Ether lipid deficiency disrupts lipid homeostasis leading to ferroptosis sensitivity.

Ferroptosis is an iron-dependent form of regulated cell death associated with uncontrolled membrane lipid peroxidation and destruction. Previously, we showed that dietary dihomo-gamma-linolenic acid (DGLA; 20: 3(n-6)) triggers ferroptosis in the germ cells of the model organism, Caenorhabditis elegans. We also demonstrated that ether lipid-deficient mutant strains are sensitive to DGLA-induced ferroptosis, suggesting a protective role for ether lipids. The vinyl ether bond unique to plasmalogen lipids has been hypothesized to function as an antioxidant, but this has not been tested in animal models. In this study, we used C. elegans mutants to test the hypothesis that the vinyl ether bond in plasmalogens acts as an antioxidant to protect against germ cell ferroptosis as well as to protect from whole-body tert-butyl hydroperoxide (TBHP)-induced oxidative stress. We found no role for plasmalogens in either process. Instead, we demonstrate that ether lipid-deficiency disrupts lipid homeostasis in C. elegans, leading to altered ratios of saturated and monounsaturated fatty acid (MUFA) content in cellular membranes. We demonstrate that ferroptosis sensitivity in both wild type and ether-lipid deficient mutants can be rescued in several ways that change the relative abundance of saturated fats, MUFAs and specific polyunsaturated fatty acids (PUFAs). Specifically, we reduced ferroptosis sensitivity by (1) using mutant strains unable to synthesize DGLA, (2) using a strain carrying a gain-of-function mutation in the transcriptional mediator MDT-15, or (3) by dietary supplementation of MUFAs. Furthermore, our studies reveal important differences in how dietary lipids influence germ cell ferroptosis versus whole-body peroxide-induced oxidative stress. These studies highlight a potentially beneficial role for endogenous and dietary MUFAs in the prevention of ferroptosis.

longfin causes cis-ectopic expression of the kcnh2a ether-a-go-go K+ channel to autonomously prolong fin outgrowth.

Organs stop growing to achieve a characteristic size and shape in scale with the body of an animal. Likewise, regenerating organs sense injury extents to instruct appropriate replacement growth. Fish fins exemplify both phenomena through their tremendous diversity of form and remarkably robust regeneration. The classic zebrafish mutant longfint2 develops and regenerates dramatically elongated fins and underlying ray skeleton. We show longfint2 chromosome 2 overexpresses the ether-a-go-go-related voltage-gated potassium channel kcnh2a. Genetic disruption of kcnh2a in cis rescues longfint2, indicating longfint2 is a regulatory kcnh2a allele. We find longfint2 fin overgrowth originates from prolonged outgrowth periods by showing Kcnh2a chemical inhibition during late stage regeneration fully suppresses overgrowth. Cell transplantations demonstrate longfint2-ectopic kcnh2a acts tissue autonomously within the fin intra-ray mesenchymal lineage. Temporal inhibition of the Ca2+-dependent phosphatase calcineurin indicates it likewise entirely acts late in regeneration to attenuate fin outgrowth. Epistasis experiments suggest longfint2-expressed Kcnh2a inhibits calcineurin output to supersede growth cessation signals. We conclude ion signaling within the growth-determining mesenchyme lineage controls fin size by tuning outgrowth periods rather than altering positional information or cell-level growth potency.

Ether Bond Cleavage of a Phenylcoumaran ß-5 Lignin Model Compound and Polymeric Lignin Catalysed by a LigE-type Etherase from Agrobacterium sp.

A LigE-type beta-etherase enzyme from lignin-degrading Agrobacterium sp. has been identified, which assists degradation of polymeric lignins. Testing against lignin dimer model compounds revealed that it does not catalyse the previously reported reaction of Sphingobium SYK-6 LigE, but instead shows activity for a ß-5 phenylcoumaran lignin dimer. The reaction products did not contain glutathione, indicating a catalytic role for reduced glutathione in this enzyme. Three reaction products were identified: the major product was a cis-stilbene arising from C-C fragmentation involving loss of formaldehyde; two minor products were an alkene arising from elimination of glutathione, and an oxidised ketone, proposed to arise from reaction of an intermediate with molecular oxygen. Testing of the recombinant enzyme against a soda lignin revealed the formation of new signals by two-dimensional NMR analysis, whose chemical shifts are consistent with the formation of a stilbene unit in polymeric lignin.

