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Methods in molecular exercise physiology
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Adam P. Sharples, Daniel C. Turner, Stephen Roth, Robert A. Seaborne, Brendan Egan, Mark Viggars, Jonathan C. Jarvis, Daniel J. Owens, Jatin G. Burniston, Piotr P. Gorski, Claire E. Stewart
Increasingly common are direct DNA sequencing approaches, in which either a DNA fragment or the entire genome of an individual is completely sequenced, base by base. DNA sequencing relies on a similar fluorescent technique as mentioned above, except that each DNA base (A, T, G, C) has a unique colour and the DNA fragment (or entire genome) is amplified by a PCR technique that results in many fragments of varying sizes. These different-sized fragments are then ordered by size using electrophoresis, after which computational analysis determines the base sequence. For the entire genome, this process is done in parallel across thousands of fragments, which are then spliced together using a computer analysis of the resulting sequences. The latter process, in which the entire genome is analysed simultaneously in large fragments, is known as next generation sequencing (NGS) (5) and the cost has dropped to such an extent that companies are now advertising the direct sequencing of a person’s entire genome for costs (~$1,000) that were considered unthinkable only ten years ago. NGS is covered in more detail in this chapter below.
Green Synthesis of Nanoparticles in Oligonucleotide Drug Delivery System
Published in Yashwant Pathak, Gene Delivery, 2022
Manish P. Patel, Praful D. Bharadia, Kunjan B. Bodiwala, Mustakim M. Mansuri, Jayvadan Patel
Oligonucleotides are binding with RNA through DNA base pairing and modulate the function of the targeted RNA. It suggests a wide variety of oligonucleotides that modulate RNA through a different binding mechanisms (Esau et al., 2006). Briefly, these mechanisms can be classified largely as (a) those that bind to RNA and interfere with its function without promoting RNA degradation, such as translation arrest or modulating RNA processing (b) those that promote degradation of the RNA through endogenous enzymes, such as RNase H or argonaute-2 [RNA interference (RNAi)]. Recently, researchers have shown that Anti Sense Oligonucleotides can also be used to increase protein production, either through antagonizing microRNAs, which normally suppress protein production, or through masking upstream open reading frames (Liang et al., 2016). It shows that this drug delivery system has a huge impact in management or treatment of rare diseases.
Finding a Target
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
The DNA molecule is a long unbranched polymer composed of nucleotide sub-units, which contain the bases: adenine (A), cytosine (C), guanine (G), and thymine (T). The nucleotides are linked together covalently with phosphodiester bonds between the 5’ carbon of one deoxyribose group and the 3’ carbon of the next. These linkages form the sugar-phosphate backbone of the DNA molecule to which the four bases are attached. Two strands of DNA combine via intermolecular bonding between pairs of bases; one from each strand to form the complete molecule. These base pairs are instrumental in determining the characteristic structure of DNA. Two DNA chains combine through hydrogen bonds between the bases like runs of a ladder and cause the structure to twist into the α-helix shape. This structure was discovered by Watson and Crick in the early 1950s from x-ray diffraction studies. Their model of the DNA structure revealed that the DNA bases were inside the double helix and that the bases of one strand were extremely close to those of the other, which results in the need for specific base pairing between a large purine base (A or G, which contain a large double ring structure) and a smaller pyrimidine base (T or C, each of which has a single ring) on the other chain. These requirements for spatial arrangements of atoms to satisfy hydrogen bonding results in complementary base pairing between A and T and G and C, where two and three hydrogen bonds are formed, respectively, between the bases. Alternative base pairing would result in either too greater separation for hydrogen bonding, or steric congestion between pairs large bases.
