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DNA topoisomerase IIα (TOP2A) plays a vital role in replication and cell division by catalytically altering DNA topology. It is a prominent target for anticancer drugs, but clinical efficacy is often compromised due to chemoresistance. In this study, we investigate the role of TOP2A O‐GlcNAcylation in breast cancer cells and patient tumor tissues. Our results demonstrate that elevated TOP2A, especially its O‐GlcNAcylation, promotes breast cancer malignant progression and resistance to adriamycin (Adm). O‐GlcNAcylation at Ser1469 enhances TOP2A chromatin DNA binding and catalytic activity, leading to resistance to Adm in breast cancer cells and xenograft models. Mechanistically, O‐GlcNAcylation‐modulated interactions between TOP2A and cell cycle regulators influence downstream gene expression and contribute to breast cancer drug resistance. These results reveal a previously unrecognized mechanistic role for TOP2A O‐GlcNAcylation in breast cancer chemotherapy resistance and provide support for targeting TOP2A O‐GlcNAcylation in cancer therapy. Synopsis: O‐GlcNAcylation at Ser1469 enhances chromatin binding and catalytic activity of TOP2A. O‐GlcNAcylation also enhances the interaction between TOP2A and cell cycle regulators, thereby playing a crucial role in breast cancer progression and Adm resistance. TOP2A can be O‐GlcNAcylated by OGT at Ser1469 in vitro and in vivo.O‐GlcNAcylation promotes TOP2A chromatin binding.TOP2A O‐GlcNAcylation elevates its DNA cleavage and decatenation activity.O‐GlcNAcylation of TOP2A drives breast cancer progression and drug resistance. [ABSTRACT FROM AUTHOR]

Breast cancer, one of the most frequently diagnosed and aggressive malignancies, is the major cause of cancer‐related death greatly threatening women health. Polypeptide N‐acetylgalactosaminyltransferase 4 (ppGalNAc‐T4), responsible for the initial step of mucin‐type O‐glycosylation, has been reported to be implicated in diverse types of human tumors. However, the biological role of ppGalNAc‐T4 in breast cancer is still undetermined. In this study, we investigate the effects and mechanism of ppGalNAc‐T4 to breast cancer cell proliferation. From analysis of high throughput RNA sequencing datasets of Gene Expression Omnibus and ArrayExpress, a positive correlation between ppGalNAc‐T4 and the recurrence‐free survival was observed in multigroup of human breast cancer datasets. Moreover, transcriptomes analysis using RNA‐sequencing in MCF7 cells revealed that cell cycle‐related genes induced the effects of ppGalNAc‐T4 on breast cancer cell proliferation. Additionally, investigations showed that ppGalNAc‐T4 impaired cell proliferation in MCF‐7 and MDA‐MB‐231 breast cells. Furthermore, our results suggested that the ppGalNAc‐T4 knockout activated Notch signaling pathway and enhanced cell proliferation. Collectively, our data indicated that ppGalNAc‐T4 affected the proliferation of human breast cancer cells, which appears to be a novel target for understanding the underlying molecular mechanism of breast cancer. [ABSTRACT FROM AUTHOR]

We report the design of bioinspired, reversible supramolecular thermoplastic elastomers (TPEs) functionalized with ureido‐cytosine (UCyt) complementary quadruple hydrogen bonding (QHB) sites. The polymer contained a soft poly(n‐butyl acrylate) central block that imparted flexibility and two external, hard nucleobase‐containing blocks that contributed to structural integrity. In addition, the hard block with pendant QHB motifs served as efficient physical crosslinks to further enhance the thermomechanical performance, where the polymer service window extended up to 30 °C higher compared to the controls that bear dimeric hydrogen bonding units. The resulting UCyt copolymers also exhibited improved surface and bulk morphology, which self‐assembled into well‐ordered lamellar microstructures. Moreover, the polymer displayed an unexpected moisture‐resistant property with less than 1 wt % equilibrium moisture uptake even at 95% relatively humidity, which presumably correlated with its well‐ordered and densely‐packed morphology facilitated by strong hydrogen bonding. Variable temperature Fourier‐transform infrared spectroscopy experiments further confirmed the thermoreversibility of hydrogen bonding, indicating melt‐processablility and recyclability of the polymer. These physical properties verified quadruple bonding dominated behavior, and structure–property–morphology relationships suggest key design parameters for future TPEs. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 13–23 ABA triblock copolymers functionalized with ureido‐cytosine (UCyt) pendant groups exhibit well‐ordered microstructures and enhanced moisture resistance compared to their cytosine‐functionalized precursors. Complementary quadruple hydrogen bonding between UCyt dimers serve as strong molecular stickers to direct self‐assembly, promoting molecular recognition, chain packing, and phase ordering of the polymers. [ABSTRACT FROM AUTHOR]

