Anticonvulsant valproic acid and other short-chain fatty acids as novel anticancer therapeutics: Possibilities and challenges

Lipska, Katarzyna; Gumieniczek, Anna; Filip, Agata

doi:10.2478/acph-2020-0021

Cited by 30 publications

(33 citation statements)

References 40 publications

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“…We can distinguish four families of HATs and four families of HDACs (classes I-IV) [270]. The development of HDAC inhibitors (HDACi) have allowed researchers to investigate the contribution of histone acetylation to numerous pathological conditions including cancers [275].…”

Section: Histone Modification and Microglia Activationmentioning

confidence: 99%

Microglia: Agents of the CNS Pro-Inflammatory Response

Rodríguez‐Gómez

Kavanagh

Engskog-Vlachos

et al. 2020

Cells

227

136

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The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though the research of microglia spans over a century, the last two decades have increased our understanding exponentially. Here, we discuss the phenotypic transformation from homeostatic microglia towards reactive microglia, initiated by specific ligand binding to pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering receptors expressed on myeloid cells-2 (TREM2), as well as pro-inflammatory signaling pathways triggered such as the caspase-mediated immune response. Additionally, new research disciplines such as epigenetics and immunometabolism have provided us with a more holistic view of how changes in DNA methylation, microRNAs, and the metabolome may influence the pro-inflammatory response. This review aimed to discuss our current knowledge of pro-inflammatory microglia from different angles, including recent research highlights such as the role of exosomes in spreading neuroinflammation and emerging techniques in microglia research including positron emission tomography (PET) scanning and the use of human microglia generated from induced pluripotent stem cells (iPSCs). Finally, we also discuss current thoughts on the impact of pro-inflammatory microglia in neurodegenerative diseases.

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Section: Histone Modification and Microglia Activationmentioning

confidence: 99%

Microglia: Agents of the CNS Pro-Inflammatory Response

Rodríguez‐Gómez

Kavanagh

Engskog-Vlachos

et al. 2020

Cells

227

136

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“…In 2014, an endogenous ketone beta-hydroxybutyrate was found to have HDACi activity. 156 Ketogenic diets are highly beneficial for the management of epilepsy, depression, reducing mortality and improving memory. [157][158][159] Together this demonstrates the importance for open chromatin and active gene expression in the management of neurological disease.…”

Section: Ketones and Ketogenic Dietsmentioning

confidence: 99%

Advances in Nutritional Epigenetics—A Fresh Perspective for an Old Idea. Lessons Learned, Limitations, and Future Directions

Sedley

2020

Genet Epigenet

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Nutritional epigenetics is a rapidly expanding field of research, and the natural modulation of the genome is a non-invasive, sustainable, and personalized alternative to gene-editing for chronic disease management. Genetic differences and epigenetic inflexibility resulting in abnormal gene expression, differential or aberrant methylation patterns account for the vast majority of diseases. The expanding understanding of biological evolution and the environmental influence on epigenetics and natural selection requires relearning of once thought to be well-understood concepts. This research explores the potential for natural modulation by the less understood epigenetic modifications such as ubiquitination, nitrosylation, glycosylation, phosphorylation, and serotonylation concluding that the under-appreciated acetylation and mitochondrial dependant downstream epigenetic post-translational modifications may be the pinnacle of the epigenomic hierarchy, essential for optimal health, including sustainable cellular energy production. With an emphasis on lessons learned, this conceptional exploration provides a fresh perspective on methylation, demonstrating how increases in environmental methane drive an evolutionary down regulation of endogenous methyl groups synthesis and demonstrates how epigenetic mechanisms are cell-specific, making supplementation with methyl cofactors throughout differentiation unpredictable. Interference with the epigenomic hierarchy may result in epigenetic inflexibility, symptom relief and disease concomitantly and may be responsible for the increased incidence of neurological disease such as autism spectrum disorder.

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“…For this, we decided to expand the study using patients derived cells and recruiting RSTS patients for microbiota sampling. A number of HDACi currently used for other purposes (José-Enériz et al, 2019;Lipska et al, 2020;Spartalis et al, 2019;Tarnowski et al, 2019) have been thoroughly evaluated in cell lines derived from patients compared to healthy donors. Upon HDACi exposure, RSTS cell lines showed a general boost in histone acetylation levels.…”

Section: Discussionmentioning

confidence: 99%

Exogenous and endogenous HDAC inhibitor effects in Rubinstein-Taybi syndrome models

Fede

Ottaviano

Grazioli

et al. 2020

Preprint

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Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder with specific clinical signs and neurodevelopmental impairment. The two known proteins altered in the majority of RSTS patients are the histone acetylation regulators CBP and p300. For assessing possible ameliorative effects of exogenous and endogenous HDAC inhibitors (HDACi), we exploited in vivo and in vitro RSTS models.First, HDACi effects were tested on Drosophila melanogaster, showing molecular rescue. In the same model, we observed a shift in gut microbiota composition. We then studied HDACi effects in RSTS cell lines compared to healthy donor cells. We observed patients-specific molecular rescue of acetylation defects at subtoxic concentrations. Finally, we assessed commensal gut microbiota composition in a cohort of RSTS patients compared to healthy siblings. Intriguingly, we observed a significant depletion in butyrate-producing bacteria in RSTS patients. In conclusion, this study reports the possibility of modulating acetylation equilibrium by HDACi treatments and the importance of microbiota composition in a chromatinopathy.

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Anticonvulsant valproic acid and other short-chain fatty acids as novel anticancer therapeutics: Possibilities and challenges

Cited by 30 publications

References 40 publications

Microglia: Agents of the CNS Pro-Inflammatory Response

Microglia: Agents of the CNS Pro-Inflammatory Response

Advances in Nutritional Epigenetics—A Fresh Perspective for an Old Idea. Lessons Learned, Limitations, and Future Directions

Exogenous and endogenous HDAC inhibitor effects in Rubinstein-Taybi syndrome models

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