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Article ; Online: Intraperitoneally administered native and lauroyl-modified hyaluronan films: Pharmacokinetic and metabolism studies

Brtková, Barbora / Hermannová, Martina / Chmelař, Josef / Nešporová, Kristina / Kocurková, Anna / Kubala, Lukáš / Ambrožová, Gabriela / Velebný, Vladimír / Šimek, Matěj

Carbohydrate Polymers. 2023 Jan., v. 299 p.120201-

2023

Abstract: Hyaluronan is being investigated extensively as a biocompatible and biodegradable material for use in biomedical applications. While the derivatization of hyaluronan broadens its potential therapeutic use, the pharmacokinetics and metabolization of the ... ...

Abstract	Hyaluronan is being investigated extensively as a biocompatible and biodegradable material for use in biomedical applications. While the derivatization of hyaluronan broadens its potential therapeutic use, the pharmacokinetics and metabolization of the derivatives must be thoroughly investigated. The fate of intraperitoneally-applied native and lauroyl-modified hyaluronan films with varying degrees of substitution was investigated in-vivo employing an exclusive stable isotope-labelling approach and LC-MS analysis. The materials were gradually degraded in peritoneal fluid, lymphatically absorbed, preferentially metabolized in the liver and eliminated without any observable accumulation in the body. Hyaluronan acylation prolongs its presence in the peritoneal cavity depending on the degree of substitution. The safety of acylated hyaluronan derivatives was confirmed via a metabolic study that revealed its degradation into non-toxic metabolites, i.e. native hyaluronan and free fatty acid. Stable isotope-labelling with LC-MS tracking comprises a high-quality procedure for the investigation of the metabolism and biodegradability of hyaluronan-based medical products in-vivo.
Keywords	acylation ; biodegradability ; derivatization ; free fatty acids ; hyaluronic acid ; liver ; metabolic studies ; pharmacokinetics ; therapeutics ; Hyaluronan derivatives ; Implants ; Degradation ; Stable isotope ; In-vivo evaluation
Language	English
Dates of publication	2023-01
Publishing place	Elsevier Ltd
Document type	Article ; Online
ZDB-ID	1501516-6
ISSN	1879-1344 ; 0144-8617
ISSN (online)	1879-1344
ISSN	0144-8617
DOI	10.1016/j.carbpol.2022.120201
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Intraperitoneally administered native and lauroyl-modified hyaluronan films: Pharmacokinetic and metabolism studies.

Brtková, Barbora / Hermannová, Martina / Chmelař, Josef / Nešporová, Kristina / Kocurková, Anna / Kubala, Lukáš / Ambrožová, Gabriela / Velebný, Vladimír / Šimek, Matěj

Carbohydrate polymers

2022 Volume 299, Page(s) 120201

Abstract	Hyaluronan is being investigated extensively as a biocompatible and biodegradable material for use in biomedical applications. While the derivatization of hyaluronan broadens its potential therapeutic use, the pharmacokinetics and metabolization of the derivatives must be thoroughly investigated. The fate of intraperitoneally-applied native and lauroyl-modified hyaluronan films with varying degrees of substitution was investigated in-vivo employing an exclusive stable isotope-labelling approach and LC-MS analysis. The materials were gradually degraded in peritoneal fluid, lymphatically absorbed, preferentially metabolized in the liver and eliminated without any observable accumulation in the body. Hyaluronan acylation prolongs its presence in the peritoneal cavity depending on the degree of substitution. The safety of acylated hyaluronan derivatives was confirmed via a metabolic study that revealed its degradation into non-toxic metabolites, i.e. native hyaluronan and free fatty acid. Stable isotope-labelling with LC-MS tracking comprises a high-quality procedure for the investigation of the metabolism and biodegradability of hyaluronan-based medical products in-vivo.
MeSH term(s)	Hyaluronic Acid ; Acylation ; Chromatography, Liquid ; Fatty Acids, Nonesterified ; Isotopes
Chemical Substances	Hyaluronic Acid (9004-61-9) ; Fatty Acids, Nonesterified ; Isotopes
Language	English
Publishing date	2022-10-10
Publishing country	England
Document type	Journal Article
ZDB-ID	1501516-6
ISSN	1879-1344 ; 0144-8617
ISSN (online)	1879-1344
ISSN	0144-8617
DOI	10.1016/j.carbpol.2022.120201
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Article ; Online: Endogenously produced hyaluronan contributes to the regulation of peritoneal adhesion development.

