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Article ; Online: Peptidylarginine Deiminases Inhibitors Decrease Endothelial Cells Angiogenic Potential by Affecting Akt Signaling and the Expression and Secretion of Angiogenic Factors.

Ciesielski, Oskar / Pirola, Luciano / Balcerczyk, Aneta

Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology

2024 Volume 58, Issue 1, Page(s) 63–82

Abstract: Background/aims: Endothelial cells (ECs) play a crucial role in various physiological processes, particularly those related to the cardiovascular system, but also those affecting the entire organism. The biology of ECs is regulated by multiple ... ...

Abstract	Background/aims: Endothelial cells (ECs) play a crucial role in various physiological processes, particularly those related to the cardiovascular system, but also those affecting the entire organism. The biology of ECs is regulated by multiple biochemical stimuli and epigenetic drivers that govern gene expression. We investigated the angiogenic potential of ECs from a protein citrullination perspective, regulated by peptidyl-arginine deiminases (PADs) that modify histone and non-histone proteins. Although the involvement of PADs has been demonstrated in several physiological processes, inflammation-related disorders and cancer, their role in angiogenesis remains unclear. Methods: To elucidate the role of PADs in endothelial angiogenesis, we used two human EC models: primary vein (HUVECs) and microvascular endothelial cells (HMEC-1). PADs activity was inhibited using irreversible inhibitors: BB-Cl-amidine, Cl-amidine and F-amidine. We analyzed all three steps of angiogenesis Results: All used PAD inhibitors reduced the histone H3 citrullination (H3cit) mark, inhibited endothelial cell migration and capillary-like tube formation, and favored an angiostatic activity in HMEC-1 cells, by increasing PEDF (pigment epithelium-derived factor) and reducing VEGF (vascular endothelial growth factor) mRNA expression and protein secretion. Additionally, BB-Cl-amidine reduced the total activity of MMPs (Matrix metalloproteinases). The observed effects were underlined by the inhibition of Akt phosphorylation.>. Conclusion: Our findings suggest that pharmacological inhibitors of citrullination are promising therapeutic agents to target angiogenesis.
MeSH term(s)	Humans ; Endothelial Cells/metabolism ; Histones/metabolism ; Protein-Arginine Deiminases/antagonists & inhibitors ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction ; Vascular Endothelial Growth Factor A/genetics ; Vascular Endothelial Growth Factor A/metabolism ; Amidines/chemistry ; Amidines/pharmacology ; Angiogenesis Inhibitors/chemistry ; Angiogenesis Inhibitors/pharmacology
Chemical Substances	Histones ; Protein-Arginine Deiminases (EC 3.5.3.15) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Vascular Endothelial Growth Factor A ; Amidines ; N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide ; F-amidine ; Angiogenesis Inhibitors
Language	English
Publishing date	2024-02-19
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1067572-3
ISSN	1421-9778 ; 1015-8987
ISSN (online)	1421-9778
ISSN	1015-8987
DOI	10.33594/000000683
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Article: How Warburg-Associated Lactic Acidosis Rewires Cancer Cell Energy Metabolism to Resist Glucose Deprivation.

Daverio, Zoé / Balcerczyk, Aneta / Rautureau, Gilles J P / Panthu, Baptiste

Cancers

2023 Volume 15, Issue 5

Abstract: Lactic acidosis, a hallmark of solid tumour microenvironment, originates from lactate hyperproduction and its co-secretion with protons by cancer cells displaying the Warburg effect. Long considered a side effect of cancer metabolism, lactic acidosis is ... ...

Abstract	Lactic acidosis, a hallmark of solid tumour microenvironment, originates from lactate hyperproduction and its co-secretion with protons by cancer cells displaying the Warburg effect. Long considered a side effect of cancer metabolism, lactic acidosis is now known to play a major role in tumour physiology, aggressiveness and treatment efficiency. Growing evidence shows that it promotes cancer cell resistance to glucose deprivation, a common feature of tumours. Here we review the current understanding of how extracellular lactate and acidosis, acting as a combination of enzymatic inhibitors, signal, and nutrient, switch cancer cell metabolism from the Warburg effect to an oxidative metabolic phenotype, which allows cancer cells to withstand glucose deprivation, and makes lactic acidosis a promising anticancer target. We also discuss how the evidence about lactic acidosis' effect could be integrated in the understanding of the whole-tumour metabolism and what perspectives it opens up for future research.
Language	English
Publishing date	2023-02-23
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15051417
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Article ; Online: Ketone Bodies as Metabolites and Signalling Molecules at the Crossroad between Inflammation and Epigenetic Control of Cardiometabolic Disorders.

