onto oxidized- or amino-functionalized multi-wall carbon nanotubes (MWCNT). The processes of functionalization of the MWCNT and the deposition of TiO₂ influence the photocatalytic activity of the synthesized nanocomposites. The phase composition, crystallite size, and the structural and surface properties of the obtained TiO₂/modified-MWCNT nanocomposite were analyzed from XRD, FEG-SEM, TEM/HRTEM and FTIR data, as well low temperature N₂ adsorption. In the photocatalytic study, the TiO₂/oxidized-MWCNT catalyst showed the highest and the TiO₂/amino functionalized-MWCNT catalysts somewhat lower degradation rates, indicating that the enhancement of photocatalysis was supported by the more effective electron transfer properties of the oxygen- than amino-containing functional groups, which support the efficient charge transportation and separation of the photogenerated electron-hole pairs.     

Modulatory Effects of Biosynthesized Gold Nanoparticles Conjugated with Curcumin and Paclitaxel on Tumorigenesis and Metastatic Pathways—In Vitro and In Vivo Studies

Background: Breast cancer is the most common cancer in women globally, and diagnosing it early and finding potential drug candidates against multi-drug resistant metastatic breast cancers provide the possibilities of better treatment and extending life. Methods: The current study aimed to evaluate the synergistic anti-metastatic activity of Curcumin (Cur) and Paclitaxel (Pacli) individually, the combination of Curcumin–Paclitaxel (CP), and also in conjugation with gold nanoparticles (AuNP–Curcumin (Au-C), AuNP–Paclitaxel (Au-P), and AuNP–Curcumin–Paclitaxel (Au-CP)) in various in vitro and in vivo models. Results: The results from combination treatments of CP and Au-CP demonstrated excellent synergistic cytotoxic effects in triple-negative breast cancer cell lines (MDA MB 231 and 4T1) in in vitro and in vivo mouse models. Detailed mechanistic studies were performed that reveal that the anti-cancer effects were associated with the downregulation of the expression of VEGF, CYCLIN-D1, and STAT-3 genes and upregulation of the apoptotic Caspase-9 gene. The group of mice that received CP combination therapy (with and without gold nanoparticles) showed a significant reduction in the size of tumor when compared to the Pacli alone treatment and control groups. Conclusions: Together, the results suggest that the delivery of gold conjugated Au-CP formulations may help in modulating the outcomes of chemotherapy. The present study is well supported with observations from cell-based assays, molecular and histopathological analyses.     

Platelet Mitochondrial Bioenergetics Reprogramming in Patients with Urothelial Carcinoma

Mitochondrial bioenergetics reprogramming is an essential response of cells to stress. Platelets, an accessible source of mitochondria, have a crucial role in cancer development; however, the platelet mitochondrial function has not been studied in urothelial carcinoma (UC) patients. A total of 15 patients with UC and 15 healthy controls were included in the study. Parameters of platelet mitochondrial respiration were evaluated using the high-resolution respirometry method, and the selected antioxidant levels were determined by HPLC. In addition, oxidative stress was evaluated by the thiobarbituric acid reactive substances (TBARS) concentration in plasma. We demonstrated deficient platelet mitochondrial respiratory chain functions, oxidative phosphorylation (OXPHOS), and electron transfer (ET) capacity with complex I (CI)-linked substrates, and reduced the endogenous platelet coenzyme Q₁₀ (CoQ₁₀) concentration in UC patients. The activity of citrate synthase was decreased in UC patients vs. controls (p = 0.0191). γ-tocopherol, α-tocopherol in platelets, and β-carotene in plasma were significantly lower in UC patients (p = 0.0019; p = 0.02; p = 0.0387, respectively), whereas the plasma concentration of TBARS was increased (p = 0.0022) vs. controls. The changes in platelet mitochondrial bioenergetics are consistent with cell metabolism reprogramming in UC patients. We suppose that increased oxidative stress, decreased OXPHOS, and a reduced platelet endogenous CoQ₁₀ level can contribute to the reprogramming of platelet mitochondrial OXPHOS toward the activation of glycolysis. The impaired mitochondrial function can contribute to increased oxidative stress by triggering the reverse electron transport from the CoQ₁₀ cycle (Q-junction) to CI.