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Mouth cancer is the most frequent cancer of the head and neck in both older and younger people. Achyranthes aspera L. has been used in ethnotraditional and pharmacological applications since ancient times for a variety of disorders. This study was formulated to examine bioactive phenolic and flavonoid compounds from the ethanolic extract of Achyranthes aspera and their binding efficacy targeting growth factor receptors (GFRs) against mouth cancer through in silico molecular docking and simulation studies. Phytochemicals were investigated through the UHPLC technique. A molecular docking study was accomplished using docking software AutoDock 4.2, and MD simulation was executed through GROMACS software. Drug‐likeness, pharmacokinetics, and toxicity profiles of phytocompounds were evaluated using Molinspiration, Swiss ADME, OSIRIS Data Warrior tools, respectively. UHPLC analysis detected phenolics and flavonoids, viz., fisetin, rutin, and fumaric acid, which satisfied Lipinski's rule of five and pharmacokinetic properties. In molecular docking assessment, fisetin exhibited promising interactions with core targeted proteins VEGFR‐2 (B.E. = −8.30 kcal mol−1) and FGFR‐2 (B.E. = −7.64 kcal mol−1) of mouth cancer. Moreover, molecular dynamics simulation data demonstrated stable interactions with both VEGFR‐2 and FGFR‐2 proteins. This binding interaction and stability of A. aspera phytocompounds with therapeutic proteins might contribute to their therapeutic potential in mouth cancer management. [ABSTRACT FROM AUTHOR]

The cellular response to oxidants or xenobiotics comprises two key pathways, resulting in modulation of NRF2 and FOXO transcription factors, respectively. Both mount a cytoprotective response, and their activation relies on crucial protein thiol moieties. Using fumaric acid esters (FAEs), known thiol‐reactive compounds, we tested for activation of NRF2 and FOXO pathways in cultured human hepatoma cells by dimethyl/diethyl as well as monomethyl/monoethyl fumarate. Whereas only the diesters caused acute glutathione depletion and activation of the stress kinase p38MAPK, all four FAEs stimulated NRF2 stabilization and upregulation of NRF2 target genes. However, no significant FAE‐induced activation of FOXO‐dependent target gene expression was observed. Therefore, while both NRF2 and FOXO pathways are responsive to oxidants and xenobiotics, FAEs selectively activate NRF2 signaling. [ABSTRACT FROM AUTHOR]

Biocatalytic hydroamination of alkenes is an efficient and selective method to synthesize natural and unnatural amino acids. Phenylalanine ammonia‐lyases (PALs) have been previously engineered to access a range of substituted phenylalanines and heteroarylalanines, but their substrate scope remains limited, typically including only arylacrylic acids. Moreover, the enantioselectivity in the hydroamination of electron‐deficient substrates is often poor. Here, we report the structure‐based engineering of PAL from Planctomyces brasiliensis (PbPAL), enabling preparative‐scale enantioselective hydroaminations of previously inaccessible yet synthetically useful substrates, such as amide‐ and ester‐containing fumaric acid derivatives. Through the elucidation of cryo‐electron microscopy (cryo‐EM) PbPAL structure and screening of the structure‐based mutagenesis library, we identified the key active site residue L205 as pivotal for dramatically enhancing the enantioselectivity of hydroamination reactions involving electron‐deficient substrates. Our engineered PALs demonstrated exclusive α‐regioselectivity, high enantioselectivity, and broad substrate scope. The potential utility of the developed biocatalysts was further demonstrated by a preparative‐scale hydroamination yielding tert‐butyl protected l‐aspartic acid, widely used as intermediate in peptide solid‐phase synthesis. [ABSTRACT FROM AUTHOR]