Bendridi, Nadia / Selmi, Anna / Balcerczyk, Aneta / Pirola, Luciano

International journal of molecular sciences

2022 Volume 23, Issue 23

Abstract: For many years, it has been clear that a Western diet rich in saturated fats and sugars promotes an inflammatory environment predisposing a person to chronic cardiometabolic diseases. In parallel, the emergence of ketogenic diets, deprived of ... ...

Abstract	For many years, it has been clear that a Western diet rich in saturated fats and sugars promotes an inflammatory environment predisposing a person to chronic cardiometabolic diseases. In parallel, the emergence of ketogenic diets, deprived of carbohydrates and promoting the synthesis of ketone bodies imitating the metabolic effects of fasting, has been shown to provide a possible nutritional solution to alleviating diseases triggered by an inflammatory environment. The main ketone body, β-hydroxybutyrate (BHB), acts as an alternative fuel, and also as a substrate for a novel histone post-translational modification, β-hydroxybutyrylation. β-hydroxybutyrylation influences the state of chromatin architecture and promotes the transcription of multiple genes. BHB has also been shown to modulate inflammation in chronic diseases. In this review, we discuss, in the pathological context of cardiovascular risks, the current understanding of how ketone bodies, or a ketogenic diet, are able to modulate, trigger, or inhibit inflammation and how the epigenome and chromatin remodeling may be a key contributor.
Language	English
Publishing date	2022-11-23
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms232314564
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Article ; Online: Fat not so bad? The role of ketone bodies and ketogenic diet in the treatment of endothelial dysfunction and hypertension.

Pirola, Luciano / Ciesielski, Oskar / Balcerczyk, Aneta

Biochemical pharmacology

2022 Volume 206, Page(s) 115346

Abstract: The ketogenic diet (KD), a high-fat, low-carbohydrate dietary approach that is based on the induction of extensive ketone bodies (KB) metabolism, is recently receiving a lot of attention due to its application as effective intervention for multiple ... ...

Abstract	The ketogenic diet (KD), a high-fat, low-carbohydrate dietary approach that is based on the induction of extensive ketone bodies (KB) metabolism, is recently receiving a lot of attention due to its application as effective intervention for multiple metabolic disorders including cardiovascular diseases. Despite its already established clinical use, especially in the treatment of drug-resistant epilepsy, GLUT1 deficiency syndromes and, in selected cases, obesity; the systemic impact of is not yet fully understood. Here, we discuss the evidence for and against the application of ketogenic diets, or ketone bodies precursors, in the etiology of hypertension and endothelial cells dysfunction. We attempt to identify the benefits and potential risks of chronic use of the ketogenic diet, also considering the molecular effects that KB exerts at multiple levels.
MeSH term(s)	Humans ; Ketone Bodies ; Diet, Ketogenic ; Endothelial Cells ; Hypertension ; Carbohydrate Metabolism, Inborn Errors
Chemical Substances	Ketone Bodies
Language	English
Publishing date	2022-11-13
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2022.115346
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Article ; Online: The selected epigenetic effects of phthalates: DBP, BBP and their metabolites: MBP, MBzP on human peripheral blood mononuclear cells (In Vitro).

Sicińska, Paulina / Jabłońska, Ewa / Bukowska, Bożena / Balcerczyk, Aneta / Reszka, Edyta

Toxicology in vitro : an international journal published in association with BIBRA

2022 Volume 82, Page(s) 105369

Abstract: Phthalates are classified as non-genotoxic carcinogens. These compounds do not cause direct DNA damage but may induce indirect DNA lesions leading to cancer development. In the presented paper we have studied the effect of di-n-butyl phthalate (DBP), ... ...

