6 results on '"Keating, Samuel T."'
Search Results
2. Metaboloepigenetics in cancer, immunity, and cardiovascular disease.
- Author
-
Keating, Samuel T and El-Osta, Assam
- Subjects
- *
CARDIOVASCULAR diseases , *WARBURG Effect (Oncology) , *EPIGENOMICS , *DIABETES complications , *GENE expression , *NATURAL immunity , *IMMUNITY - Abstract
The influence of cellular metabolism on epigenetic pathways is well documented but misunderstood. Scientists have long known of the metabolic impact on epigenetic determinants. More often than not, that title role for DNA methylation was portrayed by the metabolite S -adenosylmethionine. Technically speaking, there are many other metabolites that drive epigenetic processes that instruct seemingly distant—yet highly connect pathways—and none more so than our understanding of the cancer epigenome. Recent studies have shown that available energy links the extracellular environment to influence cellular responses. This focused review examines the recent interest in epigenomics and casts cancer, metabolism, and immunity in unfamiliar roles—cooperating. There are not only language lessons from cancer research, we have come round to appreciate that reaching into areas previously thought of as too distinct are also object lessons in understanding health and disease. The Warburg effect is one such signature of how glycolysis influences metabolic shift during oncogenesis. That shift in metabolism—now recognized as central to proliferation in cancer biology—influences core enzymes that not only control gene expression but are also central to replication, condensation, and the repair of nucleic acid. These nuclear processes rely on metabolism, and with glucose at centre stage, the role of respiration and oxidative metabolism is now synonymous with the mitochondria as the powerhouses of metaboloepigenetics. The emerging evidence for metaboloepigenetics in trained innate immunity has revealed recognizable signalling pathways with antecedent extracellular stimulation. With due consideration to immunometabolism, we discuss the striking signalling similarities influencing these core pathways. The immunometabolic-epigenetic axis in cardiovascular disease has deeply etched connections with inflammation, and we examine the chromatin template as a carrier of epigenetic indices that determine the expression of genes influencing atherosclerosis and vascular complications of diabetes. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
3. Aldosterone induces trained immunity: the role of fatty acid synthesis.
- Author
-
Heijden, Charlotte D C C van der, Keating, Samuel T, Groh, Laszlo, Joosten, Leo A B, Netea, Mihai G, and Riksen, Niels P
- Subjects
- *
FATTY acids , *ALDOSTERONE , *ALDOSTERONE antagonists , *MINERALOCORTICOID receptors , *IMMUNITY , *TOLL-like receptors - Abstract
Aims Supranormal levels of aldosterone are associated with an increased cardiovascular risk in humans, and with accelerated atherosclerosis in animal models. Atherosclerosis is a low-grade inflammatory disorder, with monocyte-derived macrophages as major drivers of plaque formation. Monocytes can adopt a long-term pro-inflammatory phenotype after brief stimulation with microbial pathogens or endogenous atherogenic lipoproteins via a process termed trained immunity. In this study, we aimed to investigate whether aldosterone can induce trained immunity in primary human monocytes in vitro and explored the underlying mechanism. Methods and results We exposed human monocytes to aldosterone for 24 h, after which they were rested to differentiate into monocyte-derived macrophages for 5 days, and re-stimulated with toll-like receptor 2 and 4 ligands on day 6. We demonstrated that aldosterone augments pro-inflammatory cytokine production and reactive oxygen species production in monocyte-derived macrophages after re-stimulation, via the mineralocorticoid receptor. Fatty acid synthesis was identified as a crucial pathway necessary for this induction of trained immunity and pharmacological inhibition of this pathway blunted aldosterone-induced trained immunity. At the level of gene regulation, aldosterone promoted enrichment of the transcriptionally permissive H3K4me3 modification at promoters of genes central to the fatty acid synthesis pathway. Conclusion Aldosterone induces trained immunity in vitro , which is dependent on epigenetically mediated up-regulation of fatty acid synthesis. These data provide mechanistic insight into the contribution of aldosterone to inflammation, atherosclerosis, and cardiovascular disease. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
