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Chemopreventive Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Cancer cells have been shown to induce epigenetic modifications to exploit many of the Hallmarks of Cancer, such as accelerated proliferative and metastatic potential, and angiogenesis. A small number of anticancer agents have been approved (e.g., 5-azacytidine, MylosarTM) that work through an epigenetic mechanism of action, and these are described in more detail in Chapter 5. It is thought that some chemopreventive agents may exert their effects through an epigenetic mechanism, for example, by inhibiting the various DNA methylase and demethylase and histone acetylase and de-acetylase enzymes.
Paediatric clinical pharmacology
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
CYP1A2. The CYP1A2 phenotype was initially studied using caffeine as a probe. More recently, it was demonstrated that CYP1A2 protein is absent in microsomes prepared from fetal and neonatal livers. Its level increases in infants 1–3 months to attain 50% of adult values at one year of age. Methoxyresoru-fine demethylase and imipramine demethylation are partially metabolised by CYP1A2 and follow the same profile of ontogenic development.
Vitamin C in Immune Cell Function
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Abel Ang, Margreet C.M. Vissers, Juliet M. Pullar
In mammals, one of the most widespread epigenetic modifications is DNA cytosine methylation, a modification that generally results in silencing of gene expression [138,139]. This modification can be actively reversed by the Tet enzymes that catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), potentially a stable epigenetic mark in itself [138], or initiate the generation of 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), which results in active regeneration of unmarked cytosine by excision-repair mechanisms [140]. Ascorbate availability has been shown to markedly enhance Tet activity [141,142] through its cofactor function, likely maintaining the active site Fe2+ of these dioxygenases [143]. Although other reducing agents could reduce Fe3+ and promote TET activity in a cell free system, ascorbate was shown to be the most efficient [143], and glutathione was incapable of increasing murine embryonic TET activity compared to equimolar ascorbate [141,142]. The Jumonji C domain-containing histone demethylases (JHDMs) are also members of the Fe- and 2-oxoglutarate dependent dioxygenase family, and similarly to TETs, full enzyme activity of JHDMs occurs when ascorbate is present [144,145]. The JHDMs are the third and largest class of demethylase enzymes, capable of removing all three histone lysine-methylation states through oxidative reactions [145].
Discovery of novel sulphonamide hybrids that inhibit LSD1 against bladder cancer cells
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Jia Liu, Xingwang Zhu, Liu Yu, Minghuan Mao
Bladder cancer is the most frequently diagnosed malignancy in the urinary system and has the high morbidity and mortality rates1. Chemotherapy plays an important role in the treatment of bladder cancer and it is urgent to develop potent anti-bladder cancer drugs2,3. Histone lysine-specific demethylase 1 (LSD1) could catalyse the demethylation of mono and dimethylated H3K4me1/2 or H3K9me1/2 and demethylate many other nonhistone substrates4. LSD1 is aberrantly expressed in many malignant tumours such as prostate, ovarian, gastric, liver, breast, lung, bladder, neuroblastoma, and blood cancers5. The inhibition of LSD1 could prevent tumour cell proliferation, stimulate antitumor immunity, and enhance antitumor efficacy of immune checkpoint blockade6. Therefore, LSD1 has been considered as a potential cancer therapeutic target to discover novel anti-bladder cancer agents7–9. LSD1 and MAO-A/-B were belonged to the monoamine oxidase family, and MAO-A/-B shared the similar enzymatic mechanisms and the same cofactor of LSD1 in the cleavage of the inactivated carbon–nitrogen bonds from their substrates10. Although a variety of LSD1 inhibitors have been reported to date, many of them show insufficient selectivity towards LSD111.
The molecular structure and biological functions of RNA methylation, with special emphasis on the roles of RNA methylation in autoimmune diseases
Published in Critical Reviews in Clinical Laboratory Sciences, 2022
Wanwan Zhou, Xiao Wang, Jun Chang, Chenglong Cheng, Chenggui Miao
In the past few years, a series of pioneering articles have described the mechanisms involved in RNA methylation. For example, methyltransferases modify adenine on RNA molecules, resulting in m6A modifications. The modified RNAs are demethylated by demethylase. After being recognized by methylated reading proteins, RNAs modified by m6A perform a series of functions including miRNA processing and mRNA transfer, translation, and splicing [27]. RNA methylation needs "writers” for methyl transfer, "erasers" for removing methyl groups, and "readers” for recognizing methyl markers [28]. With the clarification of the mechanisms of RNA methylation, the importance and universality of RNA methylation are gradually being recognized. RNA methylation affects RNA splicing and mRNA stability, localization, translation, and translocation [29]. Some well-known RNA methylation types and molecular structures (Figure 1) are discussed below.
Azole resistance in Aspergillus species: promising therapeutic options
Published in Expert Opinion on Pharmacotherapy, 2021
Shirisha Pasula, Pranatharthi H. Chandrasekar
Azole resistance was first reported in 1997, followed by a few reports in different European countries [5,6]. Two scenarios of acquiring azole resistance by Aspergillus have been described. One among the patients with chronic pulmonary aspergillosis on a long-term azole therapy, with gradual emergence of resistance, and the other – acquisition of azole-resistant Aspergillus from the environment [7]. Demethylase inhibitors (DMIs) including azole fungicides are commonly used in agriculture [7]. If Aspergillus strains in the environment are exposed to small amounts of azoles contained in agricultural pesticides, azole-resistant strains may evolve and spread [7–9]. Aspergillus isolates with TR34/L98H mutation were first reported from the environment in the Netherlands. They were found genetically related to the azole-resistant Aspergillus isolates recovered from humans, thus supporting the theory of environmental origin for Aspergillus resistance in clinical isolates [10]. It was followed by the reports of clinical azole resistance in other European countries, China, Middle East, India, Africa, Australia, and Turkey. The possible reasons for the global spread are the ability of fungal spores to be able to travel thousands of miles in the air, and worldwide use of azole fungicides in agriculture [8,11].