Abstract	Phthalates are classified as non-genotoxic carcinogens. These compounds do not cause direct DNA damage but may induce indirect DNA lesions leading to cancer development. In the presented paper we have studied the effect of di-n-butyl phthalate (DBP), butylbenzyl phthalate (BBP), and their metabolites, such as mono-n-butyl phthalate (MBP) and monobenzyl phthalate (MBzP) on selected epigenetic parameters in human peripheral blood mononuclear cells (PBMCs). The cells were incubated with tested phthalates at 0.001, 0.01 and 0.1 μg/mL for 24 h. Next, global DNA methylation, methylation in the promoter regions of tumor suppressor genes (P16, TP53) and proto-oncogenes (BCL2, CCND1) were assessed as well as the expression profile of the indicated genes was analysed. The obtained results have revealed significant reduction of global DNA methylation level in PBMCs exposed to BBP, MBP and MBzP. Phthalates changed methylation pattern of the tested genes, decreased expression of P16 and TP53 genes and increased the expression of BCL2 and CCND1. In conclusion, our results have shown that the examined phthalates disturbed the processes of methylation and expression of tumor suppressor genes (P16, TP53) and protooncogenes (BCL2, CCND1) in human PBMCs.
MeSH term(s)	Humans ; Dibutyl Phthalate/toxicity ; Epigenesis, Genetic ; Leukocytes, Mononuclear ; Phthalic Acids/toxicity ; Proto-Oncogene Proteins c-bcl-2/metabolism
Chemical Substances	butylbenzyl phthalate (YPC4PJX59M) ; Dibutyl Phthalate (2286E5R2KE) ; monobutyl phthalate (ZI46LWZ45G) ; phthalic acid (6O7F7IX66E) ; Phthalic Acids ; Proto-Oncogene Proteins c-bcl-2
Language	English
Publishing date	2022-04-27
Publishing country	England
Document type	Journal Article
ZDB-ID	639064-x
ISSN	1879-3177 ; 0887-2333
ISSN (online)	1879-3177
ISSN	0887-2333
DOI	10.1016/j.tiv.2022.105369
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Article ; Online: Effects of Rheum rhaponticum and Rheum rhabarbarum extracts on haemostatic activity of blood plasma components and endothelial cells in vitro

Liudvytska, Oleksandra / Ponczek, Michał B. / Krzyżanowska-Kowalczyk, Justyna / Kowalczyk, Mariusz / Balcerczyk, Aneta / Kolodziejczyk-Czepas, Joanna

Journal of Ethnopharmacology. 20232023 Oct. 16, May 16, v. 315 p.116562-

2023

Abstract: Traditional medicine recommends the use of Rheum rhaponticum L. and R. rhabarbarum L. to treat over thirty complaints, including disorders related to the cardiovascular system such as heartache, pains in the pericardium, epistaxis and other types of ... ...

Abstract	Traditional medicine recommends the use of Rheum rhaponticum L. and R. rhabarbarum L. to treat over thirty complaints, including disorders related to the cardiovascular system such as heartache, pains in the pericardium, epistaxis and other types of haemorrhage, blood purification as well as disorders of venous circulation. This work was dedicated to examining for the first time the effects of extracts from petioles and roots of R. rhaponticum and R. rhabarbarum, as well as two stilbene compounds (rhapontigenin and rhaponticin) on the haemostatic activity of endothelial cells and functionality of blood plasma components of the haemostatic system. The study was based on three main experimental modules, including the activity of proteins of the human blood plasma coagulation cascade and the fibrinolytic system as well as analyses of the haemostatic activity of human vascular endothelial cells. Additionally, interactions of the main components of the rhubarb extracts with crucial serine proteases of the coagulation cascade and fibrinolysis (i.e. thrombin, the coagulation factor Xa and plasmin) were analyzed in silico. The examined extracts displayed anticoagulant properties and significantly reduced the tissue factor-induced clotting of human blood plasma (by about 40%). Inhibitory effects of the tested extracts on thrombin and the coagulation factor Xa (FXa) were found as well. For the extracts, the IC₅₀ was ranging from 20.26 to 48.11 μg/ml. Modulatory effects on the haemostatic response of endothelial cells, including the release of von Willebrand factor, tissue-type plasminogen activator and the plasminogen activator inhibitor-1, have been also found. Our results indicated for the first time that the examined Rheum extracts influenced the haemostatic properties of blood plasma proteins and endothelial cells, with the prevalence of the anticoagulant action. The anticoagulant effect of the investigated extracts may be partly attributed to the inhibition of the FXa and thrombin activities, the key serine proteases of the blood coagulation cascade.
Keywords	Rheum rhabarbarum ; Rheum rhaponticum ; anticoagulant activity ; anticoagulants ; blood circulation ; blood coagulation ; blood plasma ; coagulation ; computer simulation ; fibrinolysis ; hemorrhage ; humans ; pericardium ; plasmin ; plasminogen activator ; plasminogen activator inhibitors ; rhubarb ; stilbenes ; thrombin ; traditional medicine ; Endothelium ; Haemostasis ; HR-QTOF/MS ; Multivariate analyses ; Anthraquinones ; Taxifolin ; Total polyphenol content
Language	English
Dates of publication	2023-0516
Publishing place	Elsevier B.V.
Document type	Article ; Online
ZDB-ID	134511-4
ISSN	1872-7573 ; 0378-8741
ISSN (online)	1872-7573
ISSN	0378-8741
DOI	10.1016/j.jep.2023.116562
Database	NAL-Catalogue (AGRICOLA)

