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Pharmacology Research & Perspectives Jun 2023Syringin is a natural chemical compound first isolated from the bark of lilac and is known to have neuroprotective effects in middle cerebral artery occlusion (MCAO)....
Syringin is a natural chemical compound first isolated from the bark of lilac and is known to have neuroprotective effects in middle cerebral artery occlusion (MCAO). Volume regulated anion channel (VRAC) is a cell swelling-activated anion channel, which is implicated in brain ischemia. However, the mechanism underlying the syringin protecting the neuron from damage in MCAO is still unclear. We hypothesized that syringin has an inhibitory effect on the opening of VRAC channels. To access the effect of syringin on VRAC currents and predict how syringin interacts with VRAC proteins, we performed whole-cell patch-clamp experiments using HEK293 cells. Initially, HEK293 cells were perfused with isotonic extracellular solution, followed by hypotonic extracellular solution to stimulate endogenous VRAC currents. Once the VRAC currents reached a steady state, the hypotonic solution containing syringin was perfused to study the effect of syringin on VRAC currents. The potential interaction between syringin and the VRAC protein was investigated using molecular docking as a predictive model. In this study, we found that syringin moderately inhibited VRAC currents in a dose-dependent manner. The potential binding of syringin to LRRC8 protein was predicted through in silico molecular docking, which suggests an affinity of -6.6 kcal/mol and potential binding sites of arginine 103 and leucine 101. Our results herein characterize syringin as an inhibitor of the VRAC channels, which provides valuable insights for the future development of VRAC channel inhibitors.
Topics: Humans; HEK293 Cells; Membrane Proteins; Molecular Docking Simulation; Anions
PubMed: 37278329
DOI: 10.1002/prp2.1105 -
The Journal of Physical Chemistry. B Apr 2024Since Hofmeister's seminal studies in the late 19th century, it has been known that salts and buffers can drastically affect the properties of peptides and proteins....
Since Hofmeister's seminal studies in the late 19th century, it has been known that salts and buffers can drastically affect the properties of peptides and proteins. These Hofmeister effects can be conceived of in terms of three distinct phenomena/mechanisms: water-salt interactions that indirectly induce the salting-out of a protein by water sequestration by the salt, and direct salt-protein interactions that can either salt-in or salt-out the protein. Unfortunately, direct salt-protein interactions responsible for Hofmeister effects are weak and difficult to quantify. As such, they are frequently construed of as being nonspecific. Nevertheless, there has been considerable effort to better specify these interactions. Here, we use pentapeptides to demonstrate the utility of the H-dimension of nuclear magnetic resonance (NMR) spectroscopy to assess anion binding using N-H signal shifts. We qualify binding using these, demonstrating the upfield shifts induced by anion association and revealing how they are much larger than the corresponding downfield shifts induced by magnetic susceptibility and other ionic strength change effects. We also qualify binding in terms of how the pattern of signal shifts changes with point mutations. In general, we find that the observed upfield shifts are small compared with those induced by anion binding to amide-based hosts, and MD simulations suggest that this is so. Thus, charge-diffuse anions associate mostly with the nonpolar regions of the peptide rather than directly interacting with the amide N-H groups. These findings reveal the utility of H NMR spectroscopy for qualifying affinity to peptides─even when affinity constants are very low─and serve as a benchmark for using NMR spectroscopy to study anion binding to more complex systems.
Topics: Peptides; Anions; Proteins; Amides; Sodium Chloride; Water
PubMed: 38592238
DOI: 10.1021/acs.jpcb.4c00657 -
Angewandte Chemie (International Ed. in... May 2024Artificial ion transport systems have emerged as an important class of compounds that promise applications in chemotherapeutics as anticancer agents or to treat...
