Targeting Selectins Mediated Biological Activities With Multivalent Probes

Selectins are type-I transmembrane glycoproteins that are ubiquitously expressed on activated platelets, endothelial cells, and leukocytes. They bind to cell surface glycoproteins and extracellular matrix ligands, regulate the rolling of leukocytes in the blood capillaries, and recruit them to inflammatory sites. Hence, they are potential markers for the early detection and inhibition of inflammatory diseases, thrombosis, cardiovascular disorders, and tumor metastasis. Fucosylated and sialylated glycans, such as sialyl Lewisx, its isoform sialyl Lewisa, and heparan sulfate, are primary selectin ligands. Functionalization of these selectin-binding ligands on multivalent probes, such as nanoparticles, liposomes, and polymers, not only inhibits selectin-mediated biological activity but is also involved in direct imaging of the inflammation site. This review briefly summarizes the selectin-mediated various diseases such as thrombosis, cancer and recent progress in the different types of multivalent probes used to target selectins.

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P-selectin mediates Ca(2+)-dependent adhesion of activated platelets to many different types of leukocytes: detection by flow cytometry

Blood ◽

10.1182/blood.v80.1.134.134 ◽

1992 ◽

Vol 80 (1) ◽

pp. 134-142 ◽

Cited By ~ 104

Author(s):

LG de Bruijne-Admiraal ◽

PW Modderman ◽

AE Von dem Borne ◽

A Sonnenberg

Keyword(s):

T Cells ◽

Divalent Cations ◽

Phosphatidyl Inositol ◽

Cell Types ◽

Inhibitory Effect ◽

Immunofluorescence Assay ◽

Cd8 Cells ◽

Activated Platelets ◽

Selectin Ligands ◽

Different Types

Abstract Previous studies have shown that thrombin-activated platelets interact through the P-selectin with neutrophils and monocytes. To identify other types of leukocytes capable of such an interaction, eosinophils, basophils, and lymphocytes were isolated from whole blood. Binding of these cells to activated platelets was examined in a double immunofluorescence assay and the results show that activated platelets not only bind to neutrophils and monocytes, but also to eosinophils, basophils, and subpopulations of T lymphocytes. Using monoclonal antibodies (MoAbs) specific for subsets of T cells, we could further demonstrate that the T cells which bind activated platelets are natural killer (NK) cells and an undefined subpopulation of CD4+ and CD8+ cells. All these interactions were dependent on divalent cations and were completely inhibited by an MoAb against P-selectin. Thus, P- selectin mediates the binding of activated platelets to many different types of leukocytes. Studies with leukocytes treated with proteases or neuraminidase have shown that the structures recognized by P-selectin are glycoproteins carrying sialic acid residues. Because the loss of binding of activated platelets to neuraminidase-treated neutrophils was almost complete, but only partial to treated eosinophils, basophils, and monocytes, the latter cell types may have different P-selectin ligands in addition to those present on neutrophils. We found that two previously identified ligands for P-selectin, the oligosaccharides Le(x) and sialyl-Le(x), had little or no inhibitory effect on adhesion of activated platelets to leukocytes and that binding was not inhibited by MoAbs against these oligosaccharides. In addition, there was no correlation between the expression of Le(x) on several cell types and their capacity to bind activated platelets. In contrast, the expression of sialyl-Le(x) on cells was almost perfectly correlated with their ability to bind activated platelets. Thus, while Le(x) cannot be a major ligand for P-selectin, a possible role for sialyl-Le(x) in P- selectin-mediated adhesion processes cannot be dismissed. Finally, activated platelets were found to bind normally to monocytes and neutrophils of patients with paroxysmal nocturnal hemoglobulinuria (PNH) and to neutrophils from which phosphatidyl inositol (PI)-linked proteins had been removed by glycosylphosphatidyl inositol-specific phospholipase C (GPI-PLC) digestion. This suggests that at least part of the P-selectin ligands on these cells are not GPI-anchored.

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Identification of a specific glycoprotein ligand for P-selectin (CD62) on myeloid cells.

The Journal of Cell Biology ◽

10.1083/jcb.118.2.445 ◽

1992 ◽

Vol 118 (2) ◽

pp. 445-456 ◽

Cited By ~ 322

Author(s):

K L Moore ◽

N L Stults ◽

S Diaz ◽

D F Smith ◽

R D Cummings ◽

...

