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Biochimica Et Biophysica Acta. Reviews... Nov 2023Caveolin-1 (Cav-1) is a structural protein of caveolae that functions as a molecular organizer for different cellular functions including endocytosis and cellular... (Review)
Review
Caveolin-1 (Cav-1) is a structural protein of caveolae that functions as a molecular organizer for different cellular functions including endocytosis and cellular signaling. Cancer cells take advantage of the physical position of Cav-1, as it can communicate with extracellular matrix, help to organize growth factor receptors, redistribute cholesterol and glycosphingolipids, and finally transduce signals within the cells for oncogenesis. Recent studies emphasize the exceeding involvement of Cav-1 with different lipid bodies and in altering the metabolism, especially lipid metabolism. However, the association of Cav-1 with different lipid bodies like lipid rafts, lipid droplets, cholesterols, sphingolipids, and fatty acids is remarkably dynamic. The lipid-Cav-1 alliance plays a dual role in carcinogenesis. Both cancer progression and regression are modified and affected by the type of lipid molecule's association with Cav-1. Accordingly, this Cav-1-lipid cooperation exemplifies a cancer-type-specific treatment strategy for a better prognosis of the disease. In this review, we first present Cav-1 as an oncogenic molecule and its communication via lipid raft. We discussed the involvement of Cav-1 with lipid droplets, Cholesterol, sphingolipids, gangliosides, and ceramides. Further, we describe the Cav-1-mediated altered Fatty acid metabolism in cancer and the strategic therapeutic approaches toward Cav-1 targeting.
Topics: Humans; Caveolin 1; Caveolae; Membrane Microdomains; Cholesterol; Sphingolipids
PubMed: 37848094
DOI: 10.1016/j.bbcan.2023.189002 -
Bioorganic & Medicinal Chemistry Letters Apr 2021Pyridones have been utilized as privileged scaffolds in drug discovery. Some of the important roles where this class of heterocycles have found utility in medicinal... (Review)
Review
Pyridones have been utilized as privileged scaffolds in drug discovery. Some of the important roles where this class of heterocycles have found utility in medicinal chemistry include the ability to 1) serve both as a hydrogen bond acceptor and/or a donor; 2) act as a bioisostere for amides, phenyls, pyridines and other nitrogen- or oxygen-containing heterocycles; and 3) impact a target drug molecule's lipophilicity, aqueous solubility and metabolic stability. Detailed discussions of recent advances in their utilization as nonpeptidic mimics and as kinase hinge binding motifs are included. Selected literature examples published from the past twenty years where pyridones have been employed as bioisosteres for phenyls, pyridines, pyridine N-oxides and phenol rings are provided. In addition, this review summarizes the current understanding of possible reactive metabolites related to the pyridone structure.
Topics: Chemistry, Pharmaceutical; Drug Discovery; Molecular Structure; Pyridones
PubMed: 33609656
DOI: 10.1016/j.bmcl.2021.127849 -
Trends in Immunology Jul 2020How innate immunity gave rise to adaptive immunity in vertebrates remains unknown. We propose an evolutionary scenario beginning with pathogen-associated molecular... (Review)
Review
How innate immunity gave rise to adaptive immunity in vertebrates remains unknown. We propose an evolutionary scenario beginning with pathogen-associated molecular pattern(s) (PAMPs) being presented by molecule(s) on one cell to specific receptor(s) on other cells, much like MHC molecules and T cell receptors (TCRs). In this model, mutations in MHC-like molecule(s) that bound new PAMP(s) would not be recognized by original TCR-like molecule(s), and new MHC-like gene(s) would be lost by neutral drift. Integrating recombination activating gene (RAG) transposon(s) in a TCR-like gene would result in greater recognition diversity, with new MHC-like variants recognized and selected, along with a new RAG/TCR-like system. MHC genes would be selected to present many peptides, through multigene families, allelic polymorphism, and peptide-binding promiscuity.
Topics: Adaptive Immunity; Animals; DNA Transposable Elements; Evolution, Molecular; Genes, RAG-1; Immunity, Innate; Major Histocompatibility Complex; Receptors, Antigen, T-Cell
PubMed: 32467030
DOI: 10.1016/j.it.2020.05.002 -
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 -
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 -
Trends in Biotechnology Oct 2020Minicircle DNA (mcDNA) is a smaller and safer version of non-viral DNA vectors that results from a cutting-edge in vivo recombination process to excise prokaryotic... (Review)
Review
Minicircle DNA (mcDNA) is a smaller and safer version of non-viral DNA vectors that results from a cutting-edge in vivo recombination process to excise prokaryotic sequences from plasmid DNA (pDNA). Considering the molecule's potential and increasing interest as a non-viral DNA-based therapeutic, biomanufacturing methodologies need to be improved, especially in downstream processing.