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Article: Citrullination in the pathology of inflammatory and autoimmune disorders: recent advances and future perspectives

Ciesielski, Oskar / Biesiekierska, Marta / Panthu, Baptiste / Soszyński, Mirosław / Pirola, Luciano / Balcerczyk, Aneta

Cellular and molecular life sciences. 2022 Feb., v. 79, no. 2

2022

Abstract: Numerous post-translational modifications (PTMs) govern the collective metabolism of a cell through altering the structure and functions of proteins. The action of the most prevalent PTMs, encompassing phosphorylation, methylation, acylations, ... ...

Abstract	Numerous post-translational modifications (PTMs) govern the collective metabolism of a cell through altering the structure and functions of proteins. The action of the most prevalent PTMs, encompassing phosphorylation, methylation, acylations, ubiquitination and glycosylation is well documented. A less explored protein PTM, conversion of peptidylarginine to citrulline, is the subject of this review. The process of citrullination is catalysed by peptidylarginine deiminases (PADs), a family of conserved enzymes expressed in a variety of human tissues. Accumulating evidence suggest that citrullination plays a significant role in regulating cellular metabolism and gene expression by affecting a multitude of pathways and modulating the chromatin status. Here, we will discuss the biochemical nature of arginine citrullination, the enzymatic machinery behind it and also provide information on the pathological consequences of citrullination in the development of inflammatory diseases (rheumatoid arthritis, multiple sclerosis, psoriasis, systemic lupus erythematosus, periodontitis and COVID-19), cancer and thromboembolism. Finally, developments on inhibitors against protein citrullination and recent clinical trials providing a promising therapeutic approach to inflammatory disease by targeting citrullination are discussed.
Keywords	COVID-19 infection ; arginine ; chromatin ; citrulline ; gene expression ; glycosylation ; humans ; lupus erythematosus ; methylation ; periodontitis ; phosphorylation ; protein-arginine deiminase ; psoriasis ; rheumatoid arthritis ; sclerosis ; therapeutics ; ubiquitination
Language	English
Dates of publication	2022-02
Size	p. 94.
Publishing place	Springer International Publishing
Document type	Article
Note	Review
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-022-04126-3
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Article ; Online: Modulation of Cellular Biochemistry, Epigenetics and Metabolomics by Ketone Bodies. Implications of the Ketogenic Diet in the Physiology of the Organism and Pathological States.

Dąbek, Arkadiusz / Wojtala, Martyna / Pirola, Luciano / Balcerczyk, Aneta

Nutrients

2020 Volume 12, Issue 3

Abstract: Ketone bodies (KBs), comprising β-hydroxybutyrate, acetoacetate and acetone, are a set of fuel molecules serving as an alternative energy source to glucose. KBs are mainly produced by the liver from fatty acids during periods of fasting, and prolonged or ...