Kocurkova, Anna / Kerberova, Michaela / Nesporova, Kristina / Lehka, Katerina / Sandanusova, Miriam / Simek, Matej / Velebny, Vladimir / Kubala, Lukas / Ambrozova, Gabriela

BioFactors (Oxford, England)

2023 Volume 49, Issue 4, Page(s) 940–955

Abstract: Peritoneal adhesions are postsurgical fibrotic complications connected to peritoneal inflammation. The exact mechanism of development is unknown; however, an important role is attributed to activated mesothelial cells (MCs) overproducing macromolecules ... ...

Abstract	Peritoneal adhesions are postsurgical fibrotic complications connected to peritoneal inflammation. The exact mechanism of development is unknown; however, an important role is attributed to activated mesothelial cells (MCs) overproducing macromolecules of extracellular matrix (ECM), including hyaluronic acid (HA). It was suggested that endogenously-produced HA contributes to the regulation of different fibrosis-related pathologies. However, little is known about the role of altered HA production in peritoneal fibrosis. We focused on the consequences of the increased turnover of HA in the murine model of peritoneal adhesions. Changes of HA metabolism were observed in early phases of peritoneal adhesion development in vivo. To study the mechanism, human MCs MeT-5A and murine MCs isolated from the peritoneum of healthy mice were pro-fibrotically activated by transforming growth factor β (TGFβ), and the production of HA was attenuated by two modulators of carbohydrate metabolism, 4-methylumbelliferone (4-MU) and 2-deoxyglucose (2-DG). The attenuation of HA production was mediated by upregulation of HAS2 and downregulation of HYAL2 and connected to the lower expression of pro-fibrotic markers, including fibronectin and α-smooth muscle actin (αSMA). Moreover, the inclination of MCs to form fibrotic clusters was also downregulated, particularly in 2-DG-treated cells. The effects of 2-DG, but not 4-MU, were connected to changes in cellular metabolism. Importantly, the inhibition of AKT phosphorylation was observed after the use of both HA production inhibitors. In summary, we identified endogenous HA as an important regulator of peritoneal fibrosis, not just a passive player during this pathological process.
MeSH term(s)	Humans ; Mice ; Animals ; Hyaluronic Acid/metabolism ; Peritoneal Fibrosis/genetics ; Peritoneal Fibrosis/metabolism ; Transforming Growth Factor beta/metabolism ; Extracellular Matrix/genetics ; Extracellular Matrix/metabolism ; Deoxyglucose
Chemical Substances	Hyaluronic Acid (9004-61-9) ; Transforming Growth Factor beta ; Deoxyglucose (9G2MP84A8W)
Language	English
Publishing date	2023-05-08
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	59230-4
ISSN	1872-8081 ; 0951-6433
ISSN (online)	1872-8081
ISSN	0951-6433
DOI	10.1002/biof.1957
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Article ; Online: How the molecular weight affects the in vivo fate of exogenous hyaluronan delivered intravenously: A stable-isotope labelling strategy.

Šimek, Matěj / Nešporová, Kristina / Kocurková, Anna / Foglová, Tereza / Ambrožová, Gabriela / Velebný, Vladimír / Kubala, Lukáš / Hermannová, Martina

Carbohydrate polymers

2021 Volume 263, Page(s) 117927

Abstract: There is inconsistent information regarding the size effects of exogenously given hyaluronan on its in vivo fate. The data are often biased by the poor quality of hyaluronan and non-ideal labelling strategies used for resolving exogenous/endogenous ... ...