Zn anodes in aqueous zinc‐ion batteries chronically suffer from pernicious side reactions and ineluctable dendrite growth, resulting in inadequate reversibility and suboptimal Coulombic efficiency (CE) and impeding commercialization. Herein, a multifunctional metal–organic coordination polymer layer (FAZ) is constructed on the zinc anode surface (FAZ@Zn) utilizing a simple self‐assembly strategy. The zincophilic FAZ interfacial layer with a high Zn2+ transfer number and low nucleation barrier effectively facilitates the de‐solvation process, supports the rapid transport of zinc ions, and contributes to the preferential growth of Zn (002) crystal planes, enabling dendrite‐free Zn deposition. Furthermore, the FAZ layer, as an interfacial pH regulating layer, effectively inhibits the direct contact between Zn and active water molecules, lowering the severity of side reactions. Consequently, the FAZ@Zn anode furnishes an eminent cycle stability over 6900 h, with a low polarization voltage at 1 mA cm−2 and 1 mA h cm−2 and a boosted CE of 99.88% over 4100 cycles. More encouragingly, when coupled with Na2V6O16·3H2O, the FAZ@Zn anode enables the full cell to deliver satisfactory rate performance and a 97% capacity retention over 1600 cycles. This work provides a simple strategy for the effective preparation of highly reversible zinc anodes for high‐performance aqueous zinc‐ion batteries. [ABSTRACT FROM AUTHOR]

The salts bis(2‐amino‐3‐methylpyridinium) fumarate dihydrate, 2C6H9N2+·C4H2O22−·2H2O (I), and 2‐amino‐3‐methylpyridinium 5‐chlorosalicylate, C6H9N2+·C7H4ClO3− (II), were synthesized from 2‐amino‐3‐methylpyridine with fumaric acid and 5‐chlorosalicylic acid, respectively. The crystal structures of these salts were characterized by single‐crystal X‐ray diffraction, revealing protonation in I and II by the transfer of a H atom from the acid to the pyridine base. In the crystals of both I and II, N—H...O interactions form an R22(8) ring motif. Hirshfeld surface analysis distinguishes the interactions present in the crystal structures of I and II, and the two‐dimensional (2D) fingerprint plot analysis shows the percentage contribution of each type of interaction in the crystal packing. The volumes of the crystal voids of I (39.65 Å3) and II (118.10 Å3) have been calculated and reveal that the crystal of I is more mechanically stable than II. Frontier molecular orbital (FMO) analysis predicts that the band gap energy of II (2.6577 eV) is lower compared to I (4.0035 eV). The Quantum Theory of Atoms In Molecules (QTAIM) analysis shows that the pyridinium–carboxylate N—H...O interaction present in I is stronger than the other interactions, whereas in II, the hydroxy–carboxylate O—H...O interaction is stronger than the pyridinium–carboxylate N—H...O interaction; the bond dissociation energies also confirm these results. The positive Laplacian [∇2ρ(r) > 0] of these interactions shows that the interactions are of the closed shell type. An in‐silico ADME (Absorption, Distribution, Metabolism and Excretion) study predicts that both salts will exhibit good pharmacokinetic properties and druglikeness. [ABSTRACT FROM AUTHOR]

Allium species are consumed extensively as folkloric medicine and dietary elements, but limited studies have been conducted on them. In this study, the effects of an ethanol–water extract obtained from the underground bulb of Allium tuncelianum (Kollmann) Özhatay, B. Mathew & Şiraneci (AT) on the behavioral, antioxidant, and metabolite parameters in rats were evaluated. AT was administered orally once a day at doses of 100 and 400 mg/kg to male Wistar albino rats for 10 consecutive days. The elevated plus maze, rotarod, and hotplate tests were used to examine anxiety‐like behaviors, locomotor activities, and pain perception in the rats, respectively. Additionally, untargeted metabolomic analyses were performed on plasma samples and AT extracts using two orthogonal analytical platforms. The phenolic components, mainly fumaric acid, malic acid, vanillic acid, quercetin‐3‐arabinoside, hydrocinnamic acid, and gallocatechin, were determined in the extract. In addition, arbutin, salicylic acid, trehalose, and nicotinic acid were analyzed in the extract for the first time. The AT extract did not decrease the catalase, glutathione peroxidase, or superoxide dismutase levels; however, diazepam decreased some of those parameters significantly in the brain, liver, and kidney. Although both the AT and diazepam treatments resulted in an increase in anxiolytic‐like effects compared to the control group, no significant differences were observed (p >.05). In the metabolomic analysis, significant changes were observed in the rats treated with AT and diazepam, and they caused significant changes in some metabolic pathways, including amino acid and fatty acid metabolism, compared to the control. [ABSTRACT FROM AUTHOR]

