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Cells Sep 2020The Epithelial Cell Adhesion Molecule or EpCAM is a well-known marker highly expressed in carcinomas and showing a strong correlation with poor cancer prognosis. While... (Review)
Review
The Epithelial Cell Adhesion Molecule or EpCAM is a well-known marker highly expressed in carcinomas and showing a strong correlation with poor cancer prognosis. While its name relates to its proposed function as a cell adhesion molecule, EpCAM has been shown to have various signalling functions. In particular, it has been identified as an important positive regulator of cell adhesion and migration, playing an essential role in embryonic morphogenesis as well as intestinal homeostasis. This activity is not due to its putative adhesive function, but rather to its ability to repress myosin contractility by impinging on a PKC signalling cascade. This mechanism confers EpCAM the unique property of favouring tissue plasticity. I review here the currently available data, comment on possible connections with other properties of EpCAM, and discuss the potential significance in the context of cancer invasion.
Topics: Antigens, Neoplasm; Carcinoma; Cell Adhesion; Cell Adhesion Molecules; Cell Movement; Cell Proliferation; Embryo, Mammalian; Epithelial Cell Adhesion Molecule; Gene Expression Regulation, Developmental; Gene Expression Regulation, Neoplastic; Humans; Myosins; Neoplasm Proteins; Neoplasms; Prognosis; Protein Kinase C; Signal Transduction
PubMed: 32961790
DOI: 10.3390/cells9092128 -
Journal of Cheminformatics Oct 2023Ultra-large chemical libraries are reaching 10s to 100s of billions of molecules. A challenge for these libraries is to efficiently check if a proposed molecule is...
Ultra-large chemical libraries are reaching 10s to 100s of billions of molecules. A challenge for these libraries is to efficiently check if a proposed molecule is present. Here we propose and study Bloom filters for testing if a molecule is present in a set using either string or fingerprint representations. Bloom filters are small enough to hold billions of molecules in just a few GB of memory and check membership in sub milliseconds. We found string representations can have a false positive rate below 1% and require significantly less storage than using fingerprints. Canonical SMILES with Bloom filters with the simple FNV (Fowler-Noll-Voll) hashing function provide fast and accurate membership tests with small memory requirements. We provide a general implementation and specific filters for detecting if a molecule is purchasable, patented, or a natural product according to existing databases at https://github.com/whitead/molbloom .
PubMed: 37828615
DOI: 10.1186/s13321-023-00765-1 -
Frontiers in Genetics 2022The collagen- and calcium-binding EGF-like domains 1 (CCBE1) is a secreted protein extensively described as indispensable for lymphangiogenesis during development... (Review)
Review
The collagen- and calcium-binding EGF-like domains 1 (CCBE1) is a secreted protein extensively described as indispensable for lymphangiogenesis during development enhancing VEGF-C signaling. In human patients, mutations in have been found to cause Hennekam syndrome, an inherited disease characterized by malformation of the lymphatic system that presents a wide variety of symptoms such as primary lymphedema, lymphangiectasia, and heart defects. Importantly, over the last decade, an essential role for CCBE1 during heart development is being uncovered. In mice, expression was initially detected in distinct cardiac progenitors such as first and second heart field, and the proepicardium. More recently, expression was identified in the epicardium and sinus venosus (SV) myocardium at E11.5-E13.5, the stage when SV endocardium-derived (VEGF-C dependent) coronary vessels start to form. Concordantly, CCBE1 is required for the correct formation of the coronary vessels and the coronary artery stem in the mouse. Additionally, was found to be enriched in mouse embryonic stem cells (ESC) and revealed as a new essential gene for the differentiation of ESC-derived early cardiac precursor cell lineages. Here, we bring an up-to-date review on the role of CCBE1 in cardiac development, function, and human disease implications. Finally, we envisage the potential of this molecule's functions from a regenerative medicine perspective, particularly novel therapeutic strategies for heart disease.
PubMed: 35222551
DOI: 10.3389/fgene.2022.836694 -
Arthritis & Rheumatology (Hoboken, N.J.) Jul 2022While endothelial dysfunction has been implicated in the widespread thromboinflammatory complications of COVID-19, the upstream mediators of endotheliopathy remain, for...
OBJECTIVE
While endothelial dysfunction has been implicated in the widespread thromboinflammatory complications of COVID-19, the upstream mediators of endotheliopathy remain, for the most part, unknown. This study was undertaken to identify circulating factors contributing to endothelial cell activation and dysfunction in COVID-19.
METHODS
Human endothelial cells were cultured in the presence of serum or plasma from 244 patients hospitalized with COVID-19 and plasma from 100 patients with non-COVID-19-related sepsis. Cell adhesion molecules (E-selectin, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1 [ICAM-1]) were quantified using in-cell enzyme-linked immunosorbent assay.
RESULTS
Serum and plasma from COVID-19 patients increased surface expression of cell adhesion molecules. Furthermore, levels of soluble ICAM-1 and E-selectin were elevated in patient serum and correlated with disease severity. The presence of circulating antiphospholipid antibodies was a strong marker of the ability of COVID-19 serum to activate endothelium. Depletion of total IgG from antiphospholipid antibody-positive serum markedly reduced the up-regulation of cell adhesion molecules. Conversely, supplementation of control serum with patient IgG was sufficient to trigger endothelial activation.