Artificial ion transport systems have emerged as an important class of compounds that promise applications in chemotherapeutics as anticancer agents or to treat channelopathies. Stimulus-responsive systems that offer spatiotemporally controlled activity for targeted applications remain rare. Here we utilize dynamic hydrogen bonding interactions of a 4,6-dihydroxy-isophthalamide core to generate a modular platform enabling access to stimuli-responsive ion transporters that can be activated in response to a wide variety of external stimuli, including light, redox, and enzymes, with excellent OFF-ON activation profiles. Alkylation of the two free hydroxyl groups with stimulus-responsive moieties locks the amide bonds through intramolecular hydrogen bonding and hence makes them unavailable for anion binding and transport. Triggering using a particular stimulus to cleave both cages reverses the hydrogen bonding arrangement, to generate a highly preorganized anion binding cavity for efficient transmembrane transport. Integration of two cages that are responsive to orthogonal stimuli enables multi-stimuli activation, where both stimuli are required to trigger transport in an AND logic process. Importantly, the strategy provides a facile method to post-functionalize the highly active transporter core with a variety of stimulus-responsive moieties for targeted activation with multiple triggers.
Topics: Hydrogen Bonding; Anions; Ionophores; Oxidation-Reduction; Molecular Structure; Ion Transport
PubMed: 38517056
DOI: 10.1002/anie.202403314 -
The New Phytologist Aug 2019We investigated the molecular basis and physiological implications of anion transport during pollen tube (PT) growth in Arabidopsis thaliana (Col-0). Patch-clamp...
We investigated the molecular basis and physiological implications of anion transport during pollen tube (PT) growth in Arabidopsis thaliana (Col-0). Patch-clamp whole-cell configuration analysis of pollen grain protoplasts revealed three subpopulations of anionic currents differentially regulated by cytoplasmic calcium ([Ca ] ). We investigated the pollen-expressed proteins AtSLAH3, AtALMT12, AtTMEM16 and AtCCC as the putative anion transporters responsible for these currents. AtCCC-GFP was observed at the shank and AtSLAH3-GFP at the tip and shank of the PT plasma membrane. Both are likely to carry the majority of anion current at negative potentials, as extracellular anionic fluxes measured at the tip of PTs with an anion vibrating probe were significantly lower in slah3 and ccc mutants, but unaffected in almt12 and tmem16 . We further characterised the effect of pH and GABA by patch clamp. Strong regulation by extracellular pH was observed in the wild-type, but not in tmem16 . Our results are compatible with AtTMEM16 functioning as an anion/H cotransporter and therefore, as a putative pH sensor. GABA presence: (1) inhibited the overall currents, an effect that is abrogated in the almt12 and (2) reduced the current in AtALMT12 transfected COS-7 cells, strongly suggesting the direct interaction of GABA with AtALMT12. Our data show that AtSLAH3 and AtCCC activity is sufficient to explain the major component of extracellular anion fluxes, and unveils a possible regulatory system linking PT growth modulation by pH, GABA, and [Ca ] through anionic transporters.
Topics: Anions; Arabidopsis; Arabidopsis Proteins; Calcium; Cell Membrane; Chlorides; Electrophysiological Phenomena; Hydrogen-Ion Concentration; Ion Channels; Ion Transport; Models, Biological; Mutation; Nitrates; Pollen; Pollen Tube; Protoplasts; Symporters; gamma-Aminobutyric Acid
PubMed: 31132313
DOI: 10.1111/nph.15863 -
Handbook of Experimental Pharmacology 2024Volume-regulated anion channels (VRACs) and the acid-sensitive outwardly rectifying anion channel (ASOR) mediate flux of chloride and small organic anions. Although...