Fruits are widely used to obtain and study bioactive compounds. Among them, the tarumã (Vitex megapotamica) is still understudied. The extraction of bioactive compounds from the powdered pulp of the ripe fruit of the tarumã was studied from the selection of several variables of the extraction process through the experimental design Plackett–Burman: the pH, the solid:liquid ratio, agitation, and temperature in an extraction time of 3 h. The extracts obtained were evaluated for antioxidant activity by 2,2′‐azino‐bis‐(3‐ethylbenzothiazoline‐6‐sulfonic acid) (ABTS), 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH), and for total phenolic compounds, as well as the presence of flavonoids, anthocyanins, carotenoids, and identification of bioactive compounds was assessed by high‐performance liquid chromatography (HPLC). Using the experimental design, the best extraction condition was defined with a pH of 5, solid:liquid ratio of 1:30, stirring at 100 rpm, with a temperature of 80°C, obtaining 104.21 mg Gallic Acid Equivalent (GAE) 100 g−1 for phenolic compounds total, 742.71 μmol Trolox g−1 for ABTS, and EC50 of 2884.98 mg L−1 for DPPH. From HPLC, the presence of fumaric acid, gallic acid, p‐coumaric acid, and caffeic acid in the extracts was detected. Regarding flavonoids, anthocyanins, and carotenoids, the values obtained were 6.38 mg ECG g−1, 1.67 mg ECG g−1, and 2.89 mg 100 g−1, respectively. The selection of extraction conditions allowed obtaining better levels of bioactive compounds in the powdered pulp of tarumã extract, even with the use of water as a solvent, to avoid the presence of chemical residues in the extract, with antioxidant potential and viability for application in food products. Practical applications: Recent research suggests a change in perspective regarding the consumption of healthier foods from plants and fruits that have important health properties. In this regard, tarumã (Vitex megapotamica) fruit has been standing out as a potential source of bioactive compounds with significant medicinal properties. The extracts obtained have a significant amount of phenolic compounds, as well as the presence of flavonoids, anthocyanins, and carotenoids, in which all of these have great potential bioactive activities. Thus, a good methodology of extraction and characterization of tarumã extract becomes a crucial part of any food, chemical, or pharmaceutical industry sector. In this regard, the present study with experimental design Plackett–Burman extraction is the way ahead due to high bioactive retention and the cost implications of the process. [ABSTRACT FROM AUTHOR]