Keyword(s):

Molecular Weight ◽

Myeloid Cells ◽

Apparent Molecular Weight ◽

Protein S ◽

Similar Molecular Weight ◽

Cell Extracts ◽

Activated Platelets ◽

Selectin Ligands ◽

Reducing Conditions ◽

Selectin Binding

P-selectin (CD62, GMP-140, PADGEM), a Ca(2+)-dependent lectin on activated platelets and endothelium, functions as a receptor for myeloid cells by interacting with sialylated, fucosylated lactosaminoglycans. P-selectin binds to a limited number of protease-sensitive sites on myeloid cells, but the protein(s) that carry the glycans recognized by P-selectin are unknown. Blotting of neutrophil or HL-60 cell membrane extracts with [125I]P-selectin and affinity chromatography of [3H]glucosamine-labeled HL-60 cell extracts were used to identify P-selectin ligands. A major ligand was identified with an approximately 250,000 M(r) under nonreducing conditions and approximately 120,000 under reducing conditions. Binding of P-selectin to the ligand was Ca2+ dependent and was blocked by mAbs to P-selectin. Brief sialidase digestion of the ligand increased its apparent molecular weight; however, prolonged digestion abolished binding of P-selectin. Peptide:N-glycosidase F treatment reduced the apparent molecular weight of the ligand by approximately 3,000 but did not affect P-selectin binding. Western blot and immunodepletion experiments indicated that the ligand was not lamp-1, lamp-2, or L-selectin, which carry sialyl Le(x), nor was it leukosialin, a heavily sialylated glycoprotein of similar molecular weight. The preferential interaction of the ligand with P-selectin suggests that it may play a role in adhesion of myeloid cells to activated platelets and endothelial cells.

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P-selectin mediates Ca(2+)-dependent adhesion of activated platelets to many different types of leukocytes: detection by flow cytometry

Blood ◽

10.1182/blood.v80.1.134.bloodjournal801134 ◽

1992 ◽

Vol 80 (1) ◽

pp. 134-142 ◽

Cited By ~ 3

Author(s):

LG de Bruijne-Admiraal ◽

PW Modderman ◽

AE Von dem Borne ◽

A Sonnenberg

Keyword(s):

T Cells ◽

Divalent Cations ◽

Phosphatidyl Inositol ◽

Cell Types ◽

Inhibitory Effect ◽

Immunofluorescence Assay ◽

Cd8 Cells ◽

Activated Platelets ◽

Selectin Ligands ◽

Different Types

Previous studies have shown that thrombin-activated platelets interact through the P-selectin with neutrophils and monocytes. To identify other types of leukocytes capable of such an interaction, eosinophils, basophils, and lymphocytes were isolated from whole blood. Binding of these cells to activated platelets was examined in a double immunofluorescence assay and the results show that activated platelets not only bind to neutrophils and monocytes, but also to eosinophils, basophils, and subpopulations of T lymphocytes. Using monoclonal antibodies (MoAbs) specific for subsets of T cells, we could further demonstrate that the T cells which bind activated platelets are natural killer (NK) cells and an undefined subpopulation of CD4+ and CD8+ cells. All these interactions were dependent on divalent cations and were completely inhibited by an MoAb against P-selectin. Thus, P- selectin mediates the binding of activated platelets to many different types of leukocytes. Studies with leukocytes treated with proteases or neuraminidase have shown that the structures recognized by P-selectin are glycoproteins carrying sialic acid residues. Because the loss of binding of activated platelets to neuraminidase-treated neutrophils was almost complete, but only partial to treated eosinophils, basophils, and monocytes, the latter cell types may have different P-selectin ligands in addition to those present on neutrophils. We found that two previously identified ligands for P-selectin, the oligosaccharides Le(x) and sialyl-Le(x), had little or no inhibitory effect on adhesion of activated platelets to leukocytes and that binding was not inhibited by MoAbs against these oligosaccharides. In addition, there was no correlation between the expression of Le(x) on several cell types and their capacity to bind activated platelets. In contrast, the expression of sialyl-Le(x) on cells was almost perfectly correlated with their ability to bind activated platelets. Thus, while Le(x) cannot be a major ligand for P-selectin, a possible role for sialyl-Le(x) in P- selectin-mediated adhesion processes cannot be dismissed. Finally, activated platelets were found to bind normally to monocytes and neutrophils of patients with paroxysmal nocturnal hemoglobulinuria (PNH) and to neutrophils from which phosphatidyl inositol (PI)-linked proteins had been removed by glycosylphosphatidyl inositol-specific phospholipase C (GPI-PLC) digestion. This suggests that at least part of the P-selectin ligands on these cells are not GPI-anchored.

