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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 ; 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: 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
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: 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 : CMLS

2022 Volume 79, Issue 2, Page(s) 94

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.
MeSH term(s)	Autoimmune Diseases/pathology ; COVID-19/pathology ; Citrullination/physiology ; Citrulline/biosynthesis ; Energy Metabolism/physiology ; Extracellular Traps/immunology ; Gene Expression Regulation/genetics ; Humans ; Inflammation/pathology ; Neoplasms/pathology ; Protein Processing, Post-Translational/physiology ; Protein-Arginine Deiminases/metabolism ; SARS-CoV-2/immunology ; Thromboembolism/pathology
Chemical Substances	Citrulline (29VT07BGDA) ; Protein-Arginine Deiminases (EC 3.5.3.15)
Language	English
Publishing date	2022-01-25
Publishing country	Switzerland
Document type	Journal Article ; 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: Rheum rhaponticum

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

Nutrients

2023 Volume 15, Issue 4

Abstract: Background: Inflammation, endothelial dysfunction, and alterations in blood physiology are key factors contributing to atherosclerosis and other cardiovascular disorders. Hence, modulation of endothelial function and reducing its pro-inflammatory and ... ...

Abstract	Background: Inflammation, endothelial dysfunction, and alterations in blood physiology are key factors contributing to atherosclerosis and other cardiovascular disorders. Hence, modulation of endothelial function and reducing its pro-inflammatory and pro-thrombotic activity is considered one of the most important cardioprotective strategies. This study aimed to evaluate the anti-inflammatory potential of rhubarb extracts isolated from petioles and underground organs of Methods: Analysis of the anti-inflammatory effects of the indicated rhubarb-derived substances involved different aspects of the endothelial cells' (HUVECs) response: release of the inflammatory mediators; cyclooxygenase (COX-2) and 5-lipoxygenase (5-LOX) expression as well as the recruitment of leukocytes to the activated HUVECs. The ability of the rhubarb-derived extracts to inhibit COX-2 and 5-LOX activities was examined as well. The study was supplemented with the in silico analysis of major components of the analyzed extracts' interactions with COX-2 and 5-LOX. Results: The obtained results indicated that the examined plant extracts and stilbenes possess anti-inflammatory properties and influence the inflammatory response of endothelial cells. Biochemical and in silico tests revealed significant inhibition of COX-2, with special importance of rhaponticin, as a compound abundant in both plant species. In addition to the reduction in COX-2 gene expression and enzyme activity, a decrease in the cytokine level and leukocyte influx was observed. Biochemical tests and computational analyses indicate that some components of rhubarb extracts may act as COX-2 inhibitors, with marginal inhibitory effect on 5-LOX.
MeSH term(s)	Anti-Inflammatory Agents ; Cyclooxygenase 2 ; Endothelial Cells/drug effects ; Plant Extracts/pharmacology ; Rheum/chemistry ; Humans ; Human Umbilical Vein Endothelial Cells
Chemical Substances	Anti-Inflammatory Agents ; Cyclooxygenase 2 (EC 1.14.99.1) ; Plant Extracts ; rhapontin (K691M2Z08V)
Language	English
Publishing date	2023-02-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu15040949
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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 ; Online: Epigallocatechin-3-gallate (EGCG) Alters Histone Acetylation and Methylation and Impacts Chromatin Architecture Profile in Human Endothelial Cells

Oskar Ciesielski / Marta Biesiekierska / Aneta Balcerczyk

Molecules, Vol 25, Iss 2326, p

2020 Volume 2326

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.
Keywords	epigallocatechin gallate ; epigenetics ; histone acetylation ; histone methylation ; endothelial cells ; Organic chemistry ; QD241-441
Subject code	570
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article: The Methylation Status of the Epigenome: Its Emerging Role in the Regulation of Tumor Angiogenesis and Tumor Growth, and Potential for Drug Targeting.

Pirola, Luciano / Ciesielski, Oskar / Balcerczyk, Aneta

Cancers

2018 Volume 10, Issue 8

Abstract: Approximately 50 years ago, Judah Folkman raised the concept of inhibiting tumor angiogenesis for treating solid tumors. The development of anti-angiogenic drugs would decrease or even arrest tumor growth by restricting the delivery of oxygen and ... ...

Abstract	Approximately 50 years ago, Judah Folkman raised the concept of inhibiting tumor angiogenesis for treating solid tumors. The development of anti-angiogenic drugs would decrease or even arrest tumor growth by restricting the delivery of oxygen and nutrient supplies, while at the same time display minimal toxic side effects to healthy tissues. Bevacizumab (Avastin)-a humanized monoclonal anti VEGF-A antibody-is now used as anti-angiogenic drug in several forms of cancers, yet with variable results. Recent years brought significant progresses in our understanding of the role of chromatin remodeling and epigenetic mechanisms in the regulation of angiogenesis and tumorigenesis. Many inhibitors of DNA methylation as well as of histone methylation, have been successfully tested in preclinical studies and some are currently undergoing evaluation in phase I, II or III clinical trials, either as cytostatic molecules-reducing the proliferation of cancerous cells-or as tumor angiogenesis inhibitors. In this review, we will focus on the methylation status of the vascular epigenome, based on the genomic DNA methylation patterns with DNA methylation being mainly transcriptionally repressive, and lysine/arginine histone post-translational modifications which either promote or repress the chromatin transcriptional state. Finally, we discuss the potential use of "epidrugs" in efficient control of tumor growth and tumor angiogenesis.
Language	English
Publishing date	2018-08-10
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers10080268
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Article ; Online: The Epigenetic Profile of Tumor Endothelial Cells. Effects of Combined Therapy with Antiangiogenic and Epigenetic Drugs on Cancer Progression.