Design and synthesis of new spirooxindole candidates and their selenium nanoparticles as potential dual Topo I/II inhibitors, DNA intercalators, and apoptotic inducers
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Samar El-Kalyoubi, Mohamed M. Khalifa, Mahmoud T. Abo-Elfadl, Ahmed A. El-Sayed, Ahmed Elkamhawy, Kyeong Lee, Ahmed A. Al-Karmalawy
The design of a new wave of compounds that dual-target Topo I and II enzymes and intercalate onto DNA depends basically upon the overlap between the reported pharmacophoric features of both Topo inhibitors and DNA intercalators. With this respect, we designed a new series of spiro[indoline-3,5′-pyrido[2,3-d:6,5-d′]dipyrimidine] candidates that fulfilled the requirements needed for a considerable binding with both receptors. Camptothecin, a Topo I inhibitor, and doxorubicin (Dox), a potent Topo II inhibitor and DNA intercalator, were our guides in the recent study. As so, the newly designed members achieved the following three features: (A) a planer heteroaromatic pyridodipyrimidine system to intercalate in between the DNA base pairs; (B) an NH basic centre to bind the negatively charged phosphate group of the sugar moiety; (C) a groove binder side chain to fit the DNA minor groove; and (D) a hydrogen bonding side chain to interact with both enzymes (Figure 3).
Topo II inhibition and DNA intercalation by new phthalazine-based derivatives as potent anticancer agents: design, synthesis, anti-proliferative, docking, and in vivo studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Mohamed M. Khalifa, Ahmed A. Al-Karmalawy, Eslam B. Elkaeed, Mohamed S. Nafie, Mohamed A. Tantawy, Ibrahim H. Eissa, Hazem A. Mahdy
The current search and discovery of new drug candidates with anticancer activities have become one of the most important issues for medicinal chemists nowadays6–11. Among the most important chemotherapeutic agents applied for cancer treatment are those that interact with DNA. Anticancer agents in the previously mentioned class belong to either alkylating agents, groove binders, or intercalating agents12. DNA intercalating agents got great attention from scientists due to their promising antitumoral activity13–18. They are classified into two major groups of compounds that intercalate between DNA base pairs (especially G and C, 70%) without covalent binding: 1) acridines and related compounds and 2) anthracyclines and related compounds19. These compounds produce local structural changes to the DNA molecule, including the lengthening of the DNA strand following the unwinding of its double helix. So, DNA intercalators are mutagenic due to their retardation or even inhibition of DNA transcription and replication20.
Ankylosing Spondylitis Patients Display Aberrant ERAP1 Gene DNA Methylation and Expression
Published in Immunological Investigations, 2022
Yubo Ma, Dazhi Fan, Shanshan Xu, Jixiang Deng, Xing Gao, Shiyang Guan, Xu Zhang, Faming Pan
DNA methylation is the most commonly reported epigenetic modification that plays a pivotal role in many life courses through programmed gene expression regulation in the genome (Chater-Diehl et al. 2021). DNA methylation is the addition of a methyl group to 5ʹ position of a cytosine DNA base in the middle of cytosine-guanine dinucleotide (CpG) (Zhu et al. 2016). The abnormal DNA methylation in the gene promoter is generally associated with transcriptional silencing and may be associated with multiple diseases (Jones et al. 2016; Zhong et al. 2016). An increasing number of epigenome-wide association studies (EWAS) indicated that DNA methylation participates in the pathogenesis of rheumatic diseases, such as systematic lupus erythematosus, rheumatoid arthritis, and AS (Hao et al. 2017; Imgenberg-Kreuz et al. 2018; Joseph et al. 2019; Webster et al. 2018; Zhu et al. 2019). A recent EWAS has identified 1915 altered DNA methylation loci in AS. Moreover, candidate gene studies also reported abnormal methylation loci in AS patients. Methylation of SOCS-1 gene was detected in the serum of HLA-B27 positive AS patients but not B27 positive controls, and it was significantly associated with higher serum cytokines and severe clinical manifestations in AS patients (Lai et al. 2014). DNMT1 and BCL11B genes were also reported to be hypermethylated in AS patients, and their expression levels were decreased (Aslani et al. 2016; Karami et al. 2017). Nevertheless, current studies focusing on DNA methylation in AS patients are still scarce and urgent.