Spinal histamine H4 receptor mediates chronic pruritus via p-ERK in acetone-ether-water (AEW)-induced dry skin mice.

Dry skin is common to many pruritic diseases and is difficult to improve with oral traditional antihistamines. Recently, increasing evidence indicated that histamine H4 receptor (H4R) plays an important role in the occurrence and development of pruritus. Extracellular signal-regulated kinase (ERK) phosphorylation activation in the spinal cord mediates histamine-induced acute and choric itch. However, whether the histamine H4 receptor regulates ERK activation in the dry skin itch remains unclear. In the study, we explore the role of the histamine H4 receptor and p-ERK in the spinal cord in a dry skin mouse model induced by acetone-ether-water (AEW). q-PCR, Western blot, pharmacology and immunofluorescence  were applied in the study. We established a dry skin itch model by repeated application of AEW on the nape of neck in mice. The AEW mice showed typically dry skin histological change and persistent spontaneous scratching behaviour. Histamine H4 receptor, instead of histamine H1 receptor, mediated spontaneous scratching behaviour in AEW mice. Moreover, c-Fos and p-ERK expression in the spinal cord neurons were increased and co-labelled with GRPR-positive neurons in AEW mice. Furthermore, H4R agonist 4-methyhistamine dihydrochloride (4-MH)induced itch. Both 4-MH-induced itch and the spontaneous itch in AEW mice were blocked by p-ERK inhibitor U0126. Finally, intrathecal H4R receptor antagonist JNJ7777120 inhibited spinal p-ERK expression in AEW mice. Our results indicated that spinal H4R mediates itch via ERK activation in the AEW-induced dry skin mice.

Toward Lung Ventilation Imaging Using Hyperpolarized Diethyl Ether Gas Contrast Agent.

Hyperpolarized 129Xe gas was FDA-approved as an inhalable contrast agent for magnetic resonance imaging of a wide range of pulmonary diseases in December 2022. Despite the remarkable success in clinical research settings, the widespread clinical translation of HP 129Xe gas faces two critical challenges: the high cost of the relatively low-throughput hyperpolarization equipment and the lack of 129Xe imaging capability on clinical MRI scanners, which have narrow-bandwidth electronics designed only for proton (1H) imaging. To solve this translational grand challenge of gaseous hyperpolarized MRI contrast agents, here we demonstrate the utility of batch-mode production of proton-hyperpolarized diethyl ether gas via heterogeneous pairwise addition of parahydrogen to ethyl vinyl ether. An approximately 0.1-liter bolus of hyperpolarized diethyl ether gas was produced in 1 second and injected in excised rabbit lungs. Lung ventilation imaging was performed using sub-second 2D MRI with up to 2×2 mm2 in-plane resolution using a clinical 0.35 T MRI scanner without any modifications. This feasibility demonstration paves the way for the use of inhalable diethyl ether as a gaseous contrast agent for pulmonary MRI applications using any clinical MRI scanner.

Disrupted intercellular bridges and spermatogenesis in fatty acyl-CoA reductase 1 knockout mice: A new model of ether lipid deficiency.

