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Epigenetic Reprogramming in Early Embryo Development
Published in Cristina Camprubí, Joan Blanco, Epigenetics and Assisted Reproduction, 2018
However, studies in isolated male and female pronuclei, using reduced representation bisulfite sequencing (RRBS) to evaluate genome-wide DNA methylation, and using aphidicolin to inhibit DNA replication, showed a marked reduction in methylated cytosines in both male and female genomes in absence of cell division (16,17), as previously suggested (15). These data demonstrated active removal of methylation mediated by TET3 in both parental genomes, particularly at certain loci, although to a lesser extent in the maternal than in the paternal DNA. Despite this, the authors concluded that DNA replication is the major contributor to paternal and maternal DNA demethylation as the zygote starts to divide and that TET3 facilitates DNA demethylation by coupling with DNA replication. Although all these experiments were performed in mice, a recent study in monkey has also shown that that both paternal and maternal genomes undergo active DNA demethylation (21).
DNA-Binding Proteins and DNA-Synthesizing Enzymes in Eukaryotes
Published in Lubomir S. Hnilica, Chromosomal Nonhistone Proteins, 2018
Differential response of DNA polymerases α, β, and γ to chemical inhibitors, NEM, ddTTP, and aphidicolin provides another approach to perform a meaningful physiological experiment. The DNA polymerase γ can be distinguished from DNA polymerase α by its aphidicolin resistance, and from DNA polymerase β by its sensitivity to NEM.12 In all physiological experiments studied, replicative DNA synthesis is completely inhibited by low concentrations of aphidicolin,13,125,143,143a whereas unscheduled DNA synthesis and the replication of mitochondrial DNA appear to be insensitive to aphidocolin. The latter two processes are affected by appropriate concentrations of ddNTP.13 DNA polymerase γ is 250 to 520 times more sensitive to ddTTP than DNA polymerase α.144–151 SV40 and cellular DNA replication is not affected by ddTTP, whereas it strongly inhibits both Ad2, Ad5, and mitochondrial DNA replication,144–152 and DNA polymerase γ activity. Therefore, DNA polymerase α is exclusvely required for cellular and papovavirus DNA replication, and DNA polymerase γ is required in mitochondrial DNA replication.
Hormonal Regulation of Cell Proliferation and Differentiation
Published in Jean Morisset, Travis E. Solomon, Growth of the Gastrointestinal Tract: Gastrointestinal Hormones and Growth Factors, 2017
In order for a eukaryotic cell to divide, it has to replicate its genome during the S phase of the cell cycle.1 Several lines of evidence indicate that DNA polymerase alpha is one of the principal enzymes that is involved in the regulation of DNA replication. Thus, aphidicolin, a specific inhibitor of this enzyme, inhibits DNA replication.37 Monoclonal antibodies against the enzyme also inhibit DNA synthesis.38,39 Enhanced activity of the enzyme correlates with enhanced DNA synthesis.40 A cell line that exhibits a temperature-sensitive defect in DNA replication is also a DNA polymerase alpha mutant.41 Although there is a slight increase in the expression of this enzyme prior to the S phase, and a slight decrease through the G2 phase, the enzyme is generally constitutively expressed throughout the cell cycle.42 Nonetheless, the regulation of the expression of this enzyme is believed to occur at the transcriptional level.42 Taken together, these observations indicate that enzymes which are involved in the regulation of cell proliferation are not necessarily active only during a specific phase of the cell cycle and that a variety of intracellular factors probably interact with cell cycle specific enzymes to regulate the exact timing of the proliferative response.
