Iduronic Acid in Chondroitin/Dermatan Sulfate Malmström, Anders; Bartolini, Barbara; Thelin, Martin A. ...
The journal of histochemistry and cytochemistry,
12/2012, Volume:
60, Issue:
12
Journal Article
Peer reviewed
Open access
The ability of chondroitin/dermatan sulfate (CS/DS) to convey biological information is enriched by the presence of iduronic acid. DS-epimerases 1 and 2 (DS-epi1 and 2), in conjunction with ...DS-4-O-sulfotransferase 1, are the enzymes responsible for iduronic acid biosynthesis and will be the major focus of this review. CS/DS proteoglycans (CS/DS-PGs) are ubiquitously found in connective tissues, basement membranes, and cell surfaces or are stored intracellularly. Such wide distribution reflects the variety of biological roles in which they are involved, from extracellular matrix organization to regulation of processes such as proliferation, migration, adhesion, and differentiation. They play roles in inflammation, angiogenesis, coagulation, immunity, and wound healing. Such versatility is achieved thanks to their variable composition, both in terms of protein core and the fine structure of the CS/DS chains. Excellent reviews have been published on the collective and individual functions of each CS/DS-PG. This short review presents the biosynthesis and functions of iduronic acid-containing structures, also as revealed by the analysis of the DS-epi1- and 2-deficient mouse models.
Abstract
Background
Remdesivir is a prodrug of the nucleoside analogue GS-441524 and is under evaluation for treatment of SARS-CoV-2-infected patients.
Objectives
To evaluate the pharmacokinetics of ...remdesivir and GS-441524 in plasma, bronchoalveolar aspirate (BAS) and CSF in two critically ill COVID-19 patients.
Methods
Remdesivir was administered at 200 mg loading dose on the first day followed by 12 days of 100 mg in two critically ill patients. Blood samples were collected immediately after (C0) and at 1 (C1) and 24 h (C24) after intravenous administration on day 3 until day 9. BAS samples were collected on Days 4, 7 and 9 from both patients while one CSF on Day 7 was obtained in one patient. Remdesivir and GS-441524 concentrations were measured in these samples using a validated UHPLC-MS/MS method.
Results
We observed higher concentrations of remdesivir at C0 (6- to 7-fold higher than EC50 from in vitro studies) and a notable decay at C1. GS-441524 plasma concentrations reached a peak at C1 and persisted until the next administration. Higher concentrations of GS-441524 were observed in the patient with mild renal dysfunction. Mean BAS/plasma concentration ratios of GS-441524 were 2.3% and 6.4% in Patient 1 and Patient 2, respectively. The CSF concentration found in Patient 2 was 25.7% with respect to plasma. GS-441524 levels in lung and CNS suggest compartmental differences in drug exposure.
Conclusions
We report the first pharmacokinetic evaluation of remdesivir and GS-441524 in recovered COVID-19 patients. Further study of the pharmacokinetic profile of remdesivir, GS-441524 and the intracellular triphosphate form are required.
Fibromodulin is a keratan-sulfate small leucine-rich proteoglycan (SLRP) regulating collagen I and II fibril formation. In vivo studies suggest that, alongside decorin, fibromodulin plays an ...important role in the maintenance of mature tissues. To characterize fibromodulin/decorin differences in binding to type I and II collagen, we tested the collagen CNBr peptides in solid-phase assays. Only one peptide from collagen II and several peptides from collagen I interacted with fibromodulin, pointing to multiple binding sites in the collagen I molecule. By Scatchard-type analysis, the fibromodulin molecule showed only one class of binding sites for collagen I and both low and high affinity (classes of) binding sites for collagen II. Lys/Hyl residues in both collagens are essential for the interaction. Fibril formation assays showed the concomitant presence of fibromodulin and decorin in fibrils and a cumulative inhibitory effect. In solid-phase assays decorin seems to inhibit fibromodulin binding, whereas the contrary does not occur. We found fibromodulin and decorin have similarities and differences that may represent the biochemical basis of redundancy in SLRP function with compensation between different (classes of) SLRPs.
•The survival probability of patients with estrogen receptor (ER) negative breast cancer is higher when the expression of HAS2-AS1 is elevated.•HAS2-AS1 overexpression reduces cell aggressiveness ...only of ER negative and not of ER positive cell lines.•HAS2-AS1 regulates neither hyaluronan accumulation nor hyaluronan synthases expression in ER negative breast cancer cells.•Microarray gene expression profiling reveals that HAS2-AS1 has a pivotal role to regulate the expression of several genes involved in tumorigenesis.•Overexpression of the Long isoform of HAS2-AS1 exon 2 induces mesenchymal to epithelial transition in ER negative breast cancer cells.
