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The Scientific Basis of Medicine
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
Chris O'Callaghan, Rachel Allen
An effective mechanism is required to remove cells that are damaged or no longer necessary. This programmed cell death is generally known as apoptosis (Figure 2.7), and follows a carefully controlled series of events allowing the cell to condense its cytoskeleton and fragment its DNA. Apoptosis is driven by members of the caspase protein family. Bcl proteins regulate caspase activity. Programmed cell death can be triggered in response to stimuli such as cell surface signals or mitochondrial stress. Following ligand binding, cell-surface death receptors such as Fas recruit adaptor proteins to trigger procaspase activation, and thus elicit apoptosis. Mitochondria can initiate an alternative apoptotic pathway in response to DNA damage or intracellular oxidative stress. A dying cell will show membrane blebbing, cell shrinkage and protein fragmentation as it collapses in upon itself. Within the nucleus, chromatin condensation and DNA degradation occur. Finally, the cell is flagged for uptake by phagocytic cells.
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
A GeneICETM agent consists of a combination of two peptidic components, a specific DNA-binding module that binds selectively to the gene to be silenced, and a repressor module with the ability to recruit HDAC complexes to the gene. Deacetylation of the histones associated with the gene then leads to localized chromatin condensation that “closes” the DNA-histone complex and down-regulates or blocks transcription (Figure 5.73).
Epigenetic Alterations in Alzheimer’s Disease and Its Therapeutic and Dietary Interventions
Published in Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu, Phytomedicine and Alzheimer’s Disease, 2020
P. M. Aswathy, C. M. Shafeeque, Moinak Banerjee
Histone methylation is also dynamic and is carried out by the opposing actions of histone methyltransferases (HMTs) and histone demethylases (HDMTs). Methylation occurs on lysine (mono-, di- or tri-methylated) or arginine residues and does not seem to alter the charge of the altered residues but confers unique structural alterations. Similarly, histone phosphorylation is mediated by the opposing activities of protein kinases and phosphatases. Histone phosphorylation regulates multiple processes, such as DNA damage response, gene expression, chromatin condensation etc.
Heterogeneity of triple-negative breast cancer: understanding the Daedalian labyrinth and how it could reveal new drug targets
Published in Expert Opinion on Therapeutic Targets, 2022
Alberto Zambelli, Riccardo Sgarra, Rita De Sanctis, Elisa Agostinetto, Armando Santoro, Guidalberto Manfioletti
DNA methyltrasferase 1 (DNMT1) is the most crucial enzyme in the DNMTs family in humans and it is highly expressed in TNBC compared to other subtypes [128]. Notably, a preclinical study suggests that DNMT inhibitors such as 5-azacytidine can increase the efficacy of PARP inhibitors in BC cells with wild-type BRCA1 [129]. Moreover, hypomethylating agents might play a role in selected cases of breast cancer with sporadic abnormally BRCA1 gene promoter methylation [130]. The HDACs are a class of enzymes that deacetylate histones leading to chromatin condensation, repressing transcription. Therefore, HDAC inhibitors could induce tumor cell apoptosis, inhibit cell migration and invasion and sensitize cancer cells to chemotherapy [131]. Preclinical and clinical studies with HDAC inhibitors in combination with other drugs showed promising results in TNBC [125]. Another relevant candidate target, which is involved in chromatin regulation, is the architectural chromatin family of high mobility group A proteins (HMGA). Indeed, HMGA are overexpressed in cancers, regulate chromatin plasticity and, in TNBC, can act as master regulators of genes involved in epithelial-to-mesenchymal transition, migration, invasion, and angiogenesis [132,133].
Phenolics-Enriched Fraction of Pterospermum Lanceifolium Roxb. efficiently Reverses the Hepatocellular Carcinoma in NDEA-Induced HCC Rats
Published in Nutrition and Cancer, 2022
Lal Chand Pal, Prateeksha, Brahma Nand Singh, Veena Pande, Chandana Venkateswara Rao
Excess generation of ROS attributes changes in the health of cellular organelles such as mitochondrial dysregulation, chromatin condensation, and fragmentation in the nucleus. DAPI stain was used to detect chromatin condensation. Increased fluorescence intensity indicates the condensation of chromatic. When cells were exposed to PLE with the concentration of 20, 40, 60 µg/mL, the fold change in fluorescence intensity was gradually increased. To determine the mitochondrial health, the JC-1 stain was used, which can produce fluorescent differentially. JC-1 emits red fluorescence when it binds with healthy mitochondria while it fluoresces green when it binds with depolarized mitochondria. In the flow cytometric analysis, the cell density was shifted toward the green channel after the treatment of PLE (Figure 3A–C). Microscopic images of JC-1 staining showed a strong relation to flow cytometric analysis. It confirms that PLE dysregulates the functioning of mitochondria.
Targeting transcription factors in multiple myeloma: evolving therapeutic strategies
Published in Expert Opinion on Investigational Drugs, 2019
Shirong Li, Sonia Vallet, Antonio Sacco, Aldo Roccaro, Suzanne Lentzsch, Klaus Podar
Histone acetylation is regulated by either histone deacetylases (HDACs) or by histone lysine acetyltransferases (KATs: type A, type B). Histone acetylation neutralizes the positive charge of lysines, thereby opening the chromatin structure, reducing the interaction of histones with negatively charged DNA, and ultimately increasing transcriptional activity. Moreover, acetylated histones provide binding sites for BET proteins, which additionally induce transcriptional activity. In contrast, histone deacetylation is associated with chromatin condensation and transcriptional repression. MM is also associated with an increase of HDAC levels resulting in a less condensed chromatin structure, enhanced transcriptional activity of signal-activated TFs, and adverse prognosis [134]. Approaches to target histone acetyltransferases include the CBP/p300 inhibitors SGC-CBP30, I-CBP112, and A-485 [40].