Volume-regulated anion channels (VRACs) and the acid-sensitive outwardly rectifying anion channel (ASOR) mediate flux of chloride and small organic anions. Although known for a long time, they were only recently identified at the molecular level. VRACs are heteromers consisting of LRRC8 proteins A to E. Combining the essential LRRC8A with different LRRC8 paralogues changes key properties of VRAC such as conductance or substrate selectivity, which is how VRACs are involved in multiple physiological functions including regulatory volume decrease, cell proliferation and migration, cell death, purinergic signalling, fat and glucose metabolism, insulin signalling, and spermiogenesis. VRACs are also involved in pathological conditions, such as the neurotoxic release of glutamate and aspartate. Certain VRACs are also permeable to larger, organic anions, including antibiotics and anti-cancer drugs, making them an interesting therapeutic target. ASOR, also named proton-activated chloride channel (PAC), is formed by TMEM206 homotrimers on the plasma membrane and on endosomal compartments where it mediates chloride flux in response to extracytosolic acidification and plays a role in the shrinking and maturation of macropinosomes. ASOR has been shown to underlie neuronal swelling which causes cell death after stroke as well as promoting the metastasis of certain cancers, making them intriguing therapeutic targets as well.
Topics: Humans; Chlorides; Chloride Channels; Protons; Membrane Proteins; Anions
PubMed: 37468723
DOI: 10.1007/164_2023_673 -
Advances in Colloid and Interface... Sep 2020Layered Double Hydroxides (LDHs) are a group of hydrotalcite-like nano-sized materials with cationic layers and exchangeable interlayer anions. The wide range of... (Review)
Review
Layered Double Hydroxides (LDHs) are a group of hydrotalcite-like nano-sized materials with cationic layers and exchangeable interlayer anions. The wide range of divalent and trivalent cationic metals and anionic compounds are employed in the synthesis of LDH materials, which have improved their importance among the researchers. Because of their high anion exchange property, memory effect, tunable behavior, bio-friendly, simple preparation, and their affordability, these nano-materials are essentially interested today. Modification of LDHs improves their behaviours to make them appropriate in industrial fields, including biological, adsorbent, mechanical, optical, thermal, electrical fields, etc. This review has critically discussed the structural features, main properties, and also clarified the most important methods of modification and intercalation of LDH nano-materials. Moreover, some novel reported researches related to the successful modification of LDH materials have been characterized and briefly the advantages, disadvantages, and applications are presented in the industrial fields.
Topics: Hydroxides; Industry; Nanostructures
PubMed: 32763493
DOI: 10.1016/j.cis.2020.102216 -
Electrophoresis Sep 2019The efficient profiling of highly polar and charged metabolites in biological samples remains a huge analytical challenge in metabolomics. Over the last decade, new... (Review)
Review
The efficient profiling of highly polar and charged metabolites in biological samples remains a huge analytical challenge in metabolomics. Over the last decade, new analytical techniques have been developed for the selective and sensitive analysis of polar ionogenic compounds in various matrices. Still, the analysis of such compounds, notably for acidic ionogenic metabolites, remains a challenging endeavor, even more when the available sample size becomes an issue for the total analytical workflow. In this paper, we give an overview of the possibilities of capillary electrophoresis-mass spectrometry (CE-MS) for anionic metabolic profiling by focusing on main methodological developments. Attention is paid to the development of improved separation conditions and new interfacing designs in CE-MS for anionic metabolic profiling. A complete overview of all CE-MS-based methods developed for this purpose is provided in table format (Table 1) which includes information on sample type, separation conditions, mass analyzer and limits of detection (LODs). Selected applications are discussed to show the utility of CE-MS for anionic metabolic profiling, especially for small-volume biological samples. On the basis of the examination of the reported literature in this specific field, we conclude that there is still room for the design of a highly sensitive and reliable CE-MS method for anionic metabolic profiling. A rigorous validation and the availability of standard operating procedures would be highly favorable in order to make CE-MS an alternative, viable analytical technique for metabolomics.
Topics: Animals; Anions; Electrophoresis, Capillary; Humans; Limit of Detection; Mass Spectrometry; Metabolome; Metabolomics; Mice; Rats; Reproducibility of Results
PubMed: 31106868
DOI: 10.1002/elps.201900115 -
Analytical Chemistry Nov 2022Inorganic pyrophosphate (PPi) is an important biological functional anion and plays crucial roles in life science, environmental science, medicine, and chemical process....
