Toxicity Assessment of the Crude Ethanolic Pod Extract of Swartzia madagascariensis Desv. in Rats

This study assessed toxicity of the crude ethanolic pod extracts of Swartzia madagascariensis Desv in Wistar rats. Forty (40) Wistar rats aged 8–10 weeks were orally administered with crude extracts from pods of S. madagascariensis. Chemical analysis of serum and histopathology of liver and kidney from test animals were performed to determine the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine in serum. In addition, serum albumin levels were also determined. The levels of ALT, AST and creatinine were found to be high in groups treated with crude extracts compared to the control group, suggesting some damage in liver cells and kidney of treated groups of Wistar rats. The albumin levels in serum samples of crude extract treated groups were found to be low compared to control group, suggesting some leakage to the urine due to damage in the kidney. Histopathological analyses revealed damages in the liver and kidney treated with 1000 mg/kg of crude ethanolic pod extracts of Swartzia madagascariensis (CEPES) at days 2 and 14, corresponding to what was observed in the biochemical variables. The findings revealed that Swartzia madagascariensis pods are toxic once taken in large quantities (1000 mg/kg). Keywords: Toxicity, Wistar rats, Histopathology, biochemical parameter

Isolation and molecular characterization of novel glucarpidases:Enzymes to improve the antibody directed enzyme pro-drug therapy for cancer treatment

<div><p>Repeated cycles of antibody-directed enzyme pro-drug therapy (ADEPT) and the use of glucarpidase in the detoxification of cytotoxic methotrexate (MTX) are highly desirable during cancer therapy but are hampered by the induced human antibody response to glucarpidase. Novel variants of glucarpidase (formal name: carboxypeptidase G2, CPG2) with epitopes not recognized by the immune system are likely to allow repeated cycles of ADEPT for effective cancer therapy. Towards this aim, over two thousand soil samples were collected and screened for folate hydrolyzing bacteria using folate as the sole carbon source. The work led to the isolation and the characterization of three new glucarpidase producing strains, which were designated as: <i>Pseudomonas lubricans</i> strain SF168, <i>Stenotrophomonas</i> sp SA and <i>Xenophilus azovorans</i> SN213. The <i>CPG2</i> genes of <i>Xenophilus azovorans</i> SN213 (named <i>Xen CPG2</i>) and <i>Stenotrophomonas sp</i> SA (named <i>Sten CPG2</i>) were cloned and molecularly characterized. Both Xen CPG2 and Sten CPG2 share very close amino acid sequences (99%); we therefore, focused on the study of Xen CPG2. Finally, we demonstrated that a polyclonal antibody raised against our new CPG2, Xen CPG2, does not react with the CPG2 from <i>Pseudomonas sp</i>. strain RS-16 (Ps CPG2) that are currently in clinical use. The two enzymes, therefore could potentially be used consecutively in the ADEPT protocol to minimize the effect of the human antibody response that hampers current treatment with Ps CPG2. The identified novel CPG2 in this study will, therefore, pave the way for safer antibody directed enzyme pro-drug therapy for cancer treatment.</p></div

Structural and Electronic Properties of Theophylline- InP Diamantane Drug Carrier

Modeling   and simulation of nanostructure parameters of Theophylline bound with indium phosphide in diamantane structure have been performed with Gaussian 09 program. Density functional theory with hybrid B3LYP/3-21 basis sets was used to investigate the electronic and structural properties for Theophylline bound with InP diamantane nanocrystal as drug carrier. The optimized structures, total energies, energy gaps, highest occupied molecular orbital (HOMO), lowest unoccupied molecular  orbital (LUMO) energy, ionization potentials, electron affinities, chemical potential, global hardness, softness, and electrophilicity index have been investigated. Molecule has the smallest energy gap and the largest value of electrophilicity index in which this indicates that this molecule is more reactive than the others and has large chance to interact with the surrounding species in comparison with the other original Theophylline drug structure. A measure of molecular electrophilicity depends on both the chemical potential and the chemical hardness. The study suggests that the electrophilicity equalization principle is most likely to be a valid theoretical proposition, similar in nature to the electronegativity and hardness equalization principle. Indium Phosphide diamantane nanocrystal and its uses in drug-delivery are also discussed

Intracellular ROS Induction by Ag@ZnO Core–Shell Nanoparticles: Frontiers of Permanent Optically Active Holes in Breast Cancer Theranostic