BACKGROUND: Crataegus orientalis Pall. ex M. Bieb fruit (COPMB) is extensively used as a source of various products in the medicinal‐aromatic field and holds the potential for erosion control, ornamental purposes, food source, and economic benefits for forest villagers from its fruits. This study aims to determine the chemical components and biological activities of extracts prepared from COPMB using different solvents. RESULTS: The present work was designed to define the antioxidant activity [phosphomolybdenum (total antioxidant capacity), 2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulfonic acid) (ABTS), ferric reducing antioxidant power (FRAP), cupric ion‐reducing antioxidant capacity (CUPRAC) and metal chelating activity (MCA)], phytochemical screening analysis, enzyme inhibitor (α‐amylase, α‐glucosidase and tyrosinase) potential, and liquid chromatography‐high resolution mass spectrometry (LC‐HRMS) secondary metabolite profiling in different extracts of COPMB. The results of LC‐HRMS revealed that fumaric acid was the main phenolic compound in all extracts. Among the extracts, ethyl acetate extract has the highest phytochemical and antioxidant properties [total phenolic content (TPC): 32.5 mg GAE/g, total flavonoid content (TFC): 12.2 mg QE/g, ABTS: 213.0 mg TE/g; CUPRAC: 126.0 mg TE/g, MCA: 145.0 mg EDTA/g; FRAP: 122.8 mg TE/g; TAC: 2.8 mmol TE/g]. Ethyl acetate and methanol extracts are more effective in α‐amylase (0.27 ± 0.01 mg/mL; 0.12 ± 0.00 mg/mL), α‐glucosidase (0.63 ± 0.02 mg/mL; 0.77 ± 0.02 mg/mL) and tyrosinase (0.03 ± 0.00 mg/mL; 0.03 ± 0.00 mg/mL) enzyme inhibition potentials compared to standard acarbose (0.75 ± 0.02 mg/mL for α‐amylase; 1.11 ± 0.03 mg/mL for α‐glucosidase) and kojic acid (0.04 ± 0.00 mg/mL). CONCLUSION: The findings from this study suggest that COPMB could serve as a valuable source of natural agents for the food and pharmaceutical industry. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Polyvinyl alcohol (PVA) is a widely used polymer that is biocompatible, nontoxic, and water‐soluble due to the presence of hydroxyl groups in its domain. This study aims to investigate the effects of fumaric acid (FA) cross‐linking and thermal cross‐linking (TC) on the PVA's mechanical and thermal properties. When the FA is mixed with PVA, it was found in the chemical reaction that the OH groups of PVA are condensing with the carboxylic acid units of FA to yield new ester linkages and water as a by‐product, which further results in the reduction of the water absorption capacity. Quantitatively, the addition of 8 (wt. /wt. %) FA resulted in a minimum of 65% water absorption rate, as compared with 117% for pure PVA. The mechanical and thermal properties of PVA also enhanced with the addition of 2% to 8% FA by weight. For the TC case, the % increase in ultimate tensile strength was 30.9% and 42.5% with and without TC, respectively. As the wt. % of FA increased from 2 to 10%, the % elongation value decreased for both with and without TC films relative to pure PVA. The thermogravimetric analysis revealed the change in degradation temperature of FA‐PVA blended film in comparison with pure PVA. Dynamic mechanical analysis was utilized to analyze the viscoelastic nature and temperature variation at the glass transition temperature. The current fabricated film is a potential candidate for the food packaging films application; moreover, the results reported in this investigation will accelerate the industrial applications of biodegradable PVA. Highlights: Increasing the weight percentage of fumaric acid leads to an enhancement in mechanical and thermal properties of the film.Esterification is the usual reaction between fumaric acid and polyvinyl alcohol (PVA), in which ester linkages are formed when the carboxyl groups (‐COOH) of fumaric acid and the hydroxyl groups (‐OH) of PVA combine.Water absorption characteristics of the film reduces as the wt. % of fumaric acid increases.Thermal cross‐linking of the film leads to further improvements in mechanical and thermal properties.The overall effect of increasing the wt. % of fumaric acid is negative on the glass transition temperature of the film.The developed film is a potential candidate for the food packaging films application. [ABSTRACT FROM AUTHOR]

