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Nature Sep 2020Ferroptosis-an iron-dependent, non-apoptotic cell death process-is involved in various degenerative diseases and represents a targetable susceptibility in certain...
Ferroptosis-an iron-dependent, non-apoptotic cell death process-is involved in various degenerative diseases and represents a targetable susceptibility in certain cancers. The ferroptosis-susceptible cell state can either pre-exist in cells that arise from certain lineages or be acquired during cell-state transitions. However, precisely how susceptibility to ferroptosis is dynamically regulated remains poorly understood. Here we use genome-wide CRISPR-Cas9 suppressor screens to identify the oxidative organelles peroxisomes as critical contributors to ferroptosis sensitivity in human renal and ovarian carcinoma cells. Using lipidomic profiling we show that peroxisomes contribute to ferroptosis by synthesizing polyunsaturated ether phospholipids (PUFA-ePLs), which act as substrates for lipid peroxidation that, in turn, results in the induction of ferroptosis. Carcinoma cells that are initially sensitive to ferroptosis can switch to a ferroptosis-resistant state in vivo in mice, which is associated with extensive downregulation of PUFA-ePLs. We further find that the pro-ferroptotic role of PUFA-ePLs can be extended beyond neoplastic cells to other cell types, including neurons and cardiomyocytes. Together, our work reveals roles for the peroxisome-ether-phospholipid axis in driving susceptibility to and evasion from ferroptosis, highlights PUFA-ePL as a distinct functional lipid class that is dynamically regulated during cell-state transitions, and suggests multiple regulatory nodes for therapeutic interventions in diseases that involve ferroptosis.
Topics: Animals; CRISPR-Cas Systems; Cell Differentiation; Cell Line; Ethers; Female; Ferroptosis; Gene Editing; Humans; Kidney Neoplasms; Lipid Peroxidation; Male; Mice; Myocytes, Cardiac; Neurons; Ovarian Neoplasms; Peroxisomes; Phospholipids
PubMed: 32939090
DOI: 10.1038/s41586-020-2732-8 -
Cell Death and Differentiation Aug 2021It is well established that ferroptosis is primarily induced by peroxidation of long-chain poly-unsaturated fatty acid (PUFA) through nonenzymatic oxidation by free...
It is well established that ferroptosis is primarily induced by peroxidation of long-chain poly-unsaturated fatty acid (PUFA) through nonenzymatic oxidation by free radicals or enzymatic stimulation of lipoxygenase. Although there is emerging evidence that long-chain saturated fatty acid (SFA) might be implicated in ferroptosis, it remains unclear whether and how SFA participates in the process of ferroptosis. Using endogenous metabolites and genome-wide CRISPR screening, we have identified FAR1 as a critical factor for SFA-mediated ferroptosis. FAR1 catalyzes the reduction of C16 or C18 saturated fatty acid to fatty alcohol, which is required for the synthesis of alkyl-ether lipids and plasmalogens. Inactivation of FAR1 diminishes SFA-dependent ferroptosis. Furthermore, FAR1-mediated ferroptosis is dependent on peroxisome-driven ether phospholipid biosynthesis. Strikingly, TMEM189, a newly identified gene which introduces vinyl-ether double bond into alkyl-ether lipids to generate plasmalogens abrogates FAR1-alkyl-ether lipids axis induced ferroptosis. Our study reveals a new FAR1-ether lipids-TMEM189 axis dependent ferroptosis pathway and suggests TMEM189 as a promising druggable target for anticancer therapy.
Topics: Ether; Ferroptosis; Humans; Peroxisomes; Phospholipids
PubMed: 33731874
DOI: 10.1038/s41418-021-00769-0 -
Journal of the American Chemical Society Aug 2022We report a new class of synthetic molecular pumps that use a stepwise information ratchet mechanism to achieve the kinetic gating required to sequester their...
We report a new class of synthetic molecular pumps that use a stepwise information ratchet mechanism to achieve the kinetic gating required to sequester their macrocyclic substrates from bulk solution. Threading occurs as a result of active template reactions between the pump terminus amine and an acyl electrophile, whereby the bond-forming reaction is accelerated through the cavity of a crown ether. Carboxylation of the resulting amide results in displacement of the ring to the collection region of the thread. Conversion of the carbamate to a phenolic ester provides an intermediate rotaxane suitable for further pumping cycles. In this way rings can be ratcheted onto a thread from one or both ends of appropriately designed molecular pumps. Each pumping cycle results in one additional ring being added to the thread per terminus acyl group. The absence of pseudorotaxane states ensures that no dethreading of intermediates occurs during the pump operation. This facilitates the loading of different macrocycles in any chosen sequence, illustrated by the pump-mediated synthesis of a [4]rotaxane containing three different macrocycles as a single sequence isomer. A [5]rotaxane synthesized using a dual-opening transamidation pump was structurally characterized by single-crystal X-ray diffraction, revealing a series of stabilizing CH···O interactions between the crown ethers and the polyethylene glycol catchment region of the thread.