CONCLUSION
These data are the first to indicate that some COVID-19 patients have potentially diverse antibodies that drive endotheliopathy, providing important context regarding thromboinflammatory effects of autoantibodies in severe COVID-19.
Topics: Antibodies, Antiphospholipid; COVID-19; Cell Adhesion Molecules; E-Selectin; Endothelial Cells; Endothelium, Vascular; Humans; Immunoglobulin G; Intercellular Adhesion Molecule-1; Vascular Cell Adhesion Molecule-1
PubMed: 35174669
DOI: 10.1002/art.42094 -
International Journal of Nanomedicine 2022Bioavailability is an eternal topic that cannot be circumvented by peroral drug delivery. Adequate blood drug exposure after oral administration is a prerequisite for... (Review)
Review
Bioavailability is an eternal topic that cannot be circumvented by peroral drug delivery. Adequate blood drug exposure after oral administration is a prerequisite for effective treatment. Nanovesicles as pleiotropic oral vehicles can solubilize, encapsulate, stabilize an active ingredient and promote the payload absorption via various mechanisms. Vesicular systems with nanoscale size, such as liposomes, niosomes and polymersomes, provide a versatile platform for oral delivery of drugs with distinct nature. The amphiphilicity of vesicles in structure allows hydrophilic and lipophilic molecule(s) either or both to be loaded, being encapsulated in the aqueous cavity or the inner core, respectively. Depending on high oral transport efficiency based on their structural flexibility, gastrointestinal stability, biocompatibility, and/or intestinal epithelial affinity, nanovesicles can markedly augment the oral bioavailability of various poorly absorbed drugs. Vesicular drug delivery systems (VDDSs) demonstrate a lot of preferences and are becoming more prominent of late years in biomedical applications. Equally, these systems can potentiate a drug's therapeutic index by ameliorating the oral absorption. This review devotes to comment on various VDDSs with special emphasis on the peroral drug delivery. The classification of nanovesicles, preparative processes, intestinal transport mechanisms, in vivo fate, and design rationale were expounded. Knowledge on vesicles-mediated oral drug delivery for bioavailability enhancement has been properly provided. It can be concluded that VDDSs with many merits will step into an energetic arena in oral drug delivery.
Topics: Biological Availability; Liposomes; Administration, Oral; Hydrophobic and Hydrophilic Interactions; Excipients
PubMed: 36262189
DOI: 10.2147/IJN.S382192 -
Theranostics 2021Poisons always have fascinated humankind. Initially considered as deleterious or hazardous substances, the modern era has witnessed the controlled utilization of... (Review)
Review
Poisons always have fascinated humankind. Initially considered as deleterious or hazardous substances, the modern era has witnessed the controlled utilization of dangerous poisons in medicine and cosmetics. Simultaneously, antidotes have become crucial as reversal agents to counteract the effects of a poison, and they are also used today to positively cancel the benefits of a poison after use. Currently, the majority of poisons are composed of small molecules. This review focuses on recent developments to reverse or prevent toxic effects of poisons by encapsulation in host molecules. Cyclodextrins, cucurbiturils, acyclic cucurbituril derivatives, calixarenes, and pillararenes, have been reported to largely impact the effects of toxic compounds, thus extending the current paradigm of small molecule antidotes by adding a new family of macrocyclic compounds to the current arsenal of antidotes. Along this line of research, endogenous "harmful" species are also sequestered by one or more of these supramolecular host molecules, expanding the potential of supramolecular antidotes to diverse therapeutic areas.
Topics: Animals; Antidotes; Humans; Macrocyclic Compounds; Poisons; Small Molecule Libraries
PubMed: 33391548
DOI: 10.7150/thno.53459 -
The Journal of Biological Chemistry 2021Since the characterization of mRNA in 1961, our understanding of the roles of RNA molecules has significantly grown. Beyond serving as a link between DNA and proteins,... (Review)
Review
Since the characterization of mRNA in 1961, our understanding of the roles of RNA molecules has significantly grown. Beyond serving as a link between DNA and proteins, RNA molecules play direct effector roles by binding to various ligands, including proteins, DNA, other RNAs, and metabolites. Through these interactions, RNAs mediate cellular processes such as the regulation of gene transcription and the enhancement or inhibition of protein activity. As a result, the misregulation of RNA molecules is often associated with disease phenotypes, and RNA molecules have been increasingly recognized as potential targets for drug development efforts, which in the past had focused primarily on proteins. Although both small molecule-based and oligonucleotide-based therapies have been pursued in efforts to target RNA, small-molecule modalities are often favored owing to several advantages including greater oral bioavailability. In this review, we discuss three general frameworks (sets of premises and hypotheses) that, in our view, have so far dominated the discovery of small-molecule ligands for RNA. We highlight the unique merits of each framework as well as the pitfalls associated with exclusive focus of ligand discovery efforts within only one framework. Finally, we propose that RNA ligand discovery can benefit from using progress made within these three frameworks to move toward a paradigm that formulates RNA-targeting questions at the level of RNA structural subclasses.