Poly (ADP-ribose) polymerase inhibitors sensitize cancer cells to hypofractionated radiotherapy through altered selection of DNA double-strand break repair pathways
Published in International Journal of Radiation Biology, 2022
Yuji Seo, Keisuke Tamari, Yutaka Takahashi, Kazumasa Minami, Shotaro Tatekawa, Fumiaki Isohashi, Osamu Suzuki, Yuichi Akino, Kazuhiko Ogawa
A standard colony-forming assay was performed to measure fractions of cell survival. Cells were seeded aiming to yield approximately 100 colonies on each 60-mm dish. The drugs were added into the medium immediately after seeding at final concentrations of 5, 1, or 5 μmol/L for PJ34, olaparib, or veliparib, respectively. The same amount of vehicle was used for the control dishes. After 30-min incubation, IR was delivered. The medium was exchanged with fresh medium without drugs 48 h after administering IR. After an additional 12 days of incubation, cells were fixed and stained using 0.5% crystal violet in 70% methanol. To obtain synchronized cell populations in the G0/G1 cell cycle phases, subconfluent HCT116 cells were incubated in the culture medium without fetal bovine serum. Following the 24-h serum starvation, the cells in the G0 phase were released into the full medium and harvested 4 h later for further experiments. For S-phase cell cycle synchronization, HCT116 cells were treated with 1 μg/mL of aphidicolin for 24 h. The cells synchronized at the G1/S border were released into the full medium without aphidicolin and harvested 4 h later for the experiments. As with the asynchronous cells, the drug or vehicle was added immediately after reseeding on the dish. After 30-min incubation, cells were irradiated.
Emergence of varicella-zoster virus resistance to acyclovir: epidemiology, prevention, and treatment
Published in Expert Review of Anti-infective Therapy, 2021
Kimiyasu Shiraki, Masaya Takemoto, Tohru Daikoku
The mutation sites of VZV DNApol are divided into two recognition groups of acyclovir-resistant HSV and VZV in their DNApols, the foscarnet-arabinose moiety of the vidarabine group vs. the aphidicolin group, as described in the section on acyclovir/penciclovir-resistant mutants (Figure 4). Acyclovir-resistant mutants with foscarnet-vidarabine resistance (VZV G805C and V855M) are more sensitive to aphidicolin than the wild-type parent virus, and those with foscarnet-vidarabine hypersensitivity were more resistant to aphidicolin. Acyclovir-resistant mutants with foscarnet-arabinose (vidarabine) hypersensitivity (VZV N779S) are more resistant to acyclovir than those with foscarnet-arabinose (vidarabine) resistance [48].
Nanoparticles for antiparasitic drug delivery
Published in Drug Delivery, 2019
Yuzhu Sun, Dongmei Chen, Yuanhu Pan, Wei Qu, Haihong Hao, Xu Wang, Zhenli Liu, Shuyu Xie
Some antiparasitic drugs have been produced into nanosuspension with some prominent properties. The ivermectin nanosuspensions development by Starkloff et al. (2016) has a solubility four times larger than that of ivermectin alone due to the presence of nanoparticles and amorphous. A recent report found that ellagic acid nanoparticles prepared by antisolvent precipitation showed improved/sustained antibabesial effects in different cells and in the animal. The IC50 of ellagic acid nanoparticles for ‘B. bovis, B. bigemina, B. divergens, B. caballi and T. equi’ were ‘4.2, 9.6, 2.6 , 0.92 and 7.3 µM’, respectively, while the IC50 values of ellagic acid on ‘B. bovis, B. bigemina, B. divergens, B. caballi and T. equi’ were ‘9.58 , 7.87 , 5.41, 3.29 and 7.46 µM’, respectively (Beshbishy et al., 2019). Our groups have developed some nanosuspensions for albendazole, fenbendazole, and oxfendazole, which significantly increased their solubility, bioavailability, and peak serum drug concentrations. The bioavailability of albendazole nanosuspensions prepared by Kumar P (Mittapalli et al., 2007) is also increased by 2.14–2.96 times. When buparvaquone was administered in the form of nanosuspensions in the treatment of Cryptosporidium, many nanoparticles were found to adhere to the mucosa, and thus prolonging the residence time in the gastrointestinal tract, increasing bioavailability and simultaneous reducing the dosage and side effects of the drug (Kayser, 2001). As described in other granular pharmaceutical formulations, nanosuspensions are generally used to target phagocytic cells, but can also be delivered to specific sites such as central nervous system, spleen, liver, lung, and bone marrow depending on their particle characters and particular surfactant coating. Nanosuspensions of amphotericin B coated with polysorbate 80 and sodium cholate significantly increased the brain delivery and exhibited enhanced parasite inhibition in vitro (Lemke et al., 2010). Kayser (2000) prepared aphidicolin-nanosuspensions that can passively target macrophages via directly phagocytose by macrophages. Compared to dimethyl sulfoxide-dissolved drugs, nanosuspensions show increased activity against Leishmania about 140 times, indicating that the cellular uptake of nanoparticles is critical to improve the activity of their payload.