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Selectins belong to a group of adhesion molecules that fulfill an essential role in immune and inflammatory responses and tissue healing. Selectins are glycoproteins that decode the information carried by glycan structures, and non-covalent interactions of selectins with these glycan structures mediate biological processes. The sialylated and fucosylated tetrasaccharide sLex is an essential glycan recognized by selectins. Several glycosyltransferases are responsible for the biosynthesis of the sLex tetrasaccharide. Selectins are involved in a sequence of interactions of circulated leukocytes with endothelial cells in the blood called the adhesion cascade. Recently, it has become evident that cancer cells utilize a similar adhesion cascade to promote metastases. However, like Dr. Jekyll and Mr. Hyde's two faces, selectins also contribute to tissue destruction during some infections and inflammatory diseases. The most prominent function of selectins is associated with the initial stage of the leukocyte adhesion cascade, in which selectin binding enables tethering and rolling. The first adhesive event occurs through specific non-covalent interactions between selectins and their ligands, with glycans functioning as an interface between leukocytes or cancer cells and the endothelium. Targeting these interactions remains a principal strategy aimed at developing new therapies for the treatment of immune and inflammatory disorders and cancer. In this review, we will survey the significant contributions to and the current status of the understanding of the structure of selectins and the role of selectins in various biological processes. The potential of selectins and their ligands as therapeutic targets in chronic and acute inflammatory diseases and cancer will also be discussed. We will emphasize the structural characteristic of selectins and the catalytic mechanisms of glycosyltransferases involved in the biosynthesis of glycan recognition determinants. Furthermore, recent achievements in the synthesis of selectin inhibitors will be reviewed with a focus on the various strategies used for the development of glycosyltransferase inhibitors, including substrate analog inhibitors and transition state analog inhibitors, which are based on knowledge of the catalytic mechanism.
- MeSH
- buněčná adheze * MeSH
- leukocyty metabolismus patologie MeSH
- lidé MeSH
- nádorové proteiny metabolismus MeSH
- nádory metabolismus patologie MeSH
- rolling leukocytů * MeSH
- selektiny metabolismus MeSH
- zánět metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
OBJECTIVE AND DESIGN: Elucidate the mechanism of action of the small molecule inhibitor of protein binding to glycosaminoglycans, RX-111 and assay its anti-inflammatory activity in animal models of inflammatory disease. MATERIALS: The glycosaminoglycan, heparin, was used in the mechanism of action study of RX-111. Human T lymphocytes and umbilical vein endothelial cells were used to assay the in vitro activity of RX-111. Mouse and rat models of disease were used to assay the anti-inflammatory activity of RX-111 in vivo. METHODS: Circular dichroism and UV/Vis absorption spectroscopy were used to study the binding of RX-111 to the glycosaminoglycan, heparin. T lymphocyte rolling on endothelial cells under shear flow was used to assay RX-111 activity in vitro. Delayed-type hypersensitivity (DTH) and tri-nitrobenzene sulfonic acid (TNBS)-induced colitis in mice and experimental autoimmune encephalomyelitis (EAE) in rats were used to assay anti-inflammatory activity of RX-111 in vivo. RESULTS: RX-111 was shown to bind directly to heparin. It inhibited leukocyte rolling on endothelial cells under shear flow and reduced inflammation in the mouse model of DTH. RX-111 was efficacious in the mouse model of inflammatory bowel disease, TNBS-induced colitis and the rat model of multiple sclerosis, EAE. CONCLUSIONS: RX-111 exercises its broad spectrum anti-inflammatory activity by a singular mechanism of action, inhibition of protein binding to the cell surface GAG, heparan sulfate. RX-111 and related thieno[2,3-c]pyridine derivatives are potential therapeutics for the treatment of inflammatory and autoimmune diseases.
- MeSH
- antiflogistika farmakologie terapeutické užití MeSH
- encefalitogenní základní proteiny imunologie MeSH
- encefalomyelitida autoimunitní experimentální farmakoterapie imunologie MeSH
- endoteliální buňky pupečníkové žíly (lidské) účinky léků imunologie MeSH
- heparitinsulfát metabolismus MeSH
- kolitida chemicky indukované farmakoterapie imunologie MeSH
- krysa rodu rattus MeSH
- kyselina trinitrobenzensulfonová MeSH
- lidé MeSH
- myši inbrední BALB C MeSH
- nádorové buněčné linie MeSH
- oxazolon MeSH
- potkani inbrední LEW MeSH
- pozdní přecitlivělost chemicky indukované farmakoterapie imunologie MeSH
- pyridiny farmakologie terapeutické užití MeSH
- rolling leukocytů účinky léků MeSH
- T-lymfocyty účinky léků imunologie MeSH
- thiofeny farmakologie terapeutické užití MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The purpose of this study is to review the existing literature on chronic effects of foam rolling (FR) on flexibility and performance. Electronic databases were searched during January 2022 for topics related to FR. Included studies met the following criteria: (a) peer-reviewed articles written in English; (b) FR intervention of at least four weeks; (c) non-motorized FR device during intervention; (d) randomized controlled trial with existence of a control group; and (e) any lower body parameter related to flexibility, recovery, and performance. Nine studies met that criteria. Results revealed that chronic FR demonstrated conflicting results for improvement of flexibility. On the other hand, a majority of the articles in this review showed no beneficial effects of FR on performance. Lastly, the effect of FR on recovery is unclear. These findings suggest the need for further studies to establish the consensus about the long-term application of FR in flexibility, recovery, and performance.
35 s. ; 32 cm