Abstract	There is inconsistent information regarding the size effects of exogenously given hyaluronan on its in vivo fate. The data are often biased by the poor quality of hyaluronan and non-ideal labelling strategies used for resolving exogenous/endogenous hyaluronan, which only monitor the label and not hyaluronan itself. To overcome these drawbacks and establish the pharmacokinetics of intravenous hyaluronan in relation to its M
MeSH term(s)	Administration, Intravenous ; Animals ; Bone and Bones/metabolism ; Carbon Isotopes/chemistry ; Carbon Isotopes/metabolism ; Carbon Isotopes/pharmacokinetics ; Cartilage/metabolism ; Cyclic ADP-Ribose/metabolism ; Drug Elimination Routes ; Female ; Hyaluronic Acid/chemistry ; Hyaluronic Acid/metabolism ; Hyaluronic Acid/pharmacokinetics ; Isotope Labeling/methods ; Mice, Inbred BALB C ; Molecular Weight ; Tissue Distribution ; Uridine Diphosphate Glucose/metabolism ; Uridine Diphosphate N-Acetylglucosamine/metabolism ; Mice
Chemical Substances	Carbon Isotopes ; Cyclic ADP-Ribose (119340-53-3) ; Uridine Diphosphate N-Acetylglucosamine (528-04-1) ; Hyaluronic Acid (9004-61-9) ; Carbon-13 (FDJ0A8596D) ; Uridine Diphosphate Glucose (V50K1D7P4Y)
Language	English
Publishing date	2021-03-17
Publishing country	England
Document type	Journal Article
ZDB-ID	1501516-6
ISSN	1879-1344 ; 0144-8617
ISSN (online)	1879-1344
ISSN	0144-8617
DOI	10.1016/j.carbpol.2021.117927
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Article: How the molecular weight affects the in vivo fate of exogenous hyaluronan delivered intravenously: A stable-isotope labelling strategy

Šimek, Matěj / Nešporová, Kristina / Kocurková, Anna / Foglová, Tereza / Ambrožová, Gabriela / Velebný, Vladimír / Kubala, Lukáš / Hermannová, Martina

Carbohydrate polymers. 2021 July 01, v. 263

2021

Abstract	There is inconsistent information regarding the size effects of exogenously given hyaluronan on its in vivo fate. The data are often biased by the poor quality of hyaluronan and non-ideal labelling strategies used for resolving exogenous/endogenous hyaluronan, which only monitor the label and not hyaluronan itself. To overcome these drawbacks and establish the pharmacokinetics of intravenous hyaluronan in relation to its Mw, ¹³C-labelled HA of five Mws from 13.6–1562 kDa was prepared and administered to mice at doses 25−50 mg kg–¹. The elimination efficiency increased with decreasing Mw. Low Mw hyaluronan was rapidly eliminated as small hyaluronan fragments in urine, while high Mw hyaluronan exhibited saturable kinetics and complete metabolization within 48 h. All tested Mws exhibited a similar uptake by liver cells and metabolization into activated sugars. ¹³C-labelling combined with LC–MS provides an excellent approach to elucidating in vivo fate and biological activities of hyaluronan.
Keywords	hyaluronic acid ; intravenous injection ; liver ; molecular weight ; pharmacokinetics ; stable isotopes ; urine
Language	English
Dates of publication	2021-0701
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1501516-6
ISSN	1879-1344 ; 0144-8617
ISSN (online)	1879-1344
ISSN	0144-8617
DOI	10.1016/j.carbpol.2021.117927
Database	NAL-Catalogue (AGRICOLA)

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Article: An Effective Translation: The Development of Hyaluronan-Based Medical Products From the Physicochemical, and Preclinical Aspects.

Huerta-Ángeles, Gloria / Nešporová, Kristina / Ambrožová, Gabriela / Kubala, Lukas / Velebný, Vladimir

Frontiers in bioengineering and biotechnology

2018 Volume 6, Page(s) 62

Abstract: This review shows the steps toward material selection focalized on the design and development of medical devices based on hyaluronan (HA). The selection is based on chemical and mechanical properties, biocompatibility, sterilization, safety, and scale-up ...