Peroxisomal fatty acyl-CoA reductase 1 (FAR1) is a rate-limiting enzyme for ether lipid (EL) synthesis. Gene mutations in FAR1 cause a rare human disease. Furthermore, altered EL homeostasis has also been associated with various prevalent human diseases. Despite their importance in human health, the exact cellular functions of FAR1 and EL are not well-understood. Here, we report the generation and initial characterization of the first Far1 knockout (KO) mouse model. Far1 KO mice were subviable and displayed growth retardation. The adult KO male mice had smaller testes and were infertile. H&E and immunofluorescent staining showed fewer germ cells in seminiferous tubules. Round spermatids were present but no elongated spermatids or spermatozoa were observed, suggesting a spermatogenesis arrest at this stage. Large multi-nucleated giant cells (MGC) were found lining the lumen of seminiferous tubules with many of them undergoing apoptosis. The immunofluorescent signal of TEX14, an essential component of intercellular bridges (ICB) between developing germ cells, was greatly reduced and mislocalized in KO testis, suggesting the disrupted ICBs as an underlying cause of MGC formation. Integrative analysis of our total testis RNA-sequencing results and published single-cell RNA-sequencing data unveiled cell type-specific molecular alterations underlying the spermatogenesis arrest. Many genes essential for late germ cell development showed dramatic downregulation, whereas genes essential for extracellular matrix dynamics and cell-cell interactions were among the most upregulated genes. Together, this work identified the cell type-specific requirement of ELs in spermatogenesis and suggested a critical role of Far1/ELs in the formation/maintenance of ICB during meiosis.

Novel ether derivatives of 11-azaartemisinins with high order antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss mice.

This study investigates cutting-edge synthetic chemistry approaches for designing and producing innovative antimalarial drugs with improved efficacy and fewer adverse effects. Novel amino (-NH2) and hydroxy (-OH) functionalized 11-azaartemisinins 9, 12, and 14 were synthesized along with their derivatives 11a, 13a-e, and 15a-b through ART and were tested for their AMA (antimalarial activity) against Plasmodium yoelii via intramuscular (i.m.) and oral routes in Swiss mice. Ether derivative 13c was the most active compound by i.m. route, it has shown 100 % protection at the dose of 12 mg/kg × 4 days and showed 100 % clearance of parasitaemia on day 4 at dose of 6 mg/kg. Amine 11a, ether derivatives 13d, 13e and ether 15a also showed promising antimalarial activity. ß-Arteether gave 100 % protection at the dose of 48 mg/kg × 4 days and 20 % protection at 24 mg/kg × 4 days dose by oral route, while it showed 100 % protection at 6 mg/kg × 4 days and no protection at 3 mg/kg × 4 days by i.m. route.

Bioaccumulation and Male Reproductive Toxicity of the New Brominated Flame Retardant Tetrabromobisphenol A-Bis(2,3-dibromo-2-methylpropyl ether) in Comparison with Hexabromocyclododecane.

Tetrabromobisphenol A-bis(2,3-dibromo-2-methylpropyl ether) (TBBPA-DBMPE) has come into use as an alternative to hexabromocyclododecane (HBCD), but it is unclear whether TBBPA-DBMPE has less hazard than HBCD. Here, we compared the bioaccumulation and male reproductive toxicity between TBBPA-DBMPE and HBCD in mice following long-term oral exposure after birth. We found that the concentrations of TBBPA-DBMPE in livers significantly increased with time, exhibiting a bioaccumulation potency not substantially different from HBCD. Lactational exposure to 1000 µg/kg/d TBBPA-DBMPE as well as 50 µg/kg/d HBCD inhibited testis development in suckling pups, and extended exposure up to adulthood resulted in significant molecular and cellular alterations in testes, with slighter effects of 50 µg/kg/d TBBPA-DBMPE. When exposure was extended to 8 month age, severe reproductive impairments including reduced sperm count, increased abnormal sperm, and subfertility occurred in all treated animals, although 50 µg/kg/d TBBPA-DBMPE exerted lower effects than 50 µg/kg/d HBCD. Altogether, all data led us to conclude that TBBPA-DBMPE exerted weaker male reproductive toxicity than HBCD at the same doses but exhibited bioaccumulation potential roughly equivalent to HBCD. Our study fills the data gap regarding the bioaccumulation and toxicity of TBBPA-DBMPE and raises concerns about its use as an alternative to HBCD.

Oxidative Transformation of Nafion-Related Fluorinated Ether Sulfonates: Comparison with Legacy PFAS Structures and Opportunities of Acidic Persulfate Digestion for PFAS Precursor Analysis.