Hyaluronan (HA) is a ubiquitous extracellular matrix component playing a crucial role in the regulation of cell behaviors, including cancer. Aggressive breast cancer cells tend to proliferate, migrate and metastatize. Notably, triple-negative breast cancer cells lacking the expression of estrogen receptor (ER) as well as progesterone receptor and HER2 are more aggressive than ER-positive ones. As currently no targeted therapy is available for triple-negative breast cancer, the identification of novel therapeutic targets has a high clinical priority. In ER-negative cells, tumoral behavior can be reduced by inhibiting HA synthesis or silencing the enzymes involved in its metabolism, such as HA synthase 2 (HAS2). HAS2-AS1 is a long non-coding RNA belonging to the natural antisense transcript family which is known to favor HAS2 gene expression and HA synthesis, thus bolstering malignant progression in brain, ovary, and lung tumors. As the role of HAS2-AS1 has not yet been investigated in breast cancer, in this work we report that ER-positive breast cancers had lower HAS2-AS1 expression compared to ER-negative tumors. Moreover, the survival of patients with ER-negative tumors was higher when the expression of HAS2-AS1 was elevated. Experiments with ER-negative cell lines as MDA-MB-231 and Hs 578T revealed that the overexpression of either the full-length HAS2-AS1 or its exon 2 long or short isoforms alone, strongly reduced cell viability, migration, and invasion, whereas HAS2-AS1 silencing increased cell aggressiveness. Unexpectedly, in these ER-negative cell lines, HAS2-AS1 is involved neither in the regulation of HAS2 nor in HA deposition. Finally, transcriptome analysis revealed that HAS2-AS1 modulation affected several pathways, including apoptosis, proliferation, motility, adhesion, epithelial to mesenchymal transition, and signaling, describing this long non-coding RNA as an important regulator of breast cancer cells aggressiveness.
Vascular pathology and the role of hyaluronan Vigetti, Davide; Viola, Manuela; Karousou, Evgenia ...
The scientific world journal/TheScientificWorldjournal,
11/2008, Volume:
8
Journal Article
Peer reviewed
Open access
The development of vascular pathology is often coupled to dramatic alterations of the extracellular matrix (ECM), which provides critical support for vascular tissue as a scaffold for maintaining the ...organization of vascular cells into blood vessels, for blood vessel stabilization, morphogenesis, and for cell proliferation, migration, and survival. Hyaluronan (HA) is an important component of the ECM that has generated increasing interest because of its multitude of functions. HA is a linear polymer belonging to the family of glycosaminoglycans (GAGs), which comprises the major fraction of carbohydrates in ECM. Evidence supports the hypothesis that HA is an important contributor to human aortic smooth muscle cell (AoSMC) migration which represents a crucial point in the onset of pathology. By reducing HA synthesis and therefore the AoSMC motility, 4-Metyllumbelliferone (4-MU) could represent a new molecule with additional beneficial pharmacological effects in vivo.
Hyaluronan (HA) is the only unsulfated glycosaminoglycan (GAG) composed of repeating units of D-glucuronic acid and N-acetylglucosamine. The amount and the molecular weight of HA are important ...factors that regulate the physiology and pathology in several mammalian tissues. In fact hydrated HA makes ECM an ideal environment in which cells can move and proliferate. HA interacting with several receptors at the cellular level plays a critical role in signal transduction responses. The control of the HA synthesis is therefore a critical aspect in ECM and cells biology, but so far the information about this question is scanty. The synthesis of HA is due to several enzymes activities which not only involves its synthetic enzymes on the membranes of the cells (HA synthases 1, 2, 3, isoforms) but also the cytoplasmatic enzymes producing the UDP-sugar precursors. The UDP-sugars availability in cytoplasm is a critical point for the GAG synthesis and it seems to affect particularly the HA production. Eventually, the activity control of the enzymes involved in HA metabolism is obtained throughout both enzyme amount and their postsynthetic covalent modification, as phosphorylation. In fact, it was recently reported that HA synthase 3 may be phosphorylated after specific stimuli, and an increasing body of evidence supports the idea that the synthetic pathway of HA may be carefully regulated in all steps.
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