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Nuhn L.,Johannes Gutenberg University Mainz | Tomcin S.,Max Planck Institute for Polymer Research | Miyata K.,Johannes Gutenberg University Mainz | Mailander V.,Max Planck Institute for Polymer Research | And 5 more authors.
Biomacromolecules | Year: 2014

To overcome the poor pharmacokinetic conditions of short double-stranded RNA molecules in RNA interference therapies, cationic nanohydrogel particles can be considered as alternative safe and stable carriers for oligonucleotide delivery. For understanding key parameters during this process, two different types of well-defined cationic nanohydrogel particles were synthesized, which provided nearly identical physicochemical properties with regards to their material composition and resulting siRNA loading characteristics. Yet, according to the manufacturing process using amphiphilic reactive ester block copolymers of pentafluorophenyl methacrylate (PFPMA) and tri(ethylene glycol)methyl ether methacrylate (MEO3MA) with similar compositions but different molecular weights, the resulting nanohydrogel particles differed in size after cross-linking with spermine (average diameter 40 vs 100 nm). This affected their knockdown potential significantly. Only the 40 nm sized cationic nanogel particles were able to generate moderate gene knockdown levels, which lasted, however, up to 3 days. Interestingly, primary cell uptake and colocalization studies with lysosomal compartments revealed that only these small sized nanogels were able to avoid acidic compartments of endolysosomal uptake pathways, which may contribute to their knockdown ability exclusively. To that respect, this size-dependent intracellular distribution behavior may be considered as an essential key parameter for tuning the knockdown potential of siRNA nanohydrogel particles, which may further contribute to the development of advanced siRNA carrier systems with improved knockdown potential. © 2014 American Chemical Society. Source

Miyata K.,Center for Disease Biology and Integrative Medicine | Nishiyama N.,Center for Disease Biology and Integrative Medicine | Kataoka K.,Center for Disease Biology and Integrative Medicine | Kataoka K.,University of Tokyo
Bioconjugate Chemistry | Year: 2012

Herein, we report a unique technique to accelerate polymer-SNA conjugation based on copper-free click chemistry: gradual freeze-thawing of the reaction solution substantially increases the conjugation rate possibly because of the reactant concentration at the microenvironment scale. This technique was applied to the conjugation between a small interfering RNA (siRNA) and PEG in an aqueous buffer at/below room temperature. © 2012 American Chemical Society. Source

Ohsako S.,Center for Disease Biology and Integrative Medicine
Genes and Environment | Year: 2011

Many researchers propose that invisible internal alterations that occur through exposure to environmental factors during fetal or neonatal stages affect the risk of cancer, hypertension, and diabetes after maturation. Barker's hypothesis, which states that reduced fetal growth is strongly associated with metabolic syndromes including cardiovascular disease and diabetes, has now been widely accepted and expanded into the Developmental Origins of Health and Disease (DOHaD). Potential molecular mechanisms underlying this phenomenon include the alteration and persistence of epigenomic programming. Clear biochemical evidence has not yet been obtained in human studies; however, in laboratory animals, the fetal environment including physical and chemical factors altered epigenomic states such as DNA methylation and histone modification, and persistent changes affected specific gene expression regulation, resulting in disease susceptibility. Furthermore, in recent studies, environmental chemical exposure during pregnancy altered sperm DNA methylation patterns of male offspring, and the altered status and resulting phenotypes were inherited in the next generation. Challenging and eccentric studies focusing on epigenetic transgenerational effects are currently being conducted to demonstrate the existence of Lamarckian inheritance. © The Japanese Environmental Mutagen Society. Source

Dong B.,University of California at Davis | Nishimura N.,University of California at Davis | Nishimura N.,Japan National Institute of Environmental Studies | Vogel C.F.,University of California at Davis | And 3 more authors.
Biochemical Pharmacology | Year: 2010

Cyclooxygenase-2 (Cox-2) plays a critical role in TCDD-induced hydronephrosis in mouse neonates. In this study we found that induction of Cox-2 by TCDD in MMDD1, a mouse macula densa cell line, is accompanied with a rapid increase in the enzymatic activity of cytosolic phospholipase A2 (cPLA2) as well as activation of protein kinases. Calcium serves as a trigger for such an action of TCDD in this cell line. These observations indicate that the basic mode of action of TCDD to induce the rapid inflammatory response in MMDD1 is remarkably similar to those mediated by the nongenomic pathway of aryl hydrocarbon receptor (AhR) found in other types of cells. Such an action of TCDD to induce Cox-2 in MMDD1 was not affected by "DRE decoy oligonucleotides" treatment or by introduction of a mutation on the DRE site of Cox-2 promoter, suggesting that this route of action of TCDD is clearly different from that mediated by the classical genomic pathway. An in vivo study with Ahrnls mouse model has shown that TCDD-induces Cox-2 and renin expression in the kidneys of the Ahrnls mice as well as Ahr+/- mice, but not in the Ahr-/- mice, indicating that this initial action of TCDD in mouse kidney does not require the translocation of AhR into the nucleus, supporting our conclusion that induction of Cox-2 by TCDD in mouse kidney is largely mediated by the nongenomic pathway of TCDD-activated AhR. © 2009 Elsevier Inc. All rights reserved. Source

Osada K.,University of Tokyo | Yamasaki Y.,University of Tokyo | Kataoka K.,Center for Disease Biology and Integrative Medicine | Kataoka K.,University of Tokyo
Journal of the American Chemical Society | Year: 2010

Highly regulated folding of plasmid DNA (pDNA) through polyion complexation with the synthetic block catiomer, poly(ethylene glycol)-block-poly(l-lysine) (PEG-PLys), was found to occur in such a way that rod structures are formed with a quantized length of 1/2(n + 1) of the original pDNA length folding by n times. The folding process of pDNA was elucidated with regard to rigidity of the double-stranded DNA structure and topological restriction of the supercoiled closed-circular form, and a mechanism based on Eulers buckling theory was proposed. Folded pDNA exhibited higher gene expression efficiency compared to naked pDNA in a cell-free transcription/translation assay system, indicating that the packaging of pDNA into a polyion complex core surrounded by a PEG palisade is a promising strategy for constructing nonviral gene carrier systems. Extension of this finding may provide a reasonable model to further understand the packaging mechanism of supercoiled DNA structures in nature. © 2010 American Chemical Society. Source

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