Four new coordination polymers, including 1D, 2D and 3D structures, were synthesized via a hydrothermal method using Cd2+/Zn2+/Cu2+ metal salts as nodes. These polymers were formed through self‐assembly of four different dicarboxylic acid ligands, namely adamantane‐1,3‐dicarboxylic acid (H2adc), glutaric acid (H2glu), 5‐hydroxyisophthalic acid (H2hip) and fumaric acid (H2fum), in conjunction with the auxiliary ligand [1,4‐bis(pyridin‐4‐ylmethyl)piperazine (bpmp). The corresponding formulae are [Cd3(adc)2(bpmp)Cl2(H2O)2]n (1), {[Cd2(glu)2(bpmp)2(H2O)2]·8H2O·2CH3OH}n (2), [Zn(hip)(bpmp)(H2O)]n (3) and [Cu(fum)(bpmp)(H2O)2]n (4). Single‐crystal X‐ray diffraction studies revealed that the Cd2+ centers in complex 1 all adopt a six‐coordinate mode but two distinct {CdO2N2Cl2} and {CuO5Cl} units. The 3D network of complex 1 can be simplified to a binodal (4.6)‐connected underlying net with the point symbol (3·42·5·62)4(32·62·72·88·10). Each Cd2+ cation in complex 2 adopts a seven‐coordinate {CdO5N2} center, forming an asymmetric pentagonal bipyramidal coordination. Its stacking structure is formed by the interaction of hydrogen bonds between 2D supramolecular layers, with the adjacent layers exhibiting mirror symmetry. Each Zn2+ ion in complex 3 displays a {ZnO3N} four‐coordinate unit. Its stacking structure is formed by one‐dimensional [Zn(hip)(bpmp)(H2O)]n chains connected through hydrogen bonds. On the other hand, complex 4 features a Jahn–Teller distorted {CuO4N2} octahedral coordination. Subsequently, the thermal stability of these complexes was investigated. The solid‐state fluorescence spectroscopy was employed to analyze complexes 1, 2 and 3. Additionally, a Hirshfeld surface analysis was performed on complex 3. [ABSTRACT FROM AUTHOR]

In this article, aliphatic diols (1,3‐propylene glycol and 1,4‐butanediol), aliphatic dibasic acids (succinic acid, sebacic acid, and fumaric acid), and graphene oxide (GO), were used as raw materials to prepare the advanced biodegradable thermoplastic elastomer (BTPE)/reduced GO (rGO) nanocomposites through reactions of in situ melting condensation, chemical reduction, and chain extension. The rGO is well dispersed in BTPE matrix by means of its predispersion in aliphatic diols before the polycondensation of the polyester prepolymers. Tensile strength of the BTPE/rGO nanocomposite with GO dosage of 0.6 wt% increase from 8.2 MPa of BTPE to 15.6 MPa, and its elongation at break also increases simultaneously. Meanwhile, biodegradability and electrical conductivity of the BTPE/rGO nanocomposites with GO dosage of 1.0 wt% increase greatly compared with those of BTPE. The advanced BTPE/rGO nanocomposites have great potential values in the fields of biodegradable medical materials, antistatic and conductive materials, among other applications. [ABSTRACT FROM AUTHOR]

Because of spontaneous agglomeration effect and undesirable electronic state of Zr sites on the surface, zirconium (hydro)oxides generally exhibit suboptimal defluoridation capacity. Herein, a template confinement‐ligand anchoring strategy is developed by utilizing confined growth of zirconium hydroxide (ZH) inside chitosan hydrogel beads (CHB) and subsequent anchoring of fumaric acid (fm) on its surface Zr sites in a monodentate mononuclear coordination mode. This technique leads to uniform dispersion of ultrafine fmZH (≈3.4 nm) and tunable electron density at the Zr sites. Due to the electron‐withdrawing ability of fm, electron‐delocalized Zr sites increase the orbital energy level matching and vacate Zr 4d orbitals to promote hybridization with the F 2p orbitals. Ultimately, robust ZrF bond can be formed as a result of reduced the adsorption energy toward fluoride ions. The defluoridation capacity shows positive linear relationship with the electron extraction ability of ligands. The saturation adsorption capacity and dynamic treatment capacity of CHB@fmZH are 10.8 and 45.9 times higher than that of CHB@ZH, respectively, owing to high electron extraction (0.098 e−) of fm. This study offers a novel insight into the design and synthesis of high‐efficiency metal oxide adsorbents by steering its surface metal sites' electronic state through ligand effect. [ABSTRACT FROM AUTHOR]

