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Gene Therapy and Small Molecules Used in the Treatment of Cystic Fibrosis
Published in Yashwant Pathak, Gene Delivery, 2022
Manish P. Patel, Uma G. Daryai, Mansi N. Athalye, Praful D. Bharadia, Jayvadan Patel
A second method of non-viral gene delivery consists of complexes of DNA and cationic polymers that induce DNA condensation and a considerable size reduction of the complex within the plasma. Various cationic polymers have been used to form polyplexes with DNA, like histidylated polylysine, polylysine, polyethyleneimine, polyamidoamine dendrimer, chitosan, and polyallylamine (Montier et al., 2004). The high molecular weight, large extent of polymerization, and high degree of polydispersity of cationic polymers renders their characterization difficult (Midoux and Pichon, 2002). Therefore, low molecular weight cationic peptides have been also developed to provide controlled synthesis and defined purity of the polymers (Montier et al., 2004).
Nucleic Acids
Published in Danilo D. Lasic, LIPOSOMES in GENE DELIVERY, 2019
Bending of DNA, which is a necessary condition for its tight packing, can also be increased by specific sequences, such as the AA dinucleotide that can become an AATT stack that acts as a wedge in the DNA. Such wedge elements introduce bending anisotropy. Highly repeated sequences may induce turns; inverted repeats (also known as palindromes) may form hairpins, while moderately repetitive DNA may be responsible for winding around histones or protamines. Additionally, bending can be enhanced if only one side of DNA has its charges neutralized (Strauss and Maher, 1995). In addition to natural DNA condensation into nucleosomes, DNA can also be condensed artificially.
Epigenetic Reprogramming in Early Embryo Development
Published in Cristina Camprubí, Joan Blanco, Epigenetics and Assisted Reproduction, 2018
Histones are proteins that associate with DNA to package chromatin into nucleosomes which allows DNA condensation but also restricts access of regulatory factors to the DNA strand, affecting transcription. Histone tails are exposed on the nucleosome surface and they can be modified by addition of different molecules (acetylation, methylation, but also ubiquitination, SUMOylation, and phosphorylation) which alters the chromatin structure and increase or reduce its accessibility, according with the specific residue and/or the number of molecules that are added to histone amino acids. Histone tails modifications can correlate with different biological effects including DNA repression or activation, and configure a complex marking system called “histone code” (80,81). For example, histone acetylation affects chromatin structure (by decreasing interaction between positive charges on the histones and the negatively charged DNA) and facilitates the access of transcription factors to DNA. However, according with position and the number of methyl groups that are added to histone tails, it can correlate with either silencing (H3K9me3 and H3K27me3) or with activation (H3K4me3, H3K36me3) of DNA. But also histones modifications are connected to DNA methylation machinery or even protection of DNA from demethylation (82).
Epigenetic control of skin immunity
Published in Immunological Medicine, 2023
Human cells contain two meters of genomic DNA that is tightly folded and packed within the nucleus. Genomic DNA forms a secondary structure referred to as chromatin that fits into a limited space [7]. The basic unit of chromatin, the nucleosome, is consisted of 147 bp genomic DNA and a core histone octamer. DNA is negatively charged and histones are positively charged, and the opposing charges allow DNA to wrap itself tightly around the histone octamer to form a nucleosome. Initiation of transcription requires the binding of RNA polymerase II and several basic transcription factors, called TFIIA and TFIIB, bind to promoters located near the transcription start sites [8]. Sequence-specific DNA-binding transcription factors (TFs) are involved in the enhancement of transcription. TFs bind to enhancers and cause genomic DNA to form looped structures that shorten the distance between enhancers and promoters, thereby promoting the transcription of the target genes. Transcriptional activity is also closely related to the degree of DNA condensation associated with chromatin structure [6,8]. Tightly packed chromatin, called closed chromatin or heterochromatin, restricts the access of RNA polymerase II and the transcription factors to the regulatory sites, and consequently, suppresses the expression of target genes. Open chromatin or euchromatin that is less condensed allows easier access of the transcriptional machinery to DNA, thus setting target genes to be more actively transcribed.
Regression of prostate tumors after intravenous administration of lactoferrin-bearing polypropylenimine dendriplexes encoding TNF-α, TRAIL, and interleukin-12
Published in Drug Delivery, 2018
Najla Altwaijry, Sukrut Somani, John A. Parkinson, Rothwelle J. Tate, Patricia Keating, Monika Warzecha, Graeme R. Mackenzie, Hing Y. Leung, Christine Dufès
DAB-Lf was able to condense the negatively charged DNA via electrostatic interactions, although an excess of dendrimer (dendrimer: DNA weight ratios of 5:1 and above) was required to ensure efficient DNA condensation. The DNA condensation observed with DAB-Lf appeared to follow the same pattern as the one described by Kim et al. (2007) and by Aldawsari et al. (2011) when, respectively, using generation 2- and 3-polypropylenimine dendrimers conjugated to positively charged arginine. Both groups demonstrated that the grafting of arginine residues to the dendrimers facilitated the formation of stable dendriplexes due to their strong positive charges at high dendrimer: DNA weight ratios, but reduced the DNA condensing ability of the dendrimer at low dendrimer: DNA ratios, as observed in our current experiment. In addition, DNA condensation was improved compared to the results previously obtained with DAB-Lf synthesized with dimethysuberimidate homo-bifunctional cross-linker: the DNA condensation has increased by at least 10% depending of the dendrimer: DNA weight ratios (Lim et al., 2015).
Enhanced anti-proliferative and pro-apoptotic effects of metformin encapsulated PLGA-PEG nanoparticles on SKOV3 human ovarian carcinoma cells
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Leila Faramarzi, Mehdi Dadashpour, Hadi Sadeghzadeh, Majid Mahdavi, Nosratollah Zarghami
To observe nuclear morphology changes related to apoptosis more precisely, cells were stained by DAPI after treating with free MET and MET-loaded PLGA-PEG NPs (Figure 6). The nuclei of untreated SKOV3 cells displayed homogenous fluorescence with no sign of segmentation and fragmentation after DAPI staining. Exposure of the cells with IC50 concentration of free MET and MET-loaded PLGA-PEG NPs led to segregation of the cell nuclei into segments, demonstrating a breakdown in the chromatin followed by DNA condensation. As shown in Figure 6, the percentage of apoptotic cells induced by MET-loaded PLGA-PEG NPs was significantly higher than free MET, denoting that MET-encapsulated in PLGA-PEG NPs effectively induced apoptosis in SKOV3 cells in relation to free MET.