Inorganic pyrophosphate (PPi) is an important biological functional anion and plays crucial roles in life science, environmental science, medicine, and chemical process. Quantification of PPi in water has far-reaching significance for life exploration, disease diagnosis, and water pollution control. The label-free quantitative detection of PPi anions with a nanofluidic sensing device based on a conical single nanochannel is demonstrated. The channel surface is functionalized with a synthetic PPi receptor, triazol-methanaminium-functionalized pillar[5]arene (TAMAP5), using carbodiimide coupling chemistry. Due to the specific binding between TAMAP5 and PPi, the functionalized nanochannel can discriminate PPi from other inorganic anions with high selectivity through ionic current recording, even in the presence of various interfering anions. The current response exhibits a linear correlation with PPi concentration in the range from 1 × 10 to 1 × 10 M with a limit of detection of 6.8 × 10 M. A spike-and-recovery analysis of PPi in East Lake water samples indicates that the proposed nanofluidic sensor has the ability to quantitate micromolar concentrations of PPi in environmental water samples.
Topics: Diphosphates; Water; Anions
PubMed: 36269622
DOI: 10.1021/acs.analchem.2c02161 -
Angewandte Chemie (International Ed. in... Nov 2021Light is a convenient source of energy and the heart of light-harvesting natural systems and devices. Here, we show light-modulation of both the chemical nature and...
Light is a convenient source of energy and the heart of light-harvesting natural systems and devices. Here, we show light-modulation of both the chemical nature and ionic charge carrier concentration within a protein-based biopolymer that was covalently functionalized with photoacids or photobases. We explore the capability of the biopolymer-tethered photoacids and photobases to undergo excited-state proton transfer and capture, respectively. Electrical measurements show that both the photoacid- and photobase-functionalized biopolymers exhibit an impressive light-modulated increase in ionic conductivity. Whereas cationic protons are the charge carriers for the photoacid-functionalized biopolymer, water-derived anionic hydroxides are the suggested charge carriers for the photobase-functionalized biopolymer. Our work introduces a versatile toolbox to photomodulate both protons and hydroxides as charge carriers in polymers, which can be of interest for a variety of applications.
Topics: Animals; Anions; Biopolymers; Cations; Cattle; Electric Conductivity; Hydroxides; Light; Proteins; Protons; Serum Albumin, Bovine
PubMed: 34492153
DOI: 10.1002/anie.202111024 -
The Journal of Organic Chemistry May 2024Anions have a profound effect on the properties of soluble proteins. Such Hofmeister effects have implications in biologics stability, protein aggregation,...
Anions have a profound effect on the properties of soluble proteins. Such Hofmeister effects have implications in biologics stability, protein aggregation, amyloidogenesis, and crystallization. However, the interplay between the important noncovalent interactions (NCIs) responsible for Hofmeister effects is poorly understood. To contribute to improving this state of affairs, we report on the NCIs between anions and ammonium and guanidinium hosts and , and the consequences of these. Specifically, we investigate the properties of cavitands designed to mimic two prime residues for anion-protein NCIs─lysines and arginines─and the solubility consequences of complex formation. Thus, we report NMR and ITC affinity studies, X-ray analysis, MD simulations, and anion-induced critical precipitation concentrations. Our findings emphasize the multitude of NCIs that guanidiniums can form and how this repertoire qualitatively surpasses that of ammoniums. Additionally, our studies demonstrate the ease by which anions can dispense with a fraction of their hydration-shell waters, rearrange those that remain, and form direct NCIs with the hosts. This raises many questions concerning how solvent shell plasticity varies as a function of anion, how the energetics of this impact the different NCIs between anions and ammoniums/guanidiniums, and how this affects the aggregation of solutes at high anion concentrations.
Topics: Guanidine; Anions; Arginine; Ammonium Compounds; Lysine; Molecular Dynamics Simulation
PubMed: 38662908
DOI: 10.1021/acs.joc.4c00242