Synthetic polymer materials have been surged to the forefront of research in the fields of tissue engineering, drug delivery, and biomonitoring in recent years. Biodegradable synthetic polymers are increasingly needed as transient substrates for tissue regeneration and medicine delivery. In contrast to commonly used polymers including polyesters, polylactones, polyanhydrides, poly(propylene fumarates), polyorthoesters, and polyurethanes, biodegradable polyphosphazenes (PPZs) hold great potential for the purposes indicated above. PPZ's versatility in the synthetic process has enabled the production of a variety of polymers with various physico‐chemical, and biological properties have been produced, making them appropriate for biomedical applications. Biocompatible PPZs are often used as scaffolds in the regeneration of skeleton, bones, and other tissues. PPZs have also received special attention as potential drug vehicles of high‐value biopharmaceuticals such as anticancer drugs. Additionally, by incorporating fluorophores into the PPZ backbone to produce photoluminescent biodegradable PPZs, the utility of polyphosphazenes is further expanded as they are used in tracking the regeneration of the target tissue as well as the fate of PPZ based scaffolds or drug delivery vehicles. This review provides a summary of the evolution of PPZ applications in the fields of tissue engineering, drug delivery, and bioimaging in recent 5 years. [ABSTRACT FROM AUTHOR]

An inorganic base promoted metal‐free formal alkenylation and amination of 2‐nitrobenzofurans is established with fumaric acid amide ester derivatives. The cascade strategy provides the 2‐alkenyl and 3‐amino substituted benzofurans via Michael addition/cyclization/nitrous acid elimination/N‐demethoxylation/C−N bond cleavage and isomerization sequence. The desired 2‐(3‐aminobenzofuran‐2‐yl)malonate derivatives are obtained in moderate‐to‐good yields with high stereoselectivity under mild reaction conditions (up to 71 % yield and >20 : 1 Z : E). The structure of the products is assigned from the single crystal x‐ray structural analysis. [ABSTRACT FROM AUTHOR]

Research on biobased thermoset resins has been overlooked when compared with the rapid progress on biobased thermoplastics. The objective of this work was to develop unsaturated polyester prepolymers based on building blocks derived from renewable raw materials, namely, biobased isosorbide, 1,3‐propanediol, and fumaric acid, with petroleum‐derived phthalic anhydride. The prepolymers developed herein behaved as low‐molecular weight macromolecules (oligoesters), with Mn varying between 1.2 and 1.5 kDa, but achieved a high bio‐content of up to 87.1 wt%. The prepolymers were incorporated into reactive diluents comprising a blend of 2‐hydroxyethyl methacrylate and styrene, formulated to be eco‐friendlier and less toxic than typical styrene‐only incorporation approach, thus resulting in resins with viscosities between 750 and 950 cP. These resins are suitable for use in various fiber‐reinforced polymer production techniques, such as manual lamination, vacuum infusion, and pultrusion, having the benefit of presenting over 50 wt% of bio‐content in some formulations. Moreover, the crosslinked polyester resins (thermosets) exhibit comparable mechanical and thermomechanical behavior to their petrochemical‐based counterparts, with modulus of elasticity and tensile strength of up to 3.9 GPa and 62.1 MPa, respectively, and glass transition temperatures of up to 106°C, making them greener alternatives for high‐performance structural applications. [ABSTRACT FROM AUTHOR]

The use of non‐steroidal anti‐inflammatory drugs (NSAIDs) for treatment of musculoskeletal injuries is commonplace in the general, athletic, and military populations. While NSAIDs have been studied in a variety of tissues, the effects of NSAIDs on skeletal muscle have not been fully defined. To address this, we investigated the degree to which the cyclooxygenase (COX)‐2‐selective NSAID celecoxib affects muscle cell proliferation, differentiation, anabolic signaling, and mitochondrial function in primary human skeletal myoblasts and myotubes. Primary muscle cells were treated with celecoxib or NS‐398 (a pharmacological inhibitor of COX‐2) as a control. Celecoxib administration significantly reduced myoblast proliferation, viability, fusion, and myotube area in a dose‐dependent manner, whereas NS‐398 had no effect on any of these outcomes. Celecoxib treatment was also associated with reduced phosphorylation of ribosomal protein S6 in myoblasts, and reduced phosphorylation of AKT, p70S6K, S6, and ERK in myotubes. In contrast, NS‐398 did not alter phosphorylation of these molecules in myoblasts or myotubes. In myoblasts, celecoxib significantly reduced mitochondrial membrane potential and respiration, as evidenced by the decreased citric acid cycle (CAC) intermediates cis‐aconitic acid, alpha‐keto‐glutarate acid, succinate acid, and malic acid. Similar results were observed in myotubes, although celecoxib also reduced pyruvic acid, citric acid, and fumaric acid. NS‐398 did not affect CAC intermediates in myoblasts or myotubes. Together, these data reveal that celecoxib inhibits proliferation, differentiation, intracellular signaling, and mitochondrial function in primary human myoblasts and myotubes independent of its function as a COX‐2 inhibitor. [ABSTRACT FROM AUTHOR]