The total oxidizable precursor (TOP) assay has been extensively used for detecting PFAS pollutants that do not have analytical standards. It uses hydroxyl radicals (HO•) from the heat activation of persulfate under alkaline pH to convert H-containing precursors to perfluoroalkyl carboxylates (PFCAs) for target analysis. However, the current TOP assay oxidation method does not apply to emerging PFAS because (i) many structures do not contain C-H bonds for HO• attack and (ii) the transformation products are not necessarily PFCAs. In this study, we explored the use of classic acidic persulfate digestion, which generates sulfate radicals (SO4-•), to extend the capability of the TOP assay. We examined the oxidation of Nafion-related ether sulfonates that contain C-H or -COO-, characterized the oxidation products, and quantified the F atom balance. The SO4-• oxidation greatly expanded the scope of oxidizable precursors. The transformation was initiated by decarboxylation, followed by various spontaneous steps, such as HF elimination and ester hydrolysis. We further compared the oxidation of legacy fluorotelomers using SO4-• versus HO•. The results suggest novel product distribution patterns, depending on the functional group and oxidant dose. The general trends and strategies were also validated by analyzing a mixture of 100000- or 10000-fold diluted aqueous film-forming foam (containing various fluorotelomer surfactants and organics) and a spiked Nafion precursor. Therefore, (1) the combined use of SO4-• and HO• oxidation, (2) the expanded list of standard chemicals, and (3) further elucidation of SO4-• oxidation mechanisms will provide more critical information to probe emerging PFAS pollutants.

Exploring the plasticity of the InhA substrate-binding site using new diaryl ether inhibitors.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a worldwide scourge with more than 10 million people affected yearly. Among the proteins essential for the survival of Mtb, InhA has been and is still clinically validated as a therapeutic target. A new family of direct diaryl ether inhibitors, not requiring prior activation by the catalase peroxidase enzyme KatG, has been designed with the ambition of fully occupying the InhA substrate-binding site. Thus, eleven compounds, featuring three pharmacophores within the same molecule, were synthesized. One of them, 5-(((4-(2-hydroxyphenoxy)benzyl)(octyl)amino)methyl)-2-phenoxyphenol (compound 21), showed good inhibitory activity against InhA with IC50 of 0.70 µM. The crystal structure of compound 21 in complex with InhA/NAD+ showed how the molecule fills the substrate-binding site as well as the minor portal of InhA. This study represents a further step towards the design of new inhibitors of InhA.

The First Etherization in England: New Research Regarding the Identity of the First Patient, Miss Lonsdale.

On December 19, 1846, at the London home of Francis Boott, dentist James Robinson administered the vapor of diethyl ether to a young female patient named Miss Lonsdale. This was the earliest known attempt in England to provide painless operating conditions for a dental extraction, and it was successful. Many authors have since written much about Boott and Robinson, but scarcely anything is known about Miss Lonsdale. In contemporaneous accounts of the event, Robinson referred to his patient as a "young person" and a "young lady"; Boott, however, named her, suggesting that she was publicly recognizable. Our initial attempt to identify Miss Lonsdale was based on genealogical, United Kingdom Census, and other public records, using selection criteria based on age, name recognition, familial relationships, and London addresses. This produced 7 possible candidates from publicly recognizable families, though none was notable in her own right. Our second attempt was based primarily on contemporaneous newspaper records, among which were published 2 private letters in which Boott referred to Robinson's patient as a "girl." We found that "Miss Lonsdale" was the publicly recognizable name of 2 young stage-performing sisters, Adeline Lonsdale, a danseuse, and Annie Lonsdale, an actor-comedienne. Both subsequently emigrated to the United States where they were well-known stage performers. Accordingly, we suggest that both are highly probable candidates for that etherized patient, with the younger sister Adeline then more publicly recognizable. However, no records were found that directly associated any of the Miss Lonsdale candidates with that first dental anesthetic in England.

Semisynthesis and Cytotoxic Evaluation of an Ether Analogue Library Based on a Polyhalogenated Diphenyl Ether Scaffold Isolated from a Lamellodysidea Sponge.

