Computational modeling and synthesis of pyridine variants of benzoyl-phenoxy-acetamide with high glioblastoma cytotoxicity and brain tumor penetration.

Glioblastomas are highly aggressive brain tumors for which therapeutic options are very limited. In a quest for new anti-glioblastoma drugs, we focused on specific structural modifications to the benzoyl-phenoxy-acetamide (BPA) structure present in a common lipid-lowering drug, fenofibrate, and in our first prototype glioblastoma drug, PP1. Here, we propose extensive computational analyses to improve the selection of the most effective glioblastoma drug candidates.

Computational modeling and synthesis of Pyridine variants of Benzoyl-Phenoxy-Acetamide with high glioblastoma cytotoxicity and brain tumor penetration.

Glioblastomas are highly aggressive brain tumors for which therapeutic options are very limited. In a quest for new anti-glioblastoma drugs, we focused on specific structural modifications of benzoyl-phenoxy-acetamide (BPA) present in a common lipid-lowering drug, fenofibrate, and in our first prototype glioblastoma drug, PP1. Here, we propose extensive computational analyses to improve selection of the most effective glioblastoma drug candidates.

STAG2 expression is associated with adverse survival outcomes and regulates cell phenotype in muscle-invasive bladder cancer.

STAG2 (Stromal Antigen 2), in healthy somatic cells, functions in sister chromatid cohesion, DNA damage repair, and genome organization, but its role in muscle invasive bladder cancer (MIBC) remains unknown. Here, using whole-exome and targeted sequencing (n=119 bladder cancer clinical samples), we found several STAG2 mutations in MIBC that correlate with loss of protein expression. The analysis of a bladder cancer tissue microarray (n=346) revealed that decreased STAG2 protein expression is associated with improved overall and progression-free survival for MIBC patients.

Double Labeling Fluorescent Immunocytochemistry.

Fluorescent immunocytochemistry is a powerful technique based on detecting antigens. It leads to discoveries in cell composition and structure as well as its functioning by expanding knowledge on colocalization between its components. The potency of this method is based on findings in the areas of specific antibodies production, fluorescent labels, and microscopy.

Towards water-soluble [60]fullerenes for the delivery of siRNA in a prostate cancer model.

This paper presents two water-soluble fullerene nanomaterials (HexakisaminoC and monoglucosamineC, which is called here JK39) that were developed and synthesized as non-viral siRNA transfection nanosystems. The developed two-step Bingel-Hirsch reaction enables the chemical modification of the fullerene scaffold with the desired bioactive fragments such as D-glucosamine while keeping the crucial positive charged ethylenediamine based malonate. The ESI-MS and C-NMR analyses of JK39 confirmed its high T symmetry, while X-ray photoelectron spectroscopy revealed the presence of nitrogen and oxygen-containing C-O or C-N bonds.

Interactions of a Water-Soluble Glycofullerene with Glucose Transporter 1. Analysis of the Cellular Effects on a Pancreatic Tumor Model.

In recent years, carbon nanomaterials have been intensively investigated for their possible applications in biomedical studies, especially as drug delivery vehicles. Several surface modifications can modulate the unique molecular structure of [60]fullerene derivatives, as well as their physicochemical properties. For this reason, covalent modifications that would enable a greater water solubilization of the fullerene buckyball have been rapidly investigated.

Lipofection-Based Delivery of DNA Vaccines.

The preventive and therapeutic potential of DNA vaccines combined with benefits of lipid-based delivery (lipofection) allow efficient nucleic acid transfer and immunization applicable in treatment of infections, cancer or autoimmune disorders. Lipofecting compositions consisting of cationic and neutral lipids can be used for both in vitro and in vivo applications and may also play the role of adjuvants. Here we describe a simple protocol of DNA vaccine carrier preparation based on cationic polyprenyl derivatives (PTAI-trimethylpolyprenylammonium iodides) and commonly used helper lipids with use of basic laboratory equipment.

Polyprenol-Based Lipofecting Agents for In Vivo Delivery of Therapeutic DNA to Treat Hypertensive Rats.

