Induction of CYP1A in the beagle dog by an inhibitor of kinase insert domain-containing receptor: differential effects in vitro and in vivo on mRNA and functional activity.

Compound I [3-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-quinolin-2-one] is a potent inhibitor of human kinase insert domain-containing receptor (KDR kinase), which is under investigation for the treatment of cancer. Bile duct-cannulated male beagle dogs were administered 6 mg/kg compound I q.d. for 14 days. There was an approximately 2.5-fold decrease in the mean plasma area under the curve of I on days 7 and 14 (approximately 11.3 microM . h), relative to day 1 (28.2 microM . h). In the dog, compound I was eliminated by metabolism, with a major pathway being aromatic hydroxylation and subsequent sulfation to form the metabolite M3. Metabolic profiling suggested that the pathway leading to the formation of the sulfated conjugate M3 was induced upon multiple dosing of I. Studies conducted in vitro suggested that CYP1A1/2 was responsible for the formation of the hydroxylated metabolite, which is sulfated to yield M3. Additional studies confirmed induction of CYP1A protein and activity in the livers of dogs treated with I. However, studies in a dog hepatocyte model of induction showed a surprising decrease both in CYP1A mRNA and enzymatic activity in the presence of I, emphasizing the need to consider the results from a variety of in vitro and in vivo studies in deriving an understanding of the metabolic fate of a drug candidate. It is concluded that the autoinduction observed after multiple treatments with compound I occurs since compound I is both an inducer and a substrate for dog CYP1A.     

Cytotoxic effects of extracts obtained from plants of the Oleaceae family: bio-guided isolation and molecular docking of new secoiridoids from Jasminum humile

ContextTraditionally, Oleaceae plants are used to treat many diseases, such as rheumatism, hypercholesterolaemia, or ulcers.ObjectivesTo investigate the cytotoxic potential of Jasminum humile L., Jasminum grandiflorum L., and Olea europaea L. (Oleaceae) extracts against selected human cancer cells lines, followed by a phytochemical investigation of the most potent one.Materials and methodsThe 95% ethanol extracts of aerial parts of three oleaceous plants were examined for their cytotoxicity against HepG-2, MCF-7, and THP-1 cell lines using MTT assay and doxorubicin (positive control). J. humile was bio-selected and submitted to bio-guided fractionation. Chromatographic workup of ethyl acetate and n-butanol fractions afforded two new compounds; 1-methoxyjasmigenin (1) and 1-methyl-9-aldojasmigenin (2), along with five known ones (3–7). Structures were unambiguously elucidated using 1D/2D NMR and ESI-HRMS. Isolated compounds were assessed for their anti-proliferative potential, and both selectivity index and statistical significance were determined. Molecular docking was conducted against the Mcl-1 receptor using (AZD5991) as a standard.ResultsJasmoside (5) was the most potent anticancer compound showing IC₅₀ values of 66.47, 41.32, and 27.59 µg/mL against HepG-2, MCF-7, and THP-1 cell lines, respectively. Moreover, isojasminin (4) exhibited IC₅₀ values of 33.49, 43.12, and 51.07 µg/mL against the same cell lines, respectively. Interestingly, 5 exhibited the highest selectivity index towards MCF-7 and THP-1, even greater than doxorubicin. Molecular docking results were in full agreement with the MTT assay and the proposed SAR.ConclusionIn this study, two new compounds were purified. The biological activity highlighted jasmoside (5) as a lead anticancer drug for further future investigation.     

Vanillin-crosslinked chitosan/ZnO nanocomposites as a drug delivery system for 5-fluorouracil: study on the release behavior via mesoporous ZrO2–Co3O4 nanoparticles modified sensor and antitumor activity

Herein, a series of vanillin-crosslinked chitosan (Vn-CS) nanocomposites (NCs) containing various contents of ZnO nanoparticles (NPs) was prepared and characterized via FTIR spectroscopy, XRD, TGA, SEM and TEM. Changing the weight% of ZnO NPs in the prepared NCs resulted in an improvement in their antibacterial activity against Gram-negative and Gram-positive bacteria strains compared with the unmodified CS, and the encapsulation efficiency of 5-fluorouracil (5-FU) was found to be in the range of 61.4–69.2%. Subsequently, the release of 5-FU was monitored utilizing the mesoporous ZrO₂–Co₃O₄ NPs modified carbon paste sensor via the square-wave adsorptive anodic stripping voltammetry (SW-AdASV) technique. Also, the release mechanism of 5-FU from each NC was studied by applying the zero-order, first-order, Hixson–Crowell and Higuchi models to the experimental results. The cytotoxicity of prepared NCs and 5-FU-encapsulated NCs was evaluated against the HePG-2, MCF-7 and HCT-116 cancer cell lines, in addition to the WI-38 and WISH normal cell lines using the MTT assay. Notably, 5-FU/CV₁₀ NC exhibited the highest antitumor activity towards all tested cancer cell lines and a moderate activity against WI-38 and WISH normal cell lines with IC₅₀ values of 28.02 ± 2.5 and 31.65 ± 2.7 μg mL⁻¹, respectively. The obtained nanocomposites exhibited suitable selectivity with minimum toxicity against normal cells.

Herein, a series of vanillin-crosslinked chitosan (Vn-CS) nanocomposites (NCs) containing various contents of ZnO nanoparticles (NPs) was prepared and characterized via FTIR spectroscopy, XRD, TGA, SEM and TEM.     