Abstract	Ketone bodies (KBs), comprising β-hydroxybutyrate, acetoacetate and acetone, are a set of fuel molecules serving as an alternative energy source to glucose. KBs are mainly produced by the liver from fatty acids during periods of fasting, and prolonged or intense physical activity. In diabetes, mainly type-1, ketoacidosis is the pathological response to glucose malabsorption. Endogenous production of ketone bodies is promoted by consumption of a ketogenic diet (KD), a diet virtually devoid of carbohydrates. Despite its recently widespread use, the systemic impact of KD is only partially understood, and ranges from physiologically beneficial outcomes in particular circumstances to potentially harmful effects. Here, we firstly review ketone body metabolism and molecular signaling, to then link the understanding of ketone bodies' biochemistry to controversies regarding their putative or proven medical benefits. We overview the physiological consequences of ketone bodies' consumption, focusing on (i) KB-induced histone post-translational modifications, particularly β-hydroxybutyrylation and acetylation, which appears to be the core epigenetic mechanisms of activity of β-hydroxybutyrate to modulate inflammation; (ii) inflammatory responses to a KD; (iii) proven benefits of the KD in the context of neuronal disease and cancer; and (iv) consequences of the KD's application on cardiovascular health and on physical performance.
MeSH term(s)	3-Hydroxybutyric Acid/metabolism ; Acetoacetates/metabolism ; Animals ; Diabetes Mellitus, Type 1/diet therapy ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 1/metabolism ; Diabetes Mellitus, Type 1/pathology ; Diet, Ketogenic ; Epigenesis, Genetic ; Epigenomics ; Humans ; Ketone Bodies/genetics ; Ketone Bodies/metabolism ; Ketosis/diet therapy ; Ketosis/genetics ; Ketosis/metabolism ; Ketosis/pathology ; Metabolomics ; Neoplasms/diet therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Nervous System Diseases/diet therapy ; Nervous System Diseases/genetics ; Nervous System Diseases/metabolism ; Nervous System Diseases/pathology
Chemical Substances	Acetoacetates ; Ketone Bodies ; acetoacetic acid (4ZI204Y1MC) ; 3-Hydroxybutyric Acid (TZP1275679)
Language	English
Publishing date	2020-03-17
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu12030788
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Article ; Online: Epigallocatechin-3-gallate (EGCG) Alters Histone Acetylation and Methylation and Impacts Chromatin Architecture Profile in Human Endothelial Cells.

Ciesielski, Oskar / Biesiekierska, Marta / Balcerczyk, Aneta

Molecules (Basel, Switzerland)

2020 Volume 25, Issue 10

Abstract: Epigallocatechin gallate (EGCG), the main green tea polyphenol, exerts a wide variety of biological actions. Epigenetically, the catechin has been classified as a DNMTs inhibitor, however, its impact on histone modifications and chromatin structure is ... ...