Ciesielski, Oskar / Biesiekierska, Marta / Panthu, Baptiste / Vialichka, Varvara / Pirola, Luciano / Balcerczyk, Aneta

International journal of molecular sciences

2020 Volume 21, Issue 7

Abstract: Tumors require a constant supply of nutrients to grow which are provided through tumor blood vessels. To metastasize, tumors need a route to enter circulation, that route is also provided by tumor blood vessels. Thus, angiogenesis is necessary for both ... ...

Abstract	Tumors require a constant supply of nutrients to grow which are provided through tumor blood vessels. To metastasize, tumors need a route to enter circulation, that route is also provided by tumor blood vessels. Thus, angiogenesis is necessary for both tumor progression and metastasis. Angiogenesis is tightly regulated by a balance of angiogenic and antiangiogenic factors. Angiogenic factors of the vascular endothelial growth factor (VEGF) family lead to the activation of endothelial cells, proliferation, and neovascularization. Significant VEGF-A upregulation is commonly observed in cancer cells, also due to hypoxic conditions, and activates endothelial cells (ECs) by paracrine signaling stimulating cell migration and proliferation, resulting in tumor-dependent angiogenesis. Conversely, antiangiogenic factors inhibit angiogenesis by suppressing ECs activation. One of the best-known anti-angiogenic factors is thrombospondin-1 (TSP-1). In pathological angiogenesis, the balance shifts towards the proangiogenic factors and an angiogenic switch that promotes tumor angiogenesis. Here, we review the current literature supporting the notion of the existence of two different endothelial lineages: normal endothelial cells (NECs), representing the physiological form of vascular endothelium, and tumor endothelial cells (TECs), which are strongly promoted by the tumor microenvironment and are biologically different from NECs. The angiogenic switch would be also important for the explanation of the differences between NECs and TECs, as angiogenic factors, cytokines and growth factors secreted into the tumor microenvironment may cause genetic instability. In this review, we focus on the epigenetic differences between the two endothelial lineages, which provide a possible window for pharmacological targeting of TECs.
MeSH term(s)	Animals ; Biomarkers, Tumor ; Endothelial Cells/metabolism ; Energy Metabolism ; Epigenesis, Genetic ; Epigenome ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Molecular Targeted Therapy ; Neoplasm Metastasis ; Neoplasm Staging ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Neovascularization, Pathologic/drug therapy ; Neovascularization, Pathologic/genetics ; Neovascularization, Pathologic/metabolism ; Transcriptome
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2020-04-09
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/ijms21072606
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Article ; Online: The Epigenetic Profile of Tumor Endothelial Cells. Effects of Combined Therapy with Antiangiogenic and Epigenetic Drugs on Cancer Progression

Oskar Ciesielski / Marta Biesiekierska / Baptiste Panthu / Varvara Vialichka / Luciano Pirola / Aneta Balcerczyk

International Journal of Molecular Sciences, Vol 21, Iss 2606, p

2020 Volume 2606

Abstract	Tumors require a constant supply of nutrients to grow which are provided through tumor blood vessels. To metastasize, tumors need a route to enter circulation, that route is also provided by tumor blood vessels. Thus, angiogenesis is necessary for both tumor progression and metastasis. Angiogenesis is tightly regulated by a balance of angiogenic and antiangiogenic factors. Angiogenic factors of the vascular endothelial growth factor (VEGF) family lead to the activation of endothelial cells, proliferation, and neovascularization. Significant VEGF-A upregulation is commonly observed in cancer cells, also due to hypoxic conditions, and activates endothelial cells (ECs) by paracrine signaling stimulating cell migration and proliferation, resulting in tumor-dependent angiogenesis. Conversely, antiangiogenic factors inhibit angiogenesis by suppressing ECs activation. One of the best-known anti-angiogenic factors is thrombospondin-1 (TSP-1). In pathological angiogenesis, the balance shifts towards the proangiogenic factors and an angiogenic switch that promotes tumor angiogenesis. Here, we review the current literature supporting the notion of the existence of two different endothelial lineages: normal endothelial cells (NECs), representing the physiological form of vascular endothelium, and tumor endothelial cells (TECs), which are strongly promoted by the tumor microenvironment and are biologically different from NECs. The angiogenic switch would be also important for the explanation of the differences between NECs and TECs, as angiogenic factors, cytokines and growth factors secreted into the tumor microenvironment may cause genetic instability. In this review, we focus on the epigenetic differences between the two endothelial lineages, which provide a possible window for pharmacological targeting of TECs.
Keywords	tumor endothelial cells ; epigenetics ; cancer ; metastasis ; antiangiogenic treatment ; epi-drugs ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2020-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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