Development of efficient vectors for transfection is one of the major challenges in genetic engineering. Previous research demonstrated that cationic derivatives of polyisoprenoids (PTAI) may serve as carriers of nucleic acids. In the present study, the effectiveness of two PTAI-based formulations (PTAI-6-8 and 10-14) was investigated and compared to the commercial reagents.

Boost of serum resistance and storage stability in cationic polyprenyl-based lipofection by helper lipids compositions.

Lipofection is a widely used molecular biology technique and one of the most promising non-viral gene therapy strategies. However, one of the main drawbacks of using cationic lipids-based lipoplexes in DNA/RNA delivery is serum-associated inhibition of transfection. We have addressed this issue using PTAI (trimethylpolyprenylammonium iodides)-based lipofection model.

Exploring anticancer activity of structurally modified benzylphenoxyacetamide (BPA); I: Synthesis strategies and computational analyses of substituted BPA variants with high anti-glioblastoma potential.

Structural variations of the benzylphenoxyacetamide (BPA) molecular skeleton were explored as a viable starting point for designing new anti-glioblastoma drug candidates. Hand-to-hand computational evaluation, chemical modifications, and cell viability testing were performed to explore the importance of some of the structural properties in order to generate, retain, and improve desired anti-glioblastoma characteristics. It was demonstrated that several structural features are required to retain the anti-glioblastoma activity, including a carbonyl group of the benzophenone moiety, as well as 4'-chloro and 2,2-dimethy substituents.

Inhibition of EZH2 induces NK cell-mediated differentiation and death in muscle-invasive bladder cancer.

Lysine-specific demethylase 6A (KDM6A) and members of the Switch/Sucrose Non-Fermentable (SWI/SNF) family are known to counteract the activity of Enhancer of Zeste Homolog 2 (EZH2), which is often overexpressed and is associated with poor prognosis in muscle-invasive bladder cancer. Here we provide evidence that alterations in chromatin modifying enzymes, including KDM6A and members of the SWI/SNF complex, are frequent in muscle-invasive bladder cancer. We exploit the loss of function mutations in KDM6A and SWI/SNF complex to make bladder cancer cells susceptible to EZH2-based epigenetic therapy that activates an immune response to drive tumor cell differentiation and death.

Prolonged Idasanutlin (RG7388) Treatment Leads to the Generation of p53-Mutated Cells.

The protein p53 protects the organism against carcinogenic events by the induction of cell cycle arrest and DNA repair program upon DNA damage. Virtually all cancers inactivate p53 either by mutations/deletions of the gene or by boosting negative regulation of p53 activity. The overexpression of MDM2 protein is one of the most common mechanisms utilized by p53 cancers to keep p53 inactive.

Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer.

Aberrant DNA methylation observed in cancer can provide survival benefits to cells by silencing genes essential for anti-tumor activity. DNA-demethylating agents such as Decitabine (DAC)/Azacitidine (AZA) activate otherwise silenced tumor suppressor genes, alter immune response and epigenetically reprogram tumor cells. In this study, we show that non-cytotoxic nanomolar DAC concentrations modify the bladder cancer transcriptome to activate NOTCH1 at the mRNA and protein level, increase double-stranded RNA sensors and CK5-dependent differentiation.

Effective usage of cationic derivatives of polyprenols as carriers of DNA vaccines against influenza virus.

Background: Cationic derivatives of polyprenols (trimethylpolyprenylammonium iodides - PTAI) with variable chain length between 6 and 15 isoprene units prepared from naturally occurring poly-cis-prenols were tested as DNA vaccine carriers in chickens and mice. This study aimed to investigate if PTAI could be used as an efficient carrier of a DNA vaccine.

Methods: Several vaccine mixtures were prepared by combining different proportions of the vaccine plasmid (carrying cDNA encoding a vaccine antigen, hemagglutinin from H5N1 influenza virus) and various compositions of PTAI.

Efficient and non-toxic gene delivery by anionic lipoplexes based on polyprenyl ammonium salts and their effects on cell physiology.