Topics: Crown Ethers; Crystallography, X-Ray; Kinetics; Molecular Structure; Rotaxanes
PubMed: 35979923
DOI: 10.1021/jacs.2c06807 -
Molecules (Basel, Switzerland) Oct 2022Fluorescent molecules absorb photons of specific wavelengths and emit a longer wavelength photon within nanoseconds. Recently, fluorescent materials have been widely... (Review)
Review
Fluorescent molecules absorb photons of specific wavelengths and emit a longer wavelength photon within nanoseconds. Recently, fluorescent materials have been widely used in the life and material sciences. Fluorescently labelled heterocyclic compounds are useful in bioanalytical applications, including in vivo imaging, high throughput screening, diagnostics, and light-emitting diodes. These compounds have various therapeutic properties, including antifungal, antitumor, antimalarial, anti-inflammatory, and analgesic activities. Different neutral fluorescent markers containing nitrogen heterocycles (quinolones, azafluoranthenes, pyrazoloquinolines, etc.) have several electrochemical, biological, and nonlinear optic applications. Photodynamic therapy (PDT), which destroys tumors and keeps normal tissues safe, works in the presence of molecular oxygen with light and a photosensitizing drugs (dye) to obtain a therapeutic effect. These compounds can potentially be effective templates for producing devices used in biological research. Blending crown compounds with fluorescent residues to create sensors has been frequently investigated. Florescent heterocyclic compounds (crown ether) increase metal solubility in non-aqueous fluids, broadening the application window. Fluorescent supramolecular polymers have widespread use in fluorescent materials, fluorescence probing, data storage, bio-imaging, drug administration, reproduction, biocatalysis, and cancer treatment. The employment of fluorophores, including organic chromophores and crown ethers, which have high selectivity, sensitivity, and stability constants, opens up new avenues for research. Fluorescent organic compounds are gaining importance in the biological world daily because of their diverse functionality with remarkable structural features and positive properties in the fields of medicine, photochemistry, and spectroscopy.
Topics: Antifungal Agents; Antimalarials; Crown Ethers; Nitrogen; Oxygen; Pharmaceutical Preparations; Polymers; Quinolones
PubMed: 36235167
DOI: 10.3390/molecules27196631 -
European Journal of Paediatric Dentistry Jun 2022The aim of this scoping review was to evaluate the application of polyether-ether-ketone (PEEK) in orthodontics. (Review)
Review
AIM
The aim of this scoping review was to evaluate the application of polyether-ether-ketone (PEEK) in orthodontics.
METHODS
Search strategies were executed for electronic databases through PubMed, Scopus, Web of Science, Lilacs, Opengrey, Embase, Cochrane Library and records identified through hand or electronic search. The keywords used were: "PEEK" OR "Polyether-ether-ketone" AND "orthodontics". The period selected of article publication was from January 2015 to June 2021.
CONCLUSION
Due to excellent physical, mechanical, aesthetic properties and biocompatibility, its low plaque affinity and flexural modulus close to enamel and dentin, PEEK can be used also in orthodontics. However, more clinical research should be done to find out all the advantages and disadvantages of this material.
Topics: Benzophenones; Ethers; Humans; Ketones; Orthodontics; Polyethylene Glycols; Polymers
PubMed: 35722844
DOI: 10.23804/ejpd.2022.23.02.10 -
Marine Drugs Dec 2022Τhis mini-review summarizes the hematopoietic and immunostimulating properties of alkyl glycerol ethers (AGs) reported earlier in the literature available to us. The...
Τhis mini-review summarizes the hematopoietic and immunostimulating properties of alkyl glycerol ethers (AGs) reported earlier in the literature available to us. The role of AGs in the nervous system and aging of the body are also briefly described. We made an attempt to consider the data in terms of adaptation. The hematopoietic, immunostimulating and antioxidant properties of AGs in a variety of experimental situations, including stress, as well as the protective action of AGs against some adaptation diseases, allow us to consider them as substances that prevent some negative effects of stress and promote adaptation. The new approach to AGs as adaptogens seems promising and opens good opportunities for their new application.
Topics: Glyceryl Ethers; Adaptation, Physiological; Antioxidants; Ethers; Glycerol
PubMed: 36662177
DOI: 10.3390/md21010004 -
Molecules (Basel, Switzerland) Jun 2023Oxime ethers are a class of compounds containing the >C=N-O-R moiety. The presence of this moiety affects the biological activity of the compounds. In this review, the... (Review)
Review
Oxime ethers are a class of compounds containing the >C=N-O-R moiety. The presence of this moiety affects the biological activity of the compounds. In this review, the structures of oxime ethers with specific biological activity have been collected and presented, and bactericidal, fungicidal, antidepressant, anticancer and herbicidal activities, among others, are described. The review includes both those substances that are currently used as drugs (e.g., fluvoxamine, mayzent, ridogrel, oxiconazole), as well as non-drug structures for which various biological activity studies have been conducted. To the best of our knowledge, this is the first review of the biological activity of compounds containing such a moiety. The authors hope that this review will inspire scientists to take a greater interest in this group of compounds, as it constitutes an interesting research area.