Abstract	Epigallocatechin gallate (EGCG), the main green tea polyphenol, exerts a wide variety of biological actions. Epigenetically, the catechin has been classified as a DNMTs inhibitor, however, its impact on histone modifications and chromatin structure is still poorly understood. The purpose of this study was to find the impact of EGCG on the histone posttranslational modifications machinery and chromatin remodeling in human endothelial cells of both microvascular (HMEC-1) and vein (HUVECs) origin. We analyzed the methylation and acetylation status of histones (Western blotting), as well as assessed the activity (fluorometric assay kit) and gene expression (qPCR) of the enzymes playing a prominent role in shaping the human epigenome. The performed analyses showed that EGCG increases histone acetylation (H3K9/14ac, H3ac), and methylation of both active (H3K4me3) and repressive (H3K9me3) chromatin marks. We also found that the catechin acts as an HDAC inhibitor in cellular and cell-free models. Additionally, we observed that EGCG affects chromatin architecture by reducing the expression of heterochromatin binding proteins: HP1α, HP1γ. Our results indicate that EGCG promotes chromatin relaxation in human endothelial cells and presents a broad epigenetic potential affecting expression and activity of epigenome modulators including HDAC5 and 7, p300, CREBP, LSD1 or KMT2A.
MeSH term(s)	Acetylation/drug effects ; Activating Transcription Factor 2/genetics ; Activating Transcription Factor 2/metabolism ; Catechin/analogs & derivatives ; Catechin/isolation & purification ; Catechin/pharmacology ; Cell Line ; Chromatin/chemistry ; Chromatin/drug effects ; Chromatin/metabolism ; Chromosomal Proteins, Non-Histone/genetics ; Chromosomal Proteins, Non-Histone/metabolism ; Epigenesis, Genetic ; Histone Deacetylase Inhibitors/isolation & purification ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylases/genetics ; Histone Deacetylases/metabolism ; Histone Demethylases/genetics ; Histone Demethylases/metabolism ; Histone-Lysine N-Methyltransferase/genetics ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/genetics ; Histones/metabolism ; Human Umbilical Vein Endothelial Cells/cytology ; Human Umbilical Vein Endothelial Cells/drug effects ; Human Umbilical Vein Endothelial Cells/metabolism ; Humans ; Methylation/drug effects ; Myeloid-Lymphoid Leukemia Protein/genetics ; Myeloid-Lymphoid Leukemia Protein/metabolism ; Protein Processing, Post-Translational/drug effects ; Tea/chemistry ; p300-CBP Transcription Factors/genetics ; p300-CBP Transcription Factors/metabolism
Chemical Substances	ATF2 protein, human ; Activating Transcription Factor 2 ; CBX3 protein, human ; Chromatin ; Chromosomal Proteins, Non-Histone ; Histone Deacetylase Inhibitors ; Histones ; KMT2A protein, human ; Tea ; histone H3 trimethyl Lys4 ; heterochromatin-specific nonhistone chromosomal protein HP-1 (107283-02-3) ; Myeloid-Lymphoid Leukemia Protein (149025-06-9) ; Catechin (8R1V1STN48) ; epigallocatechin gallate (BQM438CTEL) ; Histone Demethylases (EC 1.14.11.-) ; KDM1A protein, human (EC 1.5.-) ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; p300-CBP Transcription Factors (EC 2.3.1.48) ; p300-CBP-associated factor (EC 2.3.1.48) ; HDAC5 protein, human (EC 3.5.1.98) ; HDAC7 protein, human (EC 3.5.1.98) ; Histone Deacetylases (EC 3.5.1.98)
Language	English
Publishing date	2020-05-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules25102326
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Article: Modulation of Cellular Biochemistry, Epigenetics and Metabolomics by Ketone Bodies. Implications of the Ketogenic Diet in the Physiology of the Organism and Pathological States

Dąbek, Arkadiusz / Wojtala, Martyna / Pirola, Luciano / Balcerczyk, Aneta

Nutrients. 2020 Mar. 17, v. 12, no. 3

2020

Abstract	Ketone bodies (KBs), comprising β-hydroxybutyrate, acetoacetate and acetone, are a set of fuel molecules serving as an alternative energy source to glucose. KBs are mainly produced by the liver from fatty acids during periods of fasting, and prolonged or intense physical activity. In diabetes, mainly type-1, ketoacidosis is the pathological response to glucose malabsorption. Endogenous production of ketone bodies is promoted by consumption of a ketogenic diet (KD), a diet virtually devoid of carbohydrates. Despite its recently widespread use, the systemic impact of KD is only partially understood, and ranges from physiologically beneficial outcomes in particular circumstances to potentially harmful effects. Here, we firstly review ketone body metabolism and molecular signaling, to then link the understanding of ketone bodies’ biochemistry to controversies regarding their putative or proven medical benefits. We overview the physiological consequences of ketone bodies’ consumption, focusing on (i) KB-induced histone post-translational modifications, particularly β-hydroxybutyrylation and acetylation, which appears to be the core epigenetic mechanisms of activity of β-hydroxybutyrate to modulate inflammation; (ii) inflammatory responses to a KD; (iii) proven benefits of the KD in the context of neuronal disease and cancer; and (iv) consequences of the KD’s application on cardiovascular health and on physical performance.
Keywords	acetoacetic acid ; acetone ; acetylation ; diabetes ; epigenetics ; fasting ; fatty acids ; fuels ; glucose ; histones ; inflammation ; ketogenic diet ; ketone bodies ; ketosis ; liver ; malabsorption ; metabolomics ; neurons ; nutrients ; physical activity ; post-translational modification ; renewable energy sources
Language	English
Dates of publication	2020-0317
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
Note	NAL-light
ZDB-ID	2518386-2
ISSN	2072-6643
ISSN	2072-6643
DOI	10.3390/nu12030788
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