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Methionine-Specific Staining of Collagen

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010005408x ◽

1982 ◽

Vol 40 ◽

pp. 294-295

Author(s):

E.M. Kuhn ◽

K.D. Marenus ◽

M. Beer

Keyword(s):

Amino Acids ◽

Collagen Fibers ◽

Type Iii Collagen ◽

Type I ◽

Electron Microscopic ◽

Good Correspondence ◽

Specific Staining ◽

Type Iii ◽

Different Types ◽

Sulfur Containing

Fibers composed of different types of collagen cannot be differentiated by conventional electron microscopic stains. We are developing staining procedures aimed at identifying collagen fibers of different types.Pt(Gly-L-Met)Cl binds specifically to sulfur-containing amino acids. Different collagens have methionine (met) residues at somewhat different positions. A good correspondence has been reported between known met positions and Pt(GLM) bands in rat Type I SLS (collagen aggregates in which molecules lie adjacent to each other in exact register). We have confirmed this relationship in Type III collagen SLS (Fig. 1).

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AB0012 ROLE OF IRF5 GENE ON THE PATHOGENESIS OF IMMUNOGLOBULIN-A VASCULITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1023 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1309.1-1310

Author(s):

S. Remuzgo Martinez ◽

F. Genre ◽

V. Pulito-Cueto ◽

D. Prieto-Peña ◽

B. Atienza-Mateo ◽

...

Keyword(s):

Inflammatory Diseases ◽

Disease Onset ◽

Immunoglobulin A ◽

Type I ◽

Research Support ◽

Development Fund ◽

European Regional Development Fund ◽

Social Fund ◽

Relevant Role ◽

Immunoglobulin A Vasculitis

Background:Interferon signaling pathway plays a relevant role in autoimmunity. Genetic variants in theinterferon regulatory factor (IRF) 5gene, that encodes the major regulator of the type I interferon induction [1], have been related to the development of several inflammatory diseases [2].Objectives:To determine the influence ofIRF5on Immunoglobulin-A vasculitis (IgAV), an inflammatory vascular disease.Methods:ThreeIRF5polymorphisms (rs2004640, rs2070197 and rs10954213) representative of 3 different haplotype blocks were genotyped in 372 Caucasian patients with IgAV and 876 sex and ethnically matched healthy controls.Results:No statistically significant differences between patients with IgAV and controls were observed when eachIRF5polymorphism was analyzed independently. Similarly, no statistically significant differences between patients with IgAV and controls were found whenIRF5polymorphisms were evaluated combined conforming haplotypes. Additionally, there were no statistically significant differences in genotype, allele and haplotype frequencies ofIRF5when patients with IgAV were stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations.Conclusion:Our results do not support an influence ofIRF5on the pathogenesis of IgAV.References:[1]Nat Immunol 2011; 12: 231-8;[2]Arthritis Res Ther 2014; 16: R146.Acknowledgments:This study was supported by European Union FEDER funds and “Fondo de Investigaciones Sanitarias” (grant PI18/00042) from ‘Instituto de Salud Carlos III’ (ISCIII, Health Ministry, Spain). RL-M is a recipient of a Miguel Servet type I programme fellowship from the ISCIII, co-funded by the European Social Fund (ESF, `Investing in your future´) (grant CP16/00033). SR-M is supported by funds of the RETICS Program (RD16/0012/0009) (ISCIII, co-funded by the European Regional Development Fund (ERDF)). VP-C is supported by a pre-doctoral grant from IDIVAL (PREVAL 18/01). LL-G is supported by funds of PI18/00042 (ISCIII, co-funded by ERDF).Disclosure of Interests:Sara Remuzgo Martinez: None declared, Fernanda Genre: None declared, Verónica Pulito-Cueto: None declared, D. Prieto-Peña: None declared, Belén Atienza-Mateo: None declared, Belén Sevilla: None declared, Javier Llorca: None declared, Norberto Ortego: None declared, Leticia Lera-Gómez: None declared, Maite Leonardo: None declared, Ana Peñalba: None declared, María Jesús Cabero: None declared, Luis Martín-Penagos: None declared, Jose Alberto Miranda-Filloy: None declared, Antonio Navas Parejo: None declared, Javier Sanchez Perez: None declared, Maximiliano Aragües: None declared, Esteban Rubio: None declared, MANUEL LEON LUQUE: None declared, Juan María Blanco-Madrigal: None declared, E. Galindez: None declared, Javier Martin Ibanez: None declared, Santos Castañeda: None declared, Ricardo Blanco Grant/research support from: Abbvie, MSD and Roche, Consultant of: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen, Lilly and MSD, Miguel A González-Gay Grant/research support from: Pfizer, Abbvie, MSD, Speakers bureau: Pfizer, Abbvie, MSD, Raquel López-Mejías: None declared