Frontostriatal functional connectivity underlies self-enhancement during social evaluation

Self-enhancement, the tendency to view oneself positively, is a pervasive social motive widely investigated in the psychological sciences. Relatively little is known about the neurocognitive mechanisms underlying this motive, specifically in social-evaluative situations. To investigate whether positive emotion regulation circuitry, circuitry involved in modulating positive affect, relates to the self-enhancement motive in social contexts, we conducted an functional magnetic resonance imaging (fMRI) study in a healthy young adult sample. We hypothesized that self-enhancement indices (state and trait self-esteem) would relate to greater functional connectivity between right ventrolateral prefrontal cortex (RVLPFC), a region implicated in emotion regulation, and the ventral striatum (VS), a region associated with reward-related affect, during a social feedback task. Following social evaluation, participants experienced stable or decreased state self-esteem. Results showed that stable state self-esteem from pre- to post-scan and higher trait self-esteem related to greater RVLPFC–VS connectivity during positive evaluation. Stable-state self-esteem also related to greater RVLPFC–VS connectivity during negative evaluation. Moreover, RVLPFC activation during all types of feedback processing and left VS activation during negative feedback processing was greater for participants with stable-state self-esteem. These findings implicate neurocognitive mechanisms underlying emotion regulation in the self-enhancement motive and highlight a pathway through which self-enhancement may restore feelings of self-worth during threatening situations.     

Thiosemicarbazide functionalized carbon quantum dots as a fluorescent probe for the determination of some oxicams: application to dosage forms and biological fluids

In this study, highly fluorescent water-soluble nitrogen and sulfur doped carbon quantum dots (N, S-CQDs) were synthesized via a one-step hydrothermal process utilizing citric acid as a carbon source and thiosemicarbazide as a sulfur and nitrogen source. The obtained N, S-CQDs exhibited an intense emission band at 415 nm (λ_ex = 345 nm). In the presence of either piroxicam, tenoxicam or lornoxicam, the emission band at 415 nm was significantly quenched which might be triggered due to destruction of the surface passivation layer of the N, S-CQDs. A linear correlation was found between the reduction in the fluorescence intensity of N, S-CQDs and the concentration of each drug in the ranges of 2.0–25.0 μM, 10.0–100.0 μM and 20.0–200.0 μM with correlation coefficients of more than 0.999 for all drugs. The detection limits were 0.49 μM, 1.58 μM and 4.63 μM for piroxicam, tenoxicam and lornoxicam, respectively. The effect of experimental parameters affecting the performance of the method was investigated and optimized. The developed sensor has the advantages of simplicity, time-saving, convenience and satisfactory selectivity for determination of the studied drugs in dosage forms with high % recoveries (98.86–101.69%). The method was extended for determination of piroxicam in spiked plasma with % recoveries ranging from 97.95–101.36%. The method was validated in accordance with International Council of Harmonization (ICH) standards, and the results obtained were compared statistically to those given by reported methods, indicating no significant differences in the level of accuracy and precision. The mechanism of the quenching process was studied and elucidated. The structure–activity relationship between the three drugs and the quenching efficiency was also studied and discussed.

Highly fluorescent nitrogen and sulfur doped carbon quantum dots were synthesized via hydrothermal process using citric acid and thiosemicarbazide. The dots had an emission band at 415 nm (λ_ex = 345 nm). The polarity of the studied drugs affects the method’s sensitivity.     

Contribution of different mechanisms to the resistance to fluoroquinolones in clinical isolates of Salmonella enterica

ObjectivesTo study the potential factors include gene mutation, efflux pump and alteration of permeability associated with quinolone-resistance of Salmonella enterica strains isolated from patients with acute gastroenteritis and to evaluate the degree of synergistic activity of efflux pump inhibitors when combined with ciprofloxacin against resistant isolates.MethodsAntimicrobial resistance patterns of fifty-eight Salmonella isolates were tested. Five isolates were selected to study the mechanism of resistance associated with quinolone group, including mutation in topoisomerase-encoding gene, altered cell permeability, and expression of an active efflux system. In addition, the combination between antibiotics and efflux pump inhibitors to overcome the microbial resistance was evaluated.ResultsFive Salmonella isolates totally resistant to all quinolones were studied. All isolates showed alterations in outer membrane proteins including disappearance of some or all of these proteins (Omp-A, Omp-C, Omp-D and Omp-F). Minimum inhibitory concentration values of ciprofloxacin were determined in the presence/absence of the efflux pump inhibitors: carbonyl cyanide m-chlorophenylhydrazone, norepinephrin and trimethoprim. Minimum inhibitory concentration values for two of the isolates were 2–4 fold lower with the addition of efflux pump inhibitors. All five Salmonella isolates were amplified for gyrA and parC genes and only two isolates were sequenced. S. Enteritidis 22 had double mutations at codon 83 and 87 in addition to three mutations at parC at codons 67, 76 and 80 whereas S. Typhimurium 57 had three mutations at codons 83, 87 and 119, but no mutations at parC.ConclusionsEfflux pump inhibitors may inhibit the major AcrAB-TolC in Salmonella efflux systems which are the major efflux pumps responsible for multidrug resistance in Gram-negative clinical isolates.