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Nature Communications Jun 2023The cystine transporter solute carrier family 7 member 11 (SLC7A11; also called xCT) protects cancer cells from oxidative stress and is overexpressed in many cancers....
The cystine transporter solute carrier family 7 member 11 (SLC7A11; also called xCT) protects cancer cells from oxidative stress and is overexpressed in many cancers. Here we report a surprising finding that, whereas moderate overexpression of SLC7A11 is beneficial for cancer cells treated with HO, a common oxidative stress inducer, its high overexpression dramatically increases HO-induced cell death. Mechanistically, high cystine uptake in cancer cells with high overexpression of SLC7A11 in combination with HO treatment results in toxic buildup of intracellular cystine and other disulfide molecules, NADPH depletion, redox system collapse, and rapid cell death (likely disulfidptosis). We further show that high overexpression of SLC7A11 promotes tumor growth but suppresses tumor metastasis, likely because metastasizing cancer cells with high expression of SLC7A11 are particularly susceptible to oxidative stress. Our findings reveal that SLC7A11 expression level dictates cancer cells' sensitivity to oxidative stress and suggests a context-dependent role for SLC7A11 in tumor biology.
Topics: Cystine; Cell Line, Tumor; Hydrogen Peroxide; Oxidative Stress; Disulfides; Amino Acid Transport System y+; Neoplasms
PubMed: 37339981
DOI: 10.1038/s41467-023-39401-9 -
The Journal of Physiological Sciences :... Nov 2023Physiological roles of Cl, a major anion in the body, are not well known compared with those of cations. This review article introduces: (1) roles of Cl in bodily and... (Review)
Review
Physiological roles of Cl, a major anion in the body, are not well known compared with those of cations. This review article introduces: (1) roles of Cl in bodily and cellular functions; (2) the range of cytosolic Cl concentration ([Cl]); (3) whether [Cl] could change with cell volume change under an isosmotic condition; (4) whether [Cl] could change under conditions where multiple Cl transporters and channels contribute to Cl influx and efflux in an isosmotic state; (5) whether the change in [Cl] could be large enough to act as signals; (6) effects of Cl on cytoskeletal tubulin polymerization through inhibition of GTPase activity and tubulin polymerization-dependent biological activity; (7) roles of cytosolic Cl in cell proliferation; (8) Cl-regulatory mechanisms of ciliary motility; (9) roles of Cl in sweet/umami taste receptors; (10) Cl-regulatory mechanisms of with-no-lysine kinase (WNK); (11) roles of Cl in regulation of epithelial Na transport; (12) relationship between roles of Cl and H in body functions.
Topics: Chlorides; Tubulin; Ion Transport; Biological Transport; Sodium; Chloride Channels
PubMed: 37968609
DOI: 10.1186/s12576-023-00889-x -
Circulation Jul 2023SGLT2 (sodium-glucose cotransporter 2) inhibitors interfere with the reabsorption of glucose and sodium in the early proximal renal tubule, but the magnitude and... (Review)
Review
SGLT2 (sodium-glucose cotransporter 2) inhibitors interfere with the reabsorption of glucose and sodium in the early proximal renal tubule, but the magnitude and duration of any ensuing natriuretic or diuretic effect are the result of an interplay between the degree of upregulation of SGLT2 and sodium-hydrogen exchanger 3, the extent to which downstream compensatory tubular mechanisms are activated, and (potentially) the volume set point in individual patients. A comprehensive review and synthesis of available studies reveals several renal response patterns with substantial variation across studies and clinical settings. However, the common observation is an absence of a large acute or chronic diuresis or natriuresis with these agents, either when given alone or combined with other diuretics. This limited response results from the fact that renal compensation to these drugs is rapid and nearly complete within a few days or weeks, preventing progressive volume losses. Nevertheless, the finding that fractional excretion of glucose and lithium (the latter being a marker of proximal sodium reabsorption) persists during long-term treatment with SGLT2 inhibitors indicates that pharmacological tolerance to the effects of these drugs at the level of the proximal tubule does not meaningfully occur. This persistent proximal tubular effect of SGLT2 inhibitors can be hypothesized to produce a durable improvement in the internal set point for volume homeostasis, which may become clinically important during times of fluid expansion. However, it is difficult to know whether a treatment-related change in the volume set point actually occurs or contributes to the effect of these drugs to reduce the risk of major heart failure events. SGLT2 inhibitors exert cardioprotective effects by a direct effect on cardiomyocytes that is independent of the presence of or binding to SGLT2 or the actions of these drugs on the proximal renal tubule. Nevertheless, changes in the volume set point mediated by SGLT2 inhibitors might potentially act cooperatively with the direct favorable molecular and cellular effects of these drugs on cardiomyocytes to mediate their benefits on the development and clinical course of heart failure.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Chlorides; Sodium-Glucose Transporter 2; Sodium; Water; Homeostasis; Diuretics; Heart Failure; Glucose
PubMed: 37486998
DOI: 10.1161/CIRCULATIONAHA.123.064346 -
Bioscience Reports May 2024Chloride is a key anion involved in cellular physiology by regulating its homeostasis and rheostatic processes. Changes in cellular Cl- concentration result in... (Review)
Review
Chloride is a key anion involved in cellular physiology by regulating its homeostasis and rheostatic processes. Changes in cellular Cl- concentration result in differential regulation of cellular functions such as transcription and translation, post-translation modifications, cell cycle and proliferation, cell volume, and pH levels. In intracellular compartments, Cl- modulates the function of lysosomes, mitochondria, endosomes, phagosomes, the nucleus, and the endoplasmic reticulum. In extracellular fluid (ECF), Cl- is present in blood/plasma and interstitial fluid compartments. A reduction in Cl- levels in ECF can result in cell volume contraction. Cl- is the key physiological anion and is a principal compensatory ion for the movement of the major cations such as Na+, K+, and Ca2+. Over the past 25 years, we have increased our understanding of cellular signaling mediated by Cl-, which has helped in understanding the molecular and metabolic changes observed in pathologies with altered Cl- levels. Here, we review the concentration of Cl- in various organs and cellular compartments, ion channels responsible for its transportation, and recent information on its physiological roles.