The known oxygenated polyhalogenated diphenyl ether, 2-(2',4'-dibromophenoxy)-3,5-dibromophenol (1), with previously reported activity in multiple cytotoxicity assays was isolated from the sponge Lamellodysidea sp. and proved to be an amenable scaffold for semisynthetic library generation. The phenol group of 1 was targeted to generate 12 ether analogues in low-to-excellent yields, and the new library was fully characterized by NMR, UV, and MS analyses. The chemical structures for 2, 8, and 9 were additionally determined via single-crystal X-ray diffraction analysis. All natural and semisynthetic compounds were evaluated for their ability to inhibit the growth of DU145, LNCaP, MCF-7, and MDA-MB-231 cancer cell lines. Compound 3 was shown to have near-equivalent activity compared to scaffold 1 in two in vitro assays, and the activity of the compounds with an additional benzyl ring appeared to be reliant on the presence and position of additional halogens.

Per- and polyfluoroalkyl substances in waterbird feathers around Poyang Lake, China: Compound and species-specific bioaccumulation.

As a nondestructive means of environmental monitoring, bird feathers have been used to analyze levels of per- and polyfluoroalkyl substances (PFASs) in specific environments. In this study, feather samples from 10 waterbird species around Poyang Lake were collected, and a pretreatment method for PFASs in feathers was optimized. The results showed that a combined cleaning method using ultrapure water and n-hexane effectively removed external PFASs. Twenty-three legacy and emerging PFASs were identified in the feathers of waterbirds, of which hexafluoropropylene oxides (HFPOs), chlorinated polyfluoroalkyl ether sulfonates (Cl-PFESAs), and sodium p-perfluorinated noneoxybenzene sulfonate (OBS) were reported for the first time, with their concentrations ranging from 0.060-2.4 ng·g-1 dw, 0.046-30 ng·g-1 dw, and lower than the method detection limit to 30 ng·g-1 dw, respectively. Compound- and species-specific bioaccumulation of PFASs was observed in the feathers of different waterbird species, suggesting that different PFAS types can be monitored through the selection of different species. Moreover, the concentrations of most PFCAs (except perfluorobutyric acid), perfluorooctane sulfonate (PFOS), and perfluorooctane sulfonamide (FOSA) were significantly positively correlated with δ15N (p < 0.05), while the concentrations of HFPOs, Cl-PFESAs, and OBS had significant positive correlations with δ13C. This indicates that the bioaccumulation of legacy and emerging PFASs in waterbird feathers is affected by their trophic level, feeding habits, and foraging area.

Dietary exposure to 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) induces oxidative damage promoting cell apoptosis primarily via mitochondrial pathway in the hepatopancreas of carp, Cyprinus carpio.

To investigate the mechanisms of BDE-47 on hepatotoxicity in fish, this study examined the effects of dietary exposure to BDE-47 (40 and 4000 ng/g) on carp for 42 days. The results showed that BDE-47 significantly increased carp's condition factor and hepatosomatic index. Pathological results revealed unclear hepatic cord structure, hepatocytes swelling, cellular vacuolization, and inflammatory cell infiltration in the hepatopancreas of carp. Further investigation showed that ROS levels significantly increased on days 7, 14, and 42. Moreover, the activities of antioxidant enzymes SOD, GSH, CAT, and GST increased significantly from 1 to 7 days, and the transcription levels of antioxidant enzymes CAT, Cu-Zn SOD, Mn-SOD, GST, and GPX, and antioxidant pathway genes Keap1, Nrf2, and HO-1 changed significantly at multiple time-points during the 42 days. The results of apoptosis pathway genes showed that the mitochondrial pathway genes Bax, Casp3, and Casp9 were significantly upregulated and Bcl2 was significantly downregulated, while the transcription levels of FADD and PERK were significantly enhanced. These results indicate that BDE-47 induced oxidative damage in hepatopancreas, then it promoted cell apoptosis mainly through the mitochondrial pathway. This study provides a foundation for analyzing the mechanism of hepatotoxicity induced by BDE-47 on fish.