4. Epigenetics in diabetic nephropathy, immunity and metabolism.
- Author
-
Keating, Samuel T., van Diepen, Janna A., Riksen, Niels P., and El-Osta, Assam
- Abstract
When it comes to the epigenome, there is a fine line between clarity and confusion-walk that line and you will discover another fascinating level of transcription control. With the genetic code representing the cornerstone of rules for information that is encoded to proteins somewhere above the genome level there is a set of rules by which chemical information is also read. These epigenetic modifications show a different side of the genetic code that is diverse and regulated, hence modifying genetic transcription transiently, ranging from short- to long-term alterations. While this complexity brings exquisite control it also poses a formidable challenge to efforts to decode mechanisms underlying complex disease. Recent technological and computational advances have improved unbiased acquisition of epigenomic patterns to improve our understanding of the complex chromatin landscape. Key to resolving distinct chromatin signatures of diabetic complications is the identification of the true physiological targets of regulatory proteins, such as reader proteins that recognise, writer proteins that deposit and eraser proteins that remove specific chemical moieties. But how might a diverse group of proteins regulate the diabetic landscape from an epigenomic perspective? Drawing from an ever-expanding compendium of experimental and clinical studies, this review details the current state-of-play and provides a perspective of chromatin-dependent mechanisms implicated in diabetic complications, with a special focus on diabetic nephropathy. We hypothesise a codified signature of the diabetic epigenome and provide examples of prime candidates for chemical modification. As for the pharmacological control of epigenetic marks, we explore future strategies to expedite and refine the search for clinically relevant discoveries. We also consider the challenges associated with therapeutic strategies targeting epigenetic pathways. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
5. Epigenetic-Mediated Reprogramming of Pancreatic Endocrine Cells.
- Author
-
Mathiyalagan, Prabhu, Keating, Samuel T., Al-Hasani, Keith, and El-Osta, Assam
- Subjects
- *
PANCREATIC beta cells , *EPIGENETICS , *AUTOIMMUNE diseases , *ORGAN donation , *TRANSPLANTATION of organs, tissues, etc. - Abstract
Significance: Type 1 diabetes (T1D) results from cell-mediated autoimmune destruction of insulin-secreting pancreatic beta cells (β-cells). In the context of T1D, the scarcity of organ donors has driven research to alternate sources of functionally competent, insulin-secreting β-cells as substitute for donor islets to meet the clinical need for transplantation therapy. Recent Advances: Experimental evidence of an inherent plasticity of pancreatic cells has fuelled interest in in vivo regeneration of β-cells. Transcriptional modulation and direct reprogramming of noninsulin secreting pancreatic α-cells to functionally mimic insulin-secreting β-cells is one of the promising avenues to the treatment of diabetes. Recent studies now show that adult progenitor and glucagon+ α-cells can be converted into β-like cells in vivo, as a result of specific activation of the Pax4 gene in α-cells and curing diabetes in preclinical models. Critical Issues: The challenge now is to understand the precise developmental transitions mediated by endocrine transcription factors and co-regulatory determinants responsible for pancreatic function and repair. Future Directions: Epigenetic-mediated regulation of transcription factor binding in pancreatic α-cells by specific drugs to direct reprogramming into functional insulin producing cells could be of potential innovative therapy for the treatment of T1D. Antioxid. Redox Signal. 22, 1483-1495. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
6. Epigenetics and Trained Immunity.
- Author
-
van der Heijden, Charlotte D. C. C., Noz, Marlies P., Joosten, Leo A. B., Netea, Mihai G., Riksen, Niels P., and Keating, Samuel T.
- Subjects
- *
EPIGENETICS , *NATURAL immunity , *IMMUNOLOGIC diseases , *IMMUNE system , *EPIGENOMICS - Abstract
Significance: A growing body of clinical and experimental evidence has challenged the traditional understanding that only the adaptive immune system can mount immunological memory. Recent findings describe the adaptive characteristics of the innate immune system, underscored by its ability to remember antecedent foreign encounters and respond in a nonspecific sensitized manner to reinfection. This has been termed trained innate immunity. Although beneficial in the context of recurrent infections, this might actually contribute to chronic immune-mediated diseases, such as atherosclerosis. Recent Advances: In line with its proposed role in sustaining cellular memories, epigenetic reprogramming has emerged as a critical determinant of trained immunity. Recent technological and computational advances that improve unbiased acquisition of epigenomic profiles have significantly enhanced our appreciation for the complexities of chromatin architecture in the contexts of diverse immunological challenges. Critical Issues: Key to resolving the distinct chromatin signatures of innate immune memory is a comprehensive understanding of the precise physiological targets of regulatory proteins that recognize, deposit, and remove chemical modifications from chromatin as well as other gene-regulating factors. Drawing from a rapidly expanding compendium of experimental and clinical studies, this review details a current perspective of the epigenetic pathways that support the adapted phenotypes of monocytes and macrophages. Future Directions: We explore future strategies that are aimed at exploiting the mechanism of trained immunity to improve the prevention and treatment of infections and immune-mediated chronic disorders. Antioxid. Redox Signal. 29, 1023-1040. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.