Topics: Humans; Chlorides; Animals; Homeostasis; Chloride Channels; Signal Transduction; Extracellular Fluid; Ion Transport
PubMed: 38573803
DOI: 10.1042/BSR20240029 -
Water Research Apr 2024This publication summarizes my journey in the field of chemical oxidation processes for water treatment over the last 30+ years. Initially, the efficiency of the... (Review)
Review
This publication summarizes my journey in the field of chemical oxidation processes for water treatment over the last 30+ years. Initially, the efficiency of the application of chemical oxidants for micropollutant abatement was assessed by the abatement of the target compounds only. This is controlled by reaction kinetics and therefore, second-order rate constant for these reactions are the pre-requisite to assess the efficiency and feasibility of such processes. Due to the tremendous efforts in this area, we currently have a good experimental data base for second-order rate constants for many chemical oxidants, including radicals. Based on this, predictions can be made for compounds without experimental data with Quantitative Structure Activity Relationships with Hammet/Taft constants or energies of highest occupied molecular orbitals from quantum chemical computations. Chemical oxidation in water treatment has to be economically feasible and therefore, the extent of transformation of micropollutants is often limited and mineralization of target compounds cannot be achieved under realistic conditions. The formation of transformation products from the reactions of the target compounds with chemical oxidants is inherent to oxidation processes and the following questions have evolved over the years: Are the formed transformation products biologically less active than the target compounds? Is there a new toxicity associated with transformation products? Are transformation products more biodegradable than the corresponding target compounds? In addition to the positive effects on water quality related to abatement of micropollutants, chemical oxidants react mainly with water matrix components such as the dissolved organic matter (DOM), bromide and iodide. As a matter of fact, the fraction of oxidants consumed by the DOM is typically > 99%, which makes such processes inherently inefficient. The consequences are loss of oxidation capacity and the formation of organic and inorganic disinfection byproducts also involving bromide and iodide, which can be oxidized to reactive bromine and iodine with their ensuing reactions with DOM. Overall, it has turned out in the last three decades, that chemical oxidation processes are complex to understand and to manage. However, the tremendous research efforts have led to a good understanding of the underlying processes and allow a widespread and optimized application of such processes in water treatment practice such as drinking water, municipal and industrial wastewater and water reuse systems.
Topics: Bromides; Iodides; Water Pollutants, Chemical; Oxidation-Reduction; Oxidants; Water Purification
PubMed: 38387263
DOI: 10.1016/j.watres.2024.121148 -
Cell Reports Aug 2023Volume-regulated anion channels (VRACs) are hexamers of LRRC8 proteins that are crucial for cell volume regulation. N termini (NTs) of the obligatory LRRC8A subunit...
Volume-regulated anion channels (VRACs) are hexamers of LRRC8 proteins that are crucial for cell volume regulation. N termini (NTs) of the obligatory LRRC8A subunit modulate VRACs activation and ion selectivity, but the underlying mechanisms remain poorly understood. Here, we report a 2.8-Å cryo-electron microscopy structure of human LRRC8A that displays well-resolved NTs. Amino-terminal halves of NTs fold back into the pore and constrict the permeation path, thereby determining ion selectivity together with an extracellular selectivity filter with which it works in series. They also interact with pore-surrounding helices and support their compact arrangement. The C-terminal halves of NTs interact with intracellular loops that are crucial for channel activation. Molecular dynamics simulations indicate that low ionic strength increases NT mobility and expands the radial distance between pore-surrounding helices. Our work suggests an unusual pore architecture with two selectivity filters in series and a mechanism for VRAC activation by cell swelling.