Neuroinflammation and Acetylcholinesterase Inhibitory Potentials of a Spiroketal-Enol Ether Polyyne Isolated from Artemisia pallens Wall. ex DC.

Artemisia pallens Wall. ex DC (Asteraceae) is cultivated for the production of high-value essential oil from its aerial biomass. In this study, the chemical composition of the root (crop-residue) essential oil was investigated for the first time, using column-chromatography, GC-FID, GC-MS, LC-QTOF, and NMR techniques, which led to the identification of twenty constituents, with isolation of (E)-2-(2',4'-hexadiynylidene)-1,6-dioxaspiro [4.5]dec-3-ene (D6). The D6 was evaluated in vitro for neuroinflammation and acetylcholinesterase inhibitory potential. It showed inhibition of neuroinflammation in a concentration-dependent manner with significant inhibition of pro-inflammatory cytokines (TNF-α and IL-6) in LPS-stimulated BV2 microglial cells. D6 did not have any significant effect on the viability of the cells at the therapeutic concentrations. D6 also has shown acetylcholinesterase inhibitory potential (51.90±1.19 %) at the concentration of log 106  nM. The results showed that D6 has a potential role in the resolution of neuroinflammation, and its acetylcholinesterase inhibitory potential directs further investigation of its role in the management of Alzheimer's disease-related pathogenesis.

2,2',4,4'-Tetrabromodiphenyl ether and cadmium co-exposure activates aryl hydrocarbon receptor pathway to induce ROS and GSDME-dependent pyroptosis in renal tubular epithelial cells.

We have previously found that a mixture exposure of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and cadmium (Cd) causes kidney damage; however, the mechanism was not fully understood. The aryl hydrocarbon receptor (AhR) is a ligand-receptor transcription factor that plays an important role in the adaptive response or metabolic detoxification of environmental toxins. Thus, this study aimed to examine the role of AhR in kidney toxicity. BDE-47 (50 µM) or Cd (5 µM) exposure reduced cell viability in renal tubular epithelial cells (HKC), with a larger effect observed in co-treatment. The cell morphology presented pyroptotic changes, including swollen cells, large bubbles, and plasma membrane pore formation. The gene expressions of AhR, heat shock protein 90 (Hsp90), AhR nuclear translocator (ARNT), and cytochrome P450 1B1 (CYP1B1) were increased, while CYP1A1 was decreased. Reactive oxygen species (ROS) were generated, which was reduced by the AhR antagonist CH223191. The apoptosis, necrosis, and intracellular lactated hydrogenase (LDH) release was elevated, and this was attenuated by N-acetylcysteine (NAC). Furthermore, the pyroptosis pathway was activated with increased protein levels of cleaved-caspase-3 and gasdermin E N-terminal (GSDME-NT), while caspase-8, caspase-3, and GSDME were decreased. These effects were alleviated by NAC and CH223191. Our data demonstrate a combined effect of BDE-47 and Cd on nephrotoxicity by activating AhR to induce ROS contributing to GSDME-dependent pyroptosis, and retardation of the AhR pathway could reduce this toxicity.

Surface Wear and Retention Force of Zirconia and PEKK Implant-retained Crowns.

PURPOSE: The aim of this study was to evaluate the surface wear and retention force of telescopic attachments made of zirconia primary crowns and poly-ether- ketone -ketone (PEKK) secondary crowns for 2-implant retained mandibular complete overdentures. MATERIALS AND METHODS: Ten healthy completely edentulous patients aged 55-60 years were selected for this study. Each patient received two implants in the mandibular canine regions. Maxillary conventional complete dentures were constructed against implant-retained mandibular overdentures for all patients. Zirconia- PEKK telescopic attachments were fabricated to retain the overdentures where primary copings were constructed of zirconia and secondary ones were constructed of PEKK. Retention force and surface wear were evaluated at the time of overdenture insertion (T0), and after 6 months of overdenture use (T6). RESULTS: The results revealed less wear of zirconia copings compared to PEKK ones at T0 and T6. However, both materials showed insignificant wear after 6 months of overdenture use. A significant increase in retention force was observed after 6 months of overdenture use. CONCLUSION: Within limitations of this study, PEKK may be considered a promising alternative material for telescopic secondary crowns construction combined to zirconia primary ones, regarding the wear resistance and the satisfactory retention forces.