In this study, we investigated whether ZnO coating on Ag nanoparticles (NPs) tunes electron flux and hole figuration at the metal–semiconductor interface under UV radiation. This effect triggers the photoactivity and generation of reactive oxygen species from Ag@ZnO NPs, which results in enhanced cytotoxic effects and apoptotic cell death in human breast cancer cells (MDA-MB231). In this context, upregulation of apoptotic cascade proteins (i.e., Bax/Bcl2 association, p53, cytochrome c, and caspase-3) along with activation of oxidative stress proteins suggested the occurrence of apoptosis by Ag@ZnO NPs in cancer cells through the mitochondrial pathway. Also, preincubation of breast cancer cells with Ag@ZnO NPs in dark conditions muted NP-related toxic effects and consequent apoptotic fate, highlighting biocompatible properties of unexcited Ag@ZnO NPs. Furthermore, the diagnostic efficacy of Ag@ZnO NPs as computed tomography (CT)/optical nanoprobes was investigated. Results confirmed the efficacy of the photoactivated system in obtaining desirable outcomes from CT/optical imaging, which represents novel theranostic NPs for simultaneous imaging and treatment of cancer

Virus-Induced Type I Interferon Deteriorates Control of Systemic Pseudomonas Aeruginosa Infection

BACKGROUND: Type I interferon (IFN-I) predisposes to bacterial superinfections, an important problem during viral infection or treatment with interferon-alpha (IFN-alpha). IFN-I-induced neutropenia is one reason for the impaired bacterial control; however there is evidence that more frequent bacterial infections during IFN-alpha-treatment occur independently of neutropenia. METHODS: We analyzed in a mouse model, whether Pseudomonas aeruginosa control is influenced by co-infection with the lymphocytic choriomeningitis virus (LCMV). Bacterial titers, numbers of neutrophils and the gene-expression of liver-lysozyme-2 were determined during a 24 hours systemic infection with P. aeruginosa in wild-type and Ifnar(-/-) mice under the influence of LCMV or poly(I:C). RESULTS: Virus-induced IFN-I impaired the control of Pseudomonas aeruginosa. This was associated with neutropenia and loss of lysozyme-2-expression in the liver, which had captured P. aeruginosa. A lower release of IFN-I by poly(I:C)-injection also impaired the bacterial control in the liver and reduced the expression of liver-lysozyme-2. Low concentration of IFN-I after infection with a virulent strain of P. aeruginosa alone impaired the bacterial control and reduced lysozyme-2-expression in the liver as well. CONCLUSION: We found that during systemic infection with P. aeruginosa Kupffer cells quickly controlled the bacteria in cooperation with neutrophils. Upon LCMV-infection this cooperation was disturbed

TEAD-YAP interaction inhibitors and MDM2 binders from DNA-encoded indole-focused Ugi-peptidomimetics

DNA-encoded combinatorial synthesis provides efficient and dense coverage of chemical space around privileged molecular structures. The indole side chain of tryptophan plays a prominent role in key, or “hot spot”, regions of protein–protein interactions. A DNA-encoded combinatorial peptoid library was designed based on the Ugi four-component reaction by employing tryptophan-mimetic indole side chains to probe the surface of target proteins. Several peptoids were synthesized on a chemically stable hexathymidine adapter oligonucleotide “hexT”, encoded by DNA sequences, and substituted by azide-alkyne cycloaddition to yield a library of 8112 molecules. Selection experiments for the tumor-relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD-YAP interaction inhibitors that perturbed the expression of a gene under the control of these Hippo pathway effectors

TEAD-YAP Interaction Inhibitors and MDM2 Binders from DNA-Encoded Indole-Focused Ugi Peptidomimetics

DNA-encoded combinatorial synthesis provides efficient and dense coverage of chemical space around privileged molecular structures. The indole side chain of tryptophan plays a prominent role in key, or “hot spot”, regions of protein–protein interactions. A DNA-encoded combinatorial peptoid library was designed based on the Ugi four-component reaction by employing tryptophan-mimetic indole side chains to probe the surface of target proteins. Several peptoids were synthesized on a chemically stable hexathymidine adapter oligonucleotide “hexT”, encoded by DNA sequences, and substituted by azide-alkyne cycloaddition to yield a library of 8112 molecules. Selection experiments for the tumor-relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD-YAP interaction inhibitors that perturbed the expression of a gene under the control of these Hippo pathway effectors

Integrated Ugi-Based Assembly of Functionally, Skeletally, and Stereochemically Diverse 1,4-Benzodiazepin-2-ones

A practical, integrated and versatile U-4CR-based assembly of 1,4-benzodiazepin-2-ones exhibiting functionally, skeletally, and stereochemically diverse substitution patterns is described. By virtue of its convergence, atom economy, and bond-forming efficiency, the methodology documented herein exemplifies the reconciliation of structural complexity and experimental simplicity in the context of medicinal chemistry projects.This work was financially supported by the Galician Government (Spain), Projects: 09CSA016234PR and GPC-2014-PG037. J.A. thanks FUNDAYACUCHO (Venezuela) for a predoctoral grant and Deputación da Coruña (Spain) for a postdoctoral research grant. A.N.-V. thanks the Spanish government for a Ramón y Cajal research contract