Background: One of the major challenges limiting the development of gene therapy is an absence of efficient and safe gene carriers. Among the nonviral gene delivery methods, lipofection is considered as one of the most promising. In the present study, a set of cationic polyprenyl derivatives [trimethylpolyprenylammonium iodides (PTAI)] with different lengths of polyprenyl chains (from 7, 8 and 11 to 15 isoprene units) was suggested as a component of efficient DNA vehicles.

Lamellipodia and Membrane Blebs Drive Efficient Electrotactic Migration of Rat Walker Carcinosarcoma Cells WC 256.

The endogenous electric field (EF) may provide an important signal for directional cell migration during wound healing, embryonic development and cancer metastasis but the mechanism of cell electrotaxis is poorly understood. Additionally, there is no research addressing the question on the difference in electrotactic motility of cells representing various strategies of cell movement-specifically blebbing vs. lamellipodial migration.

Mechanochemical synthesis of Au, Pd, Ru and Re nanoparticles with lignin as a bio-based reducing agent and stabilizing matrix.

A versatile, low-energy and solvent-free method to access nanoparticles (NPs) of four different transition metals, based on a bottom-up mechanochemical procedure involving milling of inorganic precursors, is presented. Lignin, a biomass waste, was used effectively as a reducing agent, for the first time in a mechanochemical context, to access MNPs where M = Au, Pd, Ru, Re. A series of metal precursors was used for this reaction and their nature was shown to be integral in determining whether NPs became incorporated within the organic lignin matrix, M@lignin, or not.

Hollow iron oxide nanoshells are active and selective catalysts for the partial oxidation of styrene with molecular oxygen.

Well defined hollow iron oxide nanoshells are active, selective and recyclable catalysts for the oxidation of styrene into benzaldehyde using difficult-to-activate molecular oxygen as the sole oxidant. Using no noble metals, unprecedented conversion of 90% was maintained while high selectivity of 73% was able to be achieved.

Functional links between Snail-1 and Cx43 account for the recruitment of Cx43-positive cells into the invasive front of prostate cancer.

Suppressive function of connexin(Cx)43 in carcinogenesis was recently contested by reports that showed a multifaceted function of Cx43 in cancer progression. These studies did not attempt to model the dynamics of intratumoral heterogeneity involved in the metastatic cascade. An unorthodox look at the phenotypic heterogeneity of prostate cancer cells in vitro enabled us to identify links between Cx43 functions and Snail-1-regulated functional speciation of invasive cells.

Lovastatin-induced decrease of intracellular cholesterol level attenuates fibroblast-to-myofibroblast transition in bronchial fibroblasts derived from asthmatic patients.

Chronic inflammation of the airways and structural changes in the bronchial wall are basic hallmarks of asthma. Human bronchial fibroblasts derived from patients with diagnosed asthma display in vitro predestination towards TGF-β-induced fibroblast-to-myofibroblast transition (FMT), a key event in the bronchial wall remodelling. Statins inhibit 3-hydroxymethyl-3-glutaryl coenzyme A reductase, a key enzyme in the cholesterol synthesis pathway and are widely used as antilipidemic drugs.

DU-145 prostate carcinoma cells that selectively transmigrate narrow obstacles express elevated levels of Cx43.

The formation of aqueous intercellular channels mediating gap junctional intercellular coupling (GJIC) is a canonical function of connexins (Cx). In contrast, mechanisms of GJIC-independent involvement of connexins in cancer formation and metastasis remain a matter of debate. Because of the role of Cx43 in the determination of carcinoma cell invasive potential, we addressed the problem of the possible Cx43 involvement in early prostate cancer invasion.

New cationic polyprenyl derivative proposed as a lipofecting agent.

Cationic linear poly-cis-isoprenoid prepared from natural plant polyprenol in a mixture with dioleyl phosphatidylethanolamine was found to be an effective lipofection agent for eukaryotic cells. The transfecting activity is related to the poly-cis structure of the polyprenyl chain.