Topics: Humans; Cryoelectron Microscopy; Membrane Proteins; Anions; Cell Size; Osmolar Concentration
PubMed: 37543949
DOI: 10.1016/j.celrep.2023.112926 -
Marine Drugs Jun 2023This review article presents past and current alginate-based materials in each application, showing the widest range of alginate's usage and development in the past and... (Review)
Review
This review article presents past and current alginate-based materials in each application, showing the widest range of alginate's usage and development in the past and in recent years. The first segment emphasizes the unique characteristics of alginates and their origin. The second segment sets alginates according to their application based on their features and limitations. Alginate is a polysaccharide and generally occurs as water-soluble sodium alginate. It constitutes hydrophilic and anionic polysaccharides originally extracted from natural brown algae and bacteria. Due to its promising properties, such as gelling, moisture retention, and film-forming, it can be used in environmental protection, cosmetics, medicine, tissue engineering, and the food industry. The comparison of publications with alginate-based products in the field of environmental protection, medicine, food, and cosmetics in scientific articles showed that the greatest number was assigned to the environmental field (30,767) and medicine (24,279), whereas fewer publications were available in cosmetic (5692) and food industries (24,334). Data are provided from the Google Scholar database (including abstract, title, and keywords), accessed in May 2023. In this review, various materials based on alginate are described, showing detailed information on modified composites and their possible usage. Alginate's application in water remediation and its significant value are highlighted. In this study, existing knowledge is compared, and this paper concludes with its future prospects.
Topics: Alginates; Polysaccharides; Tissue Engineering; Water; Biocompatible Materials
PubMed: 37367678
DOI: 10.3390/md21060353 -
Chemical Reviews Jul 2023Anionic species are omnipresent and involved in many important biological processes. A large number of artificial anion receptors has therefore been developed. Some of... (Review)
Review
Anionic species are omnipresent and involved in many important biological processes. A large number of artificial anion receptors has therefore been developed. Some of these are capable of mediating transmembrane transport. However, where transport proteins can respond to stimuli in their surroundings, creation of synthetic receptors with stimuli-responsive functions poses a major challenge. Herein, we give a full overview of the stimulus-controlled anion receptors that have been developed thus far, including their application in membrane transport. In addition to their potential operation as membrane carriers, the use of anion recognition motifs in forming responsive membrane-spanning channels is discussed. With this review article, we intend to increase interest in transmembrane transport among scientists working on host-guest complexes and dynamic functional systems in order to stimulate further developments.
Topics: Receptors, Artificial; Biological Transport; Anions
PubMed: 37342028
DOI: 10.1021/acs.chemrev.3c00039 -
Nature Structural & Molecular Biology Oct 2023Anion exchanger 1 (AE1), a member of the solute carrier (SLC) family, is the primary bicarbonate transporter in erythrocytes, regulating pH levels and CO transport...
Anion exchanger 1 (AE1), a member of the solute carrier (SLC) family, is the primary bicarbonate transporter in erythrocytes, regulating pH levels and CO transport between lungs and tissues. Previous studies characterized its role in erythrocyte structure and provided insight into transport regulation. However, key questions remain regarding substrate binding and transport, mechanisms of drug inhibition and modulation by membrane components. Here we present seven cryo-EM structures in apo, bicarbonate-bound and inhibitor-bound states. These, combined with uptake and computational studies, reveal important molecular features of substrate recognition and transport, and illuminate sterol binding sites, to elucidate distinct inhibitory mechanisms of research chemicals and prescription drugs. We further probe the substrate binding site via structure-based ligand screening, identifying an AE1 inhibitor. Together, our findings provide insight into mechanisms of solute carrier transport and inhibition.
Topics: Anion Exchange Protein 1, Erythrocyte; Bicarbonates; Membrane Transport Proteins; Binding Sites; Protein Domains
PubMed: 37679563
DOI: 10.1038/s41594-023-01085-6 -
International Journal of Molecular... Aug 2023In the last few decades, reticular chemistry has grown significantly as a field of porous crystalline molecular materials. Scientists have attempted to create the ideal... (Review)
Review
In the last few decades, reticular chemistry has grown significantly as a field of porous crystalline molecular materials. Scientists have attempted to create the ideal platform for analyzing distinct anions based on optical sensing techniques (chromogenic and fluorogenic) by assembling different metal-containing units with suitable organic linking molecules and different organic molecules to produce crystalline porous materials. This study presents novel platforms for anion recognition based on reticular chemistry with high selectivity, sensitivity, electronic tunability, structural recognition, strong emission, and thermal and chemical stability. The key materials for reticular chemistry, Metal-Organic Frameworks (MOFs), Zeolitic Imidazolate Frameworks (ZIFs), and Covalent-Organic Frameworks (COFs), and the pre- and post-synthetic modification of the linkers and the metal oxide clusters for the selective detection of the anions, have been discussed. The mechanisms involved in sensing are also discussed.
Topics: Anions; Oxides; Electronics; Metal-Organic Frameworks; Porosity
PubMed: 37685850
DOI: 10.3390/ijms241713045