Abstract	This review shows the steps toward material selection focalized on the design and development of medical devices based on hyaluronan (HA). The selection is based on chemical and mechanical properties, biocompatibility, sterilization, safety, and scale-up costs. These facts play a vital role in the industrialization process. Approved medical devices containing-HA are illustrated to identify key parameters. The first part of this work involves the steps toward a complete characterization of chemical and mechanical aspects, reproducibility of the processes and scale up. In a second stage, we aimed to describe the preclinical
Language	English
Publishing date	2018-05-17
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2719493-0
ISSN	2296-4185
ISSN	2296-4185
DOI	10.3389/fbioe.2018.00062
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Article ; Online: Lipopolysaccharides from

Moosová, Zdena / Šindlerová, Lenka / Ambrůzová, Barbora / Ambrožová, Gabriela / Vašíček, Ondřej / Velki, Mirna / Babica, Pavel / Kubala, Lukáš

Toxins

2019 Volume 11, Issue 4

Abstract: Massive toxic blooms of cyanobacteria represent a major threat to water supplies worldwide. Here, the biological activities of lipopolysaccharide (LPS) isolated ... ...

Abstract	Massive toxic blooms of cyanobacteria represent a major threat to water supplies worldwide. Here, the biological activities of lipopolysaccharide (LPS) isolated from
MeSH term(s)	Antigens, CD/metabolism ; CD11b Antigen/metabolism ; Cell Adhesion Molecules/metabolism ; Cells, Cultured ; Cytokines/blood ; Eutrophication ; GPI-Linked Proteins/metabolism ; Humans ; Immunity, Innate/drug effects ; Laboratories ; Leukocytes, Mononuclear/drug effects ; Leukocytes, Mononuclear/metabolism ; Lipopolysaccharides/toxicity ; Microcystis ; Pyrogens/toxicity
Chemical Substances	Antigens, CD ; CD11b Antigen ; CEACAM8 protein, human ; Cell Adhesion Molecules ; Cytokines ; GPI-Linked Proteins ; ITGAM protein, human ; Lipopolysaccharides ; Pyrogens
Language	English
Publishing date	2019-04-11
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2518395-3
ISSN	2072-6651 ; 2072-6651
ISSN (online)	2072-6651
ISSN	2072-6651
DOI	10.3390/toxins11040218
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Article ; Online: Biodegradable free-standing films from lauroyl derivatives of hyaluronan.

Chmelař, Josef / Mrázek, Jiří / Hermannová, Martina / Kubala, Lukáš / Ambrožová, Gabriela / Kocurková, Anna / Drmota, Tomáš / Nešporová, Kristina / Grusová, Ludmila / Velebný, Vladimír

Carbohydrate polymers

2019 Volume 224, Page(s) 115162

Abstract: Hyaluronan (HA) films exhibit properties suitable for medical applications, but the solubility of HA limits their use in aqueous environments. This can be overcome by modifying HA with hydrophobic side groups that enable physical cross-linking. In this ... ...

Abstract	Hyaluronan (HA) films exhibit properties suitable for medical applications, but the solubility of HA limits their use in aqueous environments. This can be overcome by modifying HA with hydrophobic side groups that enable physical cross-linking. In this work, we present water insoluble free-standing films from lauroyl modified HA as novel biomaterials with properties tuneable by the degree of HA substitution. The films are homogeneous, mechanically strong, and flexible and can be sterilized by ethylenoxide. To characterize the films, we measured their thickness, dry mass, content of residual organic solvent, mechanical properties, swelling and enzymatic degradation. The safety and biodegradability of the films were tested both in-vitro and in-vivo, showing that the films are safe and that their degradation can be tailored by the degree of HA substitution.
MeSH term(s)	Animals ; Biocompatible Materials/adverse effects ; Biocompatible Materials/chemistry ; Biocompatible Materials/metabolism ; Hyaluronic Acid/adverse effects ; Hyaluronic Acid/chemistry ; Hyaluronic Acid/metabolism ; Hydrophobic and Hydrophilic Interactions ; Male ; Mechanical Phenomena ; Mice ; Mice, Inbred C57BL ; Safety ; Solubility
Chemical Substances	Biocompatible Materials ; Hyaluronic Acid (9004-61-9)
Language	English
Publishing date	2019-08-08
Publishing country	England
Document type	Journal Article
ZDB-ID	1501516-6
ISSN	1879-1344 ; 0144-8617
ISSN (online)	1879-1344
ISSN	0144-8617
DOI	10.1016/j.carbpol.2019.115162
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Article ; Online: Endogenously-Produced Hyaluronan and Its Potential to Regulate the Development of Peritoneal Adhesions.