Substrate-Controlled Catalysis in the Ether Cross-Link-Forming Radical SAM Enzymes.

Darobactin is a heptapeptide antibiotic featuring an ether cross-link and a C-C cross-link, and both cross-links are installed by a radical S-adenosylmethionine (rSAM) enzyme DarE. How a single DarE enzyme affords the two chemically distinct cross-links remains largely obscure. Herein, by mapping the biosynthetic landscape for darobactin-like RiPP (daropeptide), we identified and characterized two novel daropeptides that lack the C-C cross-link present in darobactin and instead are solely composed of ether cross-links. Phylogenetic and mutagenesis analyses reveal that the daropeptide maturases possess intrinsic multifunctionality, catalyzing not only the formation of ether cross-link but also C-C cross-linking and Ser oxidation. Intriguingly, the different chemical outcomes are controlled by the exact substrate motifs. Our work not only provides a roadmap for the discovery of new daropeptide natural products but also offers insights into the regulatory mechanisms that govern these remarkably versatile ether cross-link-forming rSAM enzymes.

Cellulose ether treatment inhibits amyloid beta aggregation, neuroinflammation and cognitive deficits in transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is an incurable, progressive and devastating neurodegenerative disease. Pathogenesis of AD is associated with the aggregation and accumulation of amyloid beta (Aß), a major neurotoxic mediator that triggers neuroinflammation and memory impairment. Recently, we found that cellulose ether compounds (CEs) have beneficial effects against prion diseases by inhibiting protein misfolding and replication of prions, which share their replication mechanism with Aß. CEs are FDA-approved safe additives in foods and pharmaceuticals. Herein, for the first time we determined the therapeutic effects of the representative CE (TC-5RW) in AD using in vitro and in vivo models. Our in vitro studies showed that TC-5RW inhibits Aß aggregation, as well as neurotoxicity and immunoreactivity in Aß-exposed human and murine neuroblastoma cells. In in vivo studies, for the first time we observed that single and weekly TC-5RW administration, respectively, improved memory functions of transgenic 5XFAD mouse model of AD. We further demonstrate that TC-5RW treatment of 5XFAD mice significantly inhibited Aß oligomer and plaque burden and its associated neuroinflammation via regulating astrogliosis, microgliosis and proinflammatory mediator glial maturation factor beta (GMFß). Additionally, we determined that TC-5RW reduced lipopolysaccharide-induced activated gliosis and GMFß in vitro. In conclusion, our results demonstrate that CEs have therapeutic effects against Aß pathologies and cognitive impairments, and direct, potent anti-inflammatory activity to rescue neuroinflammation. Therefore, these FDA-approved compounds are effective candidates for developing therapeutics for AD and related neurodegenerative diseases associated with protein misfolding.

Lipase-Mediated Conversion of Protecting Group Silyl Ethers: An Unspecific Side Reaction.

Silyl ether protecting groups are important tools in organic synthesis, ensuring selective reactions of hydroxyl functional groups. Enantiospecific formation or cleavage could simultaneously enable the resolution of racemic mixtures and thus significantly increase the efficiency of complex synthetic pathways. Based on reports that lipases, which today are already particularly important tools in chemical synthesis, can catalyze the enantiospecific turnover of trimethylsilanol (TMS)-protected alcohols, the goal of this study was to determine the conditions under which such a catalysis occurs. Through detailed experimental and mechanistic investigation, we demonstrated that although lipases mediate the turnover of TMS-protected alcohols, this occurs independently of the known catalytic triad, as this is unable to stabilize a tetrahedral intermediate. The reaction is essentially non-specific and therefore most likely completely independent of the active site. This rules out lipases as catalysts for the resolution of racemic mixtures of alcohols through protection or deprotection with silyl groups.