Topics: Ethers; Structure-Activity Relationship; Oximes; Fungicides, Industrial; Anti-Bacterial Agents; Anesthetics, General
PubMed: 37446703
DOI: 10.3390/molecules28135041 -
FEBS Letters Sep 2019Ether lipids are glycerolipids further classified into alkyl-ether and alkenyl-ether (also termed plasmalogens) lipids. The two ether lipid subclasses share the first... (Review)
Review
Ether lipids are glycerolipids further classified into alkyl-ether and alkenyl-ether (also termed plasmalogens) lipids. The two ether lipid subclasses share the first steps of their synthesis. However, alkyl-ether and alkenyl-ether lipids differ in their structure and physico-chemical properties (featuring different head groups) and, thus, probably in their functions. Ether lipids have intermittent distribution across the evolutionary tree and defects in their synthesis have been shown to perturb cellular homeostasis and lead to disease in humans. Here, we review their structure, their interactions with other lipids, and their potential roles in cellular functions, such as membrane homeostasis and membrane trafficking. Moreover, we discuss still unclear aspects of these lipids such as their subcellular distribution, and the need to unravel their molecular functions as well as how novel tools to study lipid biology will help clarify these aspects.
Topics: Biological Transport; Cell Membrane; Ethers; Lipid Metabolism; Lipids
PubMed: 31166014
DOI: 10.1002/1873-3468.13465 -
Environmental Pollution (Barking, Essex... Sep 2022This review summarizes the most relevant information on PBDEs' occurrence and their impacts in cetaceans at global scale, with special attention on the species with the... (Review)
Review
This review summarizes the most relevant information on PBDEs' occurrence and their impacts in cetaceans at global scale, with special attention on the species with the highest reported levels and therefore the most potentially impacted by the current and continuous release of these substances. This review also emphasizes the anthropogenic and environmental factors that could increase concentrations and associated risks for these species in the next future. High PBDE concentrations above the toxicity threshold and stationary trends have been related to continuous import of PBDE-containing products in cetaceans of Brazil and Australia, where PBDEs have never been produced. Non-decreasing levels documented in cetaceans from the Northwest Pacific Ocean might be linked to the increased e-waste import and ongoing production and use of deca-BDE that is still allowed in China. Moreover, high levels of PBDEs in some endangered species such as beluga whales (Delphinapterus leucas) in St. Lawrence Estuary and Southern Resident killer whales (Orcinus Orca) are influenced by the discharge of contaminated waters deriving from wastewater treatment plants. Climate change related processes such as enhanced long-range transport, re-emissions from secondary sources and shifts in migration habits could lead to greater exposure and accumulation of PBDEs in cetaceans, above all in those species living in the Arctic. In addition, increased rainfall could carry greater amount of contaminants to the marine environment, thereby, enhancing the exposure and accumulation especially for coastal species. Synergic effects of all these factors and ongoing emissions of PBDEs, expected to continue at least until 2050, could increase the degree of exposure and menace for cetacean populations. In this regard, it is necessary to improve current regulations on PBDEs and broader the knowledge about their toxicological effects, in order to assess health risks and support regulatory protection for cetacean species.
Topics: Animals; Australia; Cetacea; Environmental Monitoring; Halogenated Diphenyl Ethers; Water Pollutants, Chemical
PubMed: 35752394
DOI: 10.1016/j.envpol.2022.119670 -
Molecules (Basel, Switzerland) Dec 2022The transformation of sesame lignans is interesting because the derived products possess enhanced bioactivity and a wide range of potential applications. In this study,...
The transformation of sesame lignans is interesting because the derived products possess enhanced bioactivity and a wide range of potential applications. In this study, the semisynthesis of 28 furofuran lignans using samin () as the starting material is described. Our methodology involved the protonation of samin () to generate an oxocarbenium ion followed by the attack from two different nucleophiles, namely, thiols (RSH) and alcohols (ROH). The highly diastereoselective thioether and ether furofuran lignans were obtained, and their configurations were confirmed by 2D NMR and X-ray crystallography. The mechanism underlying the reaction was studied by monitoring H NMR and computational calculations, that is, the diastereomeric α- and β-products were equally formed through the S1-like mechanism, while the β-product was gradually transformed via an S2-like mechanism to the α-congener in the late step. Upon evaluation of the inhibitory effect of the synthesized lignans against α-glucosidases and free radicals, the lignans and of the phenolic hydroxyl group were the most potent inhibitors. Additionally, the mechanisms underlying the α-glucosidase inhibition of and were verified to be of a mixed manner and noncompetitive inhibition, respectively. The results indicated that both and possessed promising antidiabetic activity, while simultaneously inhibiting α-glucosidases and free radicals.
Topics: Lignans; alpha-Glucosidases; Ether; Free Radicals; Ethyl Ethers; Ethers; Molecular Structure
PubMed: 36558136
DOI: 10.3390/molecules27249001