ABSTRACT: Reversible addition‐fragmentation chain transfer (RAFT) polymerization produced novel ABA triblock copolymers with associative urea sites within pendant groups in the external hard blocks. The ABA triblock copolymers served as models to study the influence of pendant hydrogen bonding on polymer physical properties and morphology. The triblock copolymers consisted of a soft central block of poly(di(ethylene glycol) methyl ether methacrylate) (polyDEGMEMA, 58 kg/mol) and hard copolymer external blocks of poly(2‐(3‐hexylureido)ethyl methacrylate‐co‐2‐(3‐phenylureido)ethyl methacrylate) (polyUrMA, 18‐116 kg/mol). Copolymerization of 2‐(3‐hexylureido)ethyl methacrylate (HUrMA) and 2‐(3‐phenylureido)ethyl methacrylate (PhUrMA) imparted tunable hard block Tg's from 69 to 134 °C. Tunable hard block Tg's afforded versatile thermomechanical properties for diverse applications. Dynamic mechanical analysis (DMA) of the triblock copolymers exhibited high modulus plateau regions (∼100 MPa) over a wide temperature range (−10 to 90 °C), which was indicative of microphase separation. Atomic force microscopy (AFM) confirmed surface microphase separation with various morphologies. Variable temperature FTIR (VT‐FTIR) revealed the presence of both monodentate and bidentate hydrogen bonding, and pendant hydrogen bonding remained as an ordered structure to higher than expected temperatures. This study presents a fundamental understanding of the influence of hydrogen bonding on polymer physical properties and reveals the response of pendant urea hydrogen bonding as a function of temperature as compared to main chain polyureas. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 1844–1852 [ABSTRACT FROM AUTHOR]

ABSTRACT: Non‐isocyanate polyurethanes (NIPU) have rapidly emerged as a sustainable, less toxic, and environmentally friendly alternative to traditional isocyanate‐based thermoplastic polyurethane (TPU) synthesis. TPU is widely used in the medical industry due to its excellent mechanical properties and elasticity. However, little work has been done to synthesize and electrospin NIPU into fibrous mats for biomedical applications. In this work, melt polymerization of a plant oil‐based cyclic carbonate monomer with polyether soft segments and various diamines yielded isocyanate‐free, segmented poly(amide hydroxyurethane)s (PAHUs). Electrospinning of segmented PAHUs afforded ductile, free‐standing fibrous mats with Young's modulus values between 7 and 8 MPa, suitable for tissue scaffold applications. PAHU fiber mats exhibited 3–4 times greater water uptake than the electrospun TPU control, demonstrating potential utility in drug delivery. Fibroblasts adhered to electrospun PAHU fibrous mats with viability values over 90% after 72‐h, validating its biocompatibility. The results highlight the high performance and potential of electrospun isocyanate‐free polyurethanes mats for biomedical application. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018, 135, 46464. [ABSTRACT FROM AUTHOR]

Caffeic acid phenethyl ester (CAPE) is the bioactive constituent of propolis from honeybee hives and is well known for its anti-inflammatory, anticarcinogenic, antioxidant, and immunomodulatory properties. Herein, we revisited the cellular mechanism underlying the diverse biological effects of CAPE. We demonstrated that XPO1/CRM1, a major nuclear export receptor, is a cellular target of CAPE. Through nuclear export functional assay, we observed a clear shift of XPO1 cargo proteins from a cytoplasmic localization to nucleus when treated with CAPE. In particular, we showed that CAPE could specifically target the non-catalytic and conserved Cys528 of XPO1 through the means of mass spectrometric analysis. In addition, we demonstrated that the mutation of Cys528 residue in XPO1 could rescue the nuclear export defects caused by CAPE. Furthermore, we performed position-restraint molecular dynamics simulation to show that the Michael acceptor moiety of CAPE is the warhead to enable covalent binding with Cys528 residue of XPO1. The covalent modulation of nuclear export by CAPE may explain its diverse biological effects. Our findings may have general implications for further investigation of CAPE and its structural analogs. [ABSTRACT FROM AUTHOR]

Adenine- and thymine-functionalized ammonium ionenes with variation in spacer lengths are successfully synthesized using the Michael addition post-polymerization functionalization. This report describes the influence of pendant spacer length on homoassociation and heteroassociation of complementary nucleobase-containing ionenes. The ionene homo­polymers and complementary blends with various spacer lengths show a single glass transition temperature. Higher glass transition temperatures are observed for the shorter-spacer ionene homopolymers and their blends. The hydrogen bonding interactions in both blends of adenine-containing ionenes (ionene-A) and thymine-containing ionenes (ionene-T) with both spacer lengths are studied using differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) spectroscopy, and atomic force microscopy (AFM). DSC analyses do not reveal hydrogen bonding interactions in the ionene blends with the shorter spacer length. In contrast, the longer spacer length ionene blends show the presence of hydrogen bonding interactions and demonstrate that homoassociation is stronger than heteroassociation. FTIR spectroscopy and AFM confirm hydrogen bonding interactions for the longer spacer ionene blends. [ABSTRACT FROM AUTHOR]

Summary. Malignant plasma cells generally grow within the bone marrow microenvironment; however, they can also grow at extramedullary sites. To identify the tumour-specific alterations required for extramedullary growth, we analysed the expression profiles of a series of plasma cell neoplasms including primary multiple myeloma (MM), plasma cell leukaemia (PCL) and extramedullary plasmacytoma (EPC). Hierarchical clustering analysis segregated the EPCs from the remaining samples, and revealed an expression pattern associated with angiogenesis in the EPCs, involving higher expression of the genes TIE2, NOTCH3 , CD31 and endoglin. Direct comparison of EPC samples with the MM samples identified 156 genes significantly upregulated and 85 genes significantly downregulated (P < 0·005, t -test) in the EPCs, including several genes involved in angiogenesis and adhesion that were upregulated (including angiopoietin 1, SPARC, Notch3 and fibronectin 1). Immunohistochemical staining demonstrated CD31 and endoglin protein expression in the EPC tumour cells, which are both angiogenesis related and could confer malignant plasma cells with the ability to grow outside the normal bone marrow environment. Defining how malignant plasma cell growth is regulated in the bone marrow versus at extramedullary sites will help to delineate the mechanisms underlying the dependence of tumour cell growth on angiogenesis and cell adhesion. [ABSTRACT FROM AUTHOR]