Topics: Biotechnology; DNA; Genetic Vectors; Plasmids
PubMed: 32409109
DOI: 10.1016/j.tibtech.2020.04.008 -
Methods in Molecular Biology (Clifton,... 2020Estimating the range of three-dimensional structures (conformations) that are available to a molecule is a key component of computer-aided drug design. Quantum... (Review)
Review
Estimating the range of three-dimensional structures (conformations) that are available to a molecule is a key component of computer-aided drug design. Quantum mechanical simulation offers improved accuracy over forcefield methods, but at a high computational cost. The question is whether this increased cost can be justified in a context in which high-throughput analysis of large numbers of molecules is often key. This chapter discusses the application of quantum mechanics to conformational searching, with a focus on three key challenges: (1) the generation of ensembles that include a good approximation to a molecule's bioactive conformation at as prominent a ranking as possible; (2) rational analysis and modification of a pre-established bioactive conformation in terms of its energetics; and (3) approximation of real solution-phase conformational ensembles in tandem with NMR data. The impact of QM on the high-throughput application (1) is debatable, meaning that for the moment its primary application is still lower-throughput applications such as (2) and (3). The optimal choice of QM method is also discussed. Rigorous benchmarking suggests that DFT methods are only acceptable when used with large basis sets, but a trickle of papers continue to obtain useful results with relatively low-cost methods, leading to a dilemma that the literature has yet to fully resolve.
Topics: Computer Simulation; Drug Design; Drug Discovery; Molecular Conformation; Pharmaceutical Preparations; Quantum Theory; Software
PubMed: 32016896
DOI: 10.1007/978-1-0716-0282-9_14 -
Frontiers in Chemistry 2023Supramolecular containers have long been applied to regulate organic reactions with distinct selectivity, owing to their diverse functions such as the ability to pose a... (Review)
Review
Supramolecular containers have long been applied to regulate organic reactions with distinct selectivity, owing to their diverse functions such as the ability to pose a guest molecule(s) with a certain orientation and conformation. In this review, we try to illustrate how self-assembled coordination cages could achieve this goal. Two representative cage hosts, namely, self-assembled Pd(II)-ligand octahedral coordination cages ([PdL]) and self-assembled Ga(III)-ligand tetrahedral coordination cages ([GaL]) are selected as the pilot hosts that this mini review covers. Representative works in this area are presented here in brief.
PubMed: 37731456
DOI: 10.3389/fchem.2023.1269471 -
Experimental Eye Research Sep 2023The discovery of the hydrogen sulfide (HS) and the transsulfuration pathway (TSP) responsible for its synthesis in the mammalian retina has highlighted this molecule's... (Review)
Review
The discovery of the hydrogen sulfide (HS) and the transsulfuration pathway (TSP) responsible for its synthesis in the mammalian retina has highlighted this molecule's wide range of physiological processes that influence cellular signaling, redox homeostasis, and cellular metabolism. The multi-level regulatory program that influences HS levels in the retina depends on the relative expression and activity of TSP enzymes, which regulate the abundance of competitive substrates that support or abrogate HS synthesis. In addition, and apart from TSP, intracellular HS levels are regulated by mitochondrial sulfide oxidizing pathways. Retinal layers natively express differing levels of TSP enzymes, which highlight the differences in the metabolite and substrate requirement. Recent studies indicate that these systems are susceptible to pathophysiologies affecting the retina. Dysregulation at any level can upset the balance of redox and signaling processes and possibly upset oxidative stress, apoptotic signaling, ion channels, and immune response within this sensitive tissue. HS donors are a potential therapeutic in such cases and have been demonstrated to bridge the gap, positively impacting the damaged retina. Here, we review the recent findings of HS, how its multi-level regulation impacts the retina, and how its dysregulation is implicated in retinal pathologies.
Topics: Animals; Hydrogen Sulfide; Retina; Sulfides; Oxidation-Reduction; Oxidative Stress; Mammals
PubMed: 37460081
DOI: 10.1016/j.exer.2023.109568 -
Journal of the American Chemical Society Oct 2023Reactions capable of transposing the oxidation levels of adjacent carbon atoms enable rapid and fundamental alteration of a molecule's reactivity. Herein, we report the...
Reactions capable of transposing the oxidation levels of adjacent carbon atoms enable rapid and fundamental alteration of a molecule's reactivity. Herein, we report the 1,2-transposition of the carbon atom oxidation level in cyclic and acyclic tertiary amides, resulting in the one-pot synthesis of 1,2- and 1,3-oxygenated tertiary amines. This oxidation level transfer was facilitated by the careful orchestration of an iridium-catalyzed reduction with the functionalization of transiently formed enamine intermediates. A novel 1,2-carbonyl transposition is described, and the breadth of this redox transposition strategy has been further explored by the development of aminoalcohol and enaminone syntheses. The diverse β-functionalized amine products were shown to be multifaceted and valuable synthetic intermediates, accessing challenging biologically relevant motifs.
PubMed: 37756523
DOI: 10.1021/jacs.3c08466