Topics: Drug Discovery; Ligands; Nucleic Acid Conformation; RNA; Small Molecule Libraries
PubMed: 33334887
DOI: 10.1074/jbc.REV120.015203 -
SLAS Discovery : Advancing Life... Apr 2021Targeted protein degradation (TPD) is a recent strategy, utilizing the cell's proteostasis machinery to deplete specific proteins. This represents a paradigm shift in... (Review)
Review
Targeted protein degradation (TPD) is a recent strategy, utilizing the cell's proteostasis machinery to deplete specific proteins. This represents a paradigm shift in early drug discovery, away from occupancy-driven to event-driven mechanisms.Recent efforts have focused on the development of proteolysis-targeting chimeras (PROTACs). These heterobifunctional molecules combine a target-specific binding moiety linked to an E3 ligase ligand and trigger selective ubiquitination of the target protein, marking it for proteasomal degradation. While these molecules can be highly efficacious, they generally have unfavorable physicochemical properties due to their large size.In contrast, smaller molecules that induce degradation could represent an attractive, simple option to overcoming the limitations of both traditional modulators and PROTACs. These molecules may have a range of mechanisms: recruitment of an E3 ligase (molecular glues), introduction of hydrophobic areas, or inducing local unfolding, each of which triggers degradation.We recently completed a high-throughput screen of 111,000 compounds in a cellular HiBiT assay in an effort to identify such molecules. Preliminary analysis indicates that we have been able to identify alternative small-molecule degraders. We highlight methods for triage, characterization, selectivity, and mode of action. In summary, we believe that these types of small-molecule degraders, which may possibly have more acceptable physicochemical properties than the inherently larger heterobifunctional molecules, are an exciting approach for inducing TPD, and we illustrate that a general screening approach can be successful in identifying useful start points for developing such molecules.
Topics: Drug Discovery; Eukaryotic Cells; High-Throughput Screening Assays; Humans; Hydrophobic and Hydrophilic Interactions; Ligands; Molecular Targeted Therapy; Proteasome Endopeptidase Complex; Protein Binding; Protein Processing, Post-Translational; Protein Unfolding; Proteolysis; Proteomics; Proteostasis; Small Molecule Libraries; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 33632029
DOI: 10.1177/2472555221991104 -
Pharmaceutics Nov 2022Chemical warfare or terrorism attacks with organophosphates may place intoxicated subjects under immediate life-threatening and psychologically demanding conditions....
Chemical warfare or terrorism attacks with organophosphates may place intoxicated subjects under immediate life-threatening and psychologically demanding conditions. Antidotes, such as the oxime HI-6, which must be formulated as a powder for reconstitution reflecting the molecule's light sensitivity and instability in aqueous solutions, dramatically improve recovery-but only if used soon after exposure. Muscle tremors, anxiety, and loss of consciousness after exposure jeopardize proper administration, translating into demanding specifications for the dissolution of HI-6. Reflecting the patients' catastrophic situation and anticipated desire to react immediately to chemical weapon exposure, the dissolution should be completed within ten seconds. We are developing multi-dose and single-dose autoinjectors to reliably meet these dissolution requirements. The temporal and spatial course of dissolution within the various autoinjector designs was profiled colorimetrically. Based on these colorimetric insights with model dyes, we developed experimental setups integrating online conductometry to push experiments toward the relevant molecule, HI-6. The resulting blueprints for autoinjector designs integrated small-scale rotor systems, boosting dissolution across a wide range of viscosities, and meeting the required dissolution specifications driven by the use of these drug products in extreme situations.
PubMed: 36432735
DOI: 10.3390/pharmaceutics14112544 -
Current Opinion in Virology Apr 2020Like measles virus (MV), whose primary hosts are humans, non-human animal morbilliviruses use SLAM (signaling lymphocytic activation molecule) and PVRL4 (nectin-4)... (Review)
Review
Like measles virus (MV), whose primary hosts are humans, non-human animal morbilliviruses use SLAM (signaling lymphocytic activation molecule) and PVRL4 (nectin-4) expressed on immune and epithelial cells, respectively, as receptors. PVRL4's amino acid sequence is highly conserved across species, while that of SLAM varies significantly. However, non-host animal SLAMs often function as receptors for different morbilliviruses. Uniquely, human SLAM is somewhat specific for MV, but canine distemper virus, which shows the widest host range among morbilliviruses, readily gains the ability to use human SLAM. The host range for morbilliviruses is also modulated by their ability to counteract the host's innate immunity, but the risk of cross-species transmission of non-human animal morbilliviruses to humans could occur if MV is successfully eradicated.
Topics: Animals; Cell Adhesion Molecules; Host Specificity; Humans; Morbillivirus; Morbillivirus Infections; Receptors, Virus; Signaling Lymphocytic Activation Molecule Family Member 1; Viral Zoonoses
PubMed: 32344228
DOI: 10.1016/j.coviro.2020.03.005