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Snail mucus from the mantle and foot of two land snails, Lissachatina fulica and Hemiplecta distincta, exhibits different protein profile and biological activity

BMC Research Notes ◽

10.1186/s13104-021-05557-0 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Nattaphop Noothuan ◽

Kantamas Apitanyasai ◽

Somsak Panha ◽

Anchalee Tassanakajon

Keyword(s):

Biological Activities ◽

Protein Pattern ◽

Protein Profile ◽

Antibacterial Properties ◽

Biological Properties ◽

Specific Protein ◽

Land Snails ◽

Snail Species ◽

Significant Difference ◽

Different Types

Abstract Objective Snails secrete different types of mucus that serve several functions, and are increasingly being exploited for medical and cosmetic applications. In this study, we explored the protein pattern and compared the biological properties of the mucus secreted from the mantle collar and foot of two snail species, Lissachatina fulica and Hemiplecta distincta. Result Protein profile showed a different pattern between the two species and between the two secretory parts. The mantle-specific protein bands were further characterized and among them was an antibacterial protein, achacin. Accordingly, the mucus from the mantle exhibited the higher antibacterial activity than that from the foot in both snail species. The mucus from H. distincta, first reported here, also showed antibacterial properties, but with a lower activity compared to that for L. fulica. Snail mucus also exhibited anti-tyrosinase activity and antioxidant activity but with no significant difference between the foot and mantle mucus. These results indicate some different protein compositions and biological activities of snail slime from the mantle and foot, which might be associated with their specific functions in the animal and are useful for medical applications.

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Melatonin in Cancer Treatment: Current Knowledge and Future Opportunities

Molecules ◽

10.3390/molecules26092506 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2506

Author(s):

Wamidh H. Talib ◽

Ahmad Riyad Alsayed ◽

Alaa Abuawad ◽

Safa Daoud ◽

Asma Ismail Mahmod

Keyword(s):

Clinical Trials ◽

Current Knowledge ◽

Biological Activities ◽

Experimental Studies ◽

Therapeutic Effects ◽

Cell Proliferation Inhibition ◽

Different Types ◽

Solid Foundation

Melatonin is a pleotropic molecule with numerous biological activities. Epidemiological and experimental studies have documented that melatonin could inhibit different types of cancer in vitro and in vivo. Results showed the involvement of melatonin in different anticancer mechanisms including apoptosis induction, cell proliferation inhibition, reduction in tumor growth and metastases, reduction in the side effects associated with chemotherapy and radiotherapy, decreasing drug resistance in cancer therapy, and augmentation of the therapeutic effects of conventional anticancer therapies. Clinical trials revealed that melatonin is an effective adjuvant drug to all conventional therapies. This review summarized melatonin biosynthesis, availability from natural sources, metabolism, bioavailability, anticancer mechanisms of melatonin, its use in clinical trials, and pharmaceutical formulation. Studies discussed in this review will provide a solid foundation for researchers and physicians to design and develop new therapies to treat and prevent cancer using melatonin.

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Ethnobotanical, phytochemistry, and pharmacological property of Waltheria Indica Linn

Future Journal of Pharmaceutical Sciences ◽

10.1186/s43094-020-00174-3 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

C Nirmala ◽

M Sridevi

Keyword(s):

