3-deazaneplanocin A (3-DZNeP) has been used as an inhibitor of enhancer of zeste homolog 2 (EZH2). Here, we explore the role and underlying mechanisms action of 3-DZNeP in abrogating cisplatin nephrotoxicity. Exposure of cultured mouse renal proximal tubular epithelial cells (mTECs) to cisplatin resulted in dose and time-dependent cleavage of caspase-3, decrease of cell viability, and increase of histone H3 lysine 27 trimethylation (H3K27me3), whereas expression levels of EZH2, a major methyltransferase of H3K27me3, were not affected. Treatment with 3-DZNeP significantly inhibited cisplatin-induced activation of caspase-3, apoptosis, loss of cell viability but did not alter levels of EZH2 and H3K27me3 in cultured mTECs. 3-DZNeP treatment did not affect activation of extracellular signal-regulated kinase (ERK) 1/2, p38 or c-Jun N-terminal kinases (JNK) 1/2, which contribute to renal epithelial cell death, but caused dose-dependent restoration of E-cadherin in mTECs exposed to cisplatin. Silencing of E-cadherin expression by siRNA abolished the cytoprotective effects of 3-DZNeP. In contrast, 3-DZNeP treatment potentiated the cytotoxic effect of cisplatin in H1299, a non-small cell lung cancer cell line that expresses lower E-cadherin levels. Finally, administration of 3-DZNeP attenuated renal dysfunction, morphological damage, and renal tubular cell death, which was accompanied by E-cadherin preservation, in a mouse model of cisplatin nephrotoxicity. Overall, these data indicate that 3-DZNeP suppresses cisplatin-induced tubular epithelial cell apoptosis and acute kidney injury via an E-cadherin-dependent mechanism, and suggest that combined application of 3-DZNeP with cisplatin would be a novel chemotherapeutic strategy that enhances the anti-tumor effect of cisplatin and reduces its nephrotoxicity.

The copolymers of 2-methylene-1,3-dioxepane (MDO) and N-phenyl maleimide (NPM) prepared by radical polymerization with high thermal stability, glass transition temperature and optical transparency are presented. The polymers made under specific reaction conditions, i.e., 120°C and high amounts of MDO, had degradable ester units, which were formed via radical ring-opening polymerization of MDO. The formation of charge-transfer complex between MDO and NPM also led to the formation of high-molar-mass copolymers by simple mixing and heating of monomers without the use of any initiator. Structural characterization of the copolymers including mechanistic studies was carried out using nuclear magnetic resonance spectroscopy, and their thermal properties were studied using differential scanning calorimetry and thermogravimetric analysis.

A designed 3,4-dihydroxyphenylalanine (DOPA) mimetic enzymatic degradable synthetic adhesive with good adhesion to soft tissue and metals made by a simple two-step reaction is presented in this article. This adhesive has degradable polycaprolactone-type of repeat units together with glycidyl methacrylate (GMA) and oligo(ethylene glycol) methacrylate (OEGMA) on the polymer backbone. Radical initiated copolymerization of 2-methylene-1,3-dioxepane (MDO), glycidyl methacrylate (GMA) and OEGMA followed by immobilization of catechol group on epoxy rings of GMA provided the adhesive material. Fe(acac) 3 was proved to be the most effective cross-linking agent with lap shear strength of 13.13 ± 1.74 kPa and 218.4 ± 16.0 kPa on soft tissue (porcine skin) and metal (aluminum), respectively. The cross-linked adhesive showed good adhesion stability in pH 7 PBS buffer at 37 °C for at least 1 week. Because of the high adhesive strength, enzymatic degradability, and low toxicity, the material is a promising candidate for future studies as medical glue.

A new route for the preparation of enzymatically degradable amphiphilic conetworks (APCNs) based on unsaturated polyesters by radical ring-opening copolymerization of vinylcyclopropane (VCP) with cyclic ketene acetal (CKA) is presented in this article. In the first step, the unsaturated biodegradable polyesters with random distribution of cross-linkable double bonds and degradable ester units were prepared by radical ring-opening copolymerization of VCP and CKA such as 2-methylene-4-phenyl-1,3-dioxolane (MPDO). Very similar reactivity ratios (r VCP = 0.23 ± 0.08 and r MPDO = 0.18 ± 0.02), unimodal gel permeation chromatography (GPC) curves and 2D NMR technique (heteronuclear multiple bond correlation, HMBC) showed the formation of random copolymers with unsaturation and ester units. The unsaturated units were used for cross-linking by radical polymerization with a hydrophilic macromonomer (oligo (ethylene glycol) methacrylate, OEGMA) in a second step for the formation of enzymatically degradable amphiphilic conetworks (APCNs). Enzymatic degradability was studied using Lipase from Pseudomonas cepacia. Due to the hydrophilic (HI) and hydrophobic (HO) microphase separation, the APCNs showed swelling in both water and organic solvents with different optical properties. The method provides an interesting route for making functional biodegradable APCNs using radical chemistry in the future by choosing appropriate vinyl comonomers. † Electronic supplementary information (ESI) available: Homopolymerization and characterization of VCP and reactivity ratio calculations. See