Kocurkova, Anna / Nesporova, Kristina / Sandanusova, Miriam / Kerberova, Michaela / Lehka, Katerina / Velebny, Vladimir / Kubala, Lukas / Ambrozova, Gabriela

Biomolecules

2021 Volume 12, Issue 1

Abstract: Formation of peritoneal adhesions (PA) is one of the major complications following intra-abdominal surgery. It is primarily caused by activation of the mesothelial layer and underlying tissues in the peritoneal membrane resulting in the transition of ... ...

Abstract	Formation of peritoneal adhesions (PA) is one of the major complications following intra-abdominal surgery. It is primarily caused by activation of the mesothelial layer and underlying tissues in the peritoneal membrane resulting in the transition of mesothelial cells (MCs) and fibroblasts to a pro-fibrotic phenotype. Pro-fibrotic transition of MCs-mesothelial-to-mesenchymal transition (MMT), and fibroblasts activation to myofibroblasts are interconnected to changes in cellular metabolism and culminate in the deposition of extracellular matrix (ECM) in the form of fibrotic tissue between injured sides in the abdominal cavity. However, ECM is not only a mechanical scaffold of the newly synthetized tissue but reciprocally affects fibrosis development. Hyaluronan (HA), an important component of ECM, is a non-sulfated glycosaminoglycan consisting of N-acetyl-D-glucosamine (GlcNAc) and D-glucuronic acid (GlcUA) that can affect the majority of processes involved in PA formation. This review considers the role of endogenously produced HA in the context of different fibrosis-related pathologies and its overlap in the development of PA.
MeSH term(s)	Epithelium ; Fibroblasts/physiology ; Hyaluronic Acid/metabolism ; Myofibroblasts/metabolism ; Peritoneum/metabolism
Chemical Substances	Hyaluronic Acid (9004-61-9)
Language	English
Publishing date	2021-12-29
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom12010045
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Article ; Online: Lipopolysaccharides from Microcystis Cyanobacteria-Dominated Water Bloom and from Laboratory Cultures Trigger Human Immune Innate Response

Zdena Moosová / Lenka Šindlerová / Barbora Ambrůzová / Gabriela Ambrožová / Ondřej Vašíček / Mirna Velki / Pavel Babica / Lukáš Kubala

Toxins, Vol 11, Iss 4, p

2019 Volume 218

Abstract: Massive toxic blooms of cyanobacteria represent a major threat to water supplies worldwide. Here, the biological activities of lipopolysaccharide (LPS) isolated from Microcystis aeruginosa , the most prominent cyanobacteria in water bloom, were studied. ... ...

Abstract	Massive toxic blooms of cyanobacteria represent a major threat to water supplies worldwide. Here, the biological activities of lipopolysaccharide (LPS) isolated from Microcystis aeruginosa , the most prominent cyanobacteria in water bloom, were studied. LPS was isolated from complex environmental water bloom samples dominated by M. aeruginosa , and from laboratory cultures of non-axenic as well as axenic M. aeruginosa strains PCC7806 and HAMBI/UHCC130. Employing human blood-based in vitro tests, the LPS isolated from complex water bloom revealed the priming of both major blood phagocyte population monocytes and polymorphonuclear leukocytes documented by the increased surface expression of CD11b and CD66b. This was accompanied by a water bloom LPS-mediated dose-dependent induction of tumor necrosis factor α, interleukin-1β, and interleukin-6 production. In accordance with its priming effects, water bloom LPS induced significant activation of p38 and ERK1/2 kinases, as well as NF-κB phosphorylation, in isolated polymorphonuclear leukocytes. Interestingly, the pro-inflammatory potential of LPS from the axenic strain of M. aeruginosa was not lower compared to that of LPS isolated from non-axenic strains. In contrast to the biological activity, water bloom LPS revealed almost twice higher pyrogenicity levels compared to Escherichia coli LPS, as analyzed by the PyroGene test. Moreover, LPS from the non-axenic culture exhibited higher endotoxin activity in comparison to LPS from axenic strains. Taking the above findings together, M. aeruginosa LPS can contribute to the health risks associated with contamination by complex water bloom mass.
Keywords	water bloom ; cyanobacteria ; endotoxin ; lipopolysaccharide ; inflammation ; leukocytes ; Medicine ; R
Subject code	630
Language	English
Publishing date	2019-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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