Inflammatory Diseases ◽

Biological Activities ◽

Perennial Herb ◽

Main Body ◽

Biological Targets ◽

Traditional Uses ◽

Whole Plant ◽

Anti Cancer ◽

Microbial Infections ◽

Anti Fungal

Abstract Background In modern therapeutics, various human pathological disturbances were treated with the plant-based products. Waltheria indica Linn, a perennial herb, was commonly used in traditional medicine worldwide against various ailments such as cough, dysentery, diarrhea, bladder disorder, hemoptysis, inflammations, neuralgia, wounds, and ulcers. Main body The shrub was majorly distributed in tropical, subtropical regions and exists in many distinct local forms. Both the crude extracts and purified compounds from the whole plant and its parts showed wide pharmacological properties like antioxidant, analgesic, sedative, anti-bacterial, anti-fungal, and anti-parasitic. The phytochemical profile and traditional usage highlight the potency of the plant in the treatment of microbial infections and inflammatory diseases. Yet, additional studies are required for the confirmations of its traditional uses against other diseases. More detailed understanding of anti-cataract, anti-diabetics, asthma, anemia, and anti-cancer mechanism has to be explored. Though many research articles on the proposed plant are available, there has been a rising concern in the therapeutic property, especially on the alkaloids and flavonoids from this plant for drug design. Conclusion This article aims in a systematic and updated review on distribution, botany, traditional uses, phytocompounds, and relevant biological activities from each part of the plant. The information was collected from databases like PubMed, ScienceDirect, Web of Science, Google Scholar, books, dissertation, and reports via academic libraries that included more than 100 articles published since 1937. This ethnopharmacological study of the plant may create new insight into drug discovery to develop important novel leads against various biological targets.

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Immunological Determined Plasminogen Groups And Its Possible Biological Relevance

10.1055/s-0038-1652204 ◽

1981 ◽

Author(s):

V Sachs ◽

R Dörner ◽

E Szirmai

Keyword(s):

Human Plasma ◽

Type I ◽

Type Ii ◽

Precipitation Line ◽

Gene Frequencies ◽

Type Iii ◽

Different Types ◽

Human Plasminogen ◽

Gel Diffusion ◽

Good Agreement

Anti human plasminogen sera of the rabbit precipitate human plasma in the agar gel diffusion test by means of intra-basin absorption with plasminogenfree human plasma with three different types: type I is represented by one strong precipitation line, type II by two lines, a big one and a small one, and type III by three slight but distinct lines. The following frequencies of the different types have been observed in a sample of 516 human plasmas: type I 65%, type II 33% and type III 2%. Suppose the types are phenotypical groups of a diallelic system where the types I and III represent the homozygous genotypes and the type II the heterozygous the estimated gene frequencies are in good agreement with the expected values. There is also a good agreement of the distribution of plasminogen groups determined by electrofocussing from RAUM et al. and HOBART. The plasminogen groups possibly may have also a biological meaning because the plasmas of type III always have a lesser fibrinolytic activity than the plasmas of the other types.

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Movement of Calcium Ions and their Role in the Activation of Platelets

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648654 ◽

1978 ◽

Vol 40 (02) ◽

pp. 212-218 ◽

Cited By ~ 60

Author(s):

P Massini ◽

R Käser-Glanzmann ◽

E F Lüscher

Keyword(s):

Plasma Membrane ◽

Platelet Activation ◽

Calcium Ions ◽

Binding Sites ◽

Shape Change ◽

Release Reaction ◽

Dense Bodies ◽

Activated Platelets ◽

Different Types ◽

Ca Ions

SummaryThe increase of the cytoplasmic Ca-concentration plays a central role in the initiation of platelet activation. Four kinds of movements of Ca-ions are presumed to occur during this process: a) Ca-ions liberated from membranes induce the rapid shape change, b) Vesicular organelles release Ca-ions into the cytoplasm which initiate the release reaction, c) The storage organelles called dense bodies, secrete their contents including Ca-ions to the outside during the release reaction, d) At the same time a rearrangement of the plasma membrane occurs, resulting in an increase in its permeability for Ca-ions as well as in an increase in the number of Ca-binding sites.Since most processes occurring during platelet activation are reversible, the platelet must be equipped with a mechanism which removes Ca-ions from the cytoplasm. A vesicular fraction obtained from homogenized platelets indeed accumulates Ca actively. This Ca- pump is stimulated by cyclic AMP and protein kinase; it may be involved in the recovery of platelets after activation.It becomes increasingly clear that the various manifestations of platelet activation are triggered by a rise in the cytoplasmic Ca2+-concentration. The evidence for this and possible mechanisms involved are discussed in some detail in the contributions by Detwiler et al. and by Gerrard and White to this symposium. In this article we shall discuss four different types of mobilization of Ca-ions which occur in the course of the activation of platelets. In addition, at least one transport step involved in the removal of Ca2+ must occur during relaxation of activated platelets.

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