Fumarate‐co‐PEG‐co‐sebacates with different fumaric/sebacic acid ratios are prepared by a simple thermal polycondensation reaction using p‐toluensulfonic acid as catalyst. These polymeric precursors are purified by washing with an appropriate organic solvent and the dried materials were photocured to yield elastic films under mild conditions. The properties of polymeric precursors and elastic materials are studied in detail and correlated with fumaric acid/sebacic acid ratios used in the thermal esterification reactions. It is shown that a higher amount of sebacic in the starting polymer leads to softer final film materials, with lower Tg and G' values, which also show higher degradation rates in vitro. Finally, the films are also evaluated as drug release carriers for in vitro release of Cephalexin and Progesterone. The results obtained in these studies indicate that the careful tailoring of the fumaric acid/sebacic acid ratio in the esterification reaction allows to finely tune the thermal, mechanical a degradation properties of the final cross‐linked elastic films. [ABSTRACT FROM AUTHOR]

The study aimed to determine the effect of fumaric and maleic acids on the ensiling process. The corn herbage was ensiled without additives (control silage) or with 0.25% fumaric acid (FA25), 0.50% fumaric acid (FA50), 0.25% maleic acid (MA25), 0.50% maleic acid (MA50), FA25 + MA25 (FA25MA25) and FA50 + MA50 (FA50MA50) (treatment silages) as wet basis. The starch contents of FA50 and MA50 silages were lower than the content of the control silage (p <.05). The lactic acid content of the FA50MA50 silage was lower than that of the control silage (p <.05). Percentages of linoleic acid of MA25 and MA50 silages were higher than that of the FA50 silage (p <.05). The in vitro methane production and metabolic energy (ME) value of FA50MA50 silage was lower than that of the control silage (p <.05). The in vitro organic matter digestion (OMD) values of FA25, MA25 and FA50MA50 silages were lower than that of control silage (p <.05). The molarities of acetic (AA), propionic (PA), butyric (BA), isovaleric (IVA), isobutyric (IBA) and total volatile fatty (TVFA) acids of the in vitro ruminal fermentation fluid for the FA50MA50 silage were lower than that of the control silage (p <.05). As a result, the addition of fumaric and maleic acids (0.25% alone and together, or 0.5% alone) in ensiling of corn herbage did not change the quality, acidity (except for propionic, butyric and isobutyric acids) and nutrient contents (except for non‐fiber carbohydrates and starch) and in vitro ruminal fermentation values (gas–methane production and organic acids). The combined use of 0.5% fumaric plus 0.5% maleic acid harmed silage quality and in vitro ruminal fermentation values. However, 0.5% maleic acid was partially more effective than those other organic acid additions in preserving linoleic and α‐linolenic acids in the silage material. [ABSTRACT FROM AUTHOR]

The valorization of alkenoic acids possibly deriving from biomass (fumaric and citraconic acids) was carried out through conversion in important building blocks, such as γ‐keto acids and succinic acid derivatives. The functionalization was carried out by addition onto the C=C double bond of radicals generated under photocatalyzed conditions from suitable hydrogen donors (mainly aldehydes) and by adopting a decatungstate salt as the photocatalyst. Syntheses were performed under batch (in a glass vessel) and flow (by using 3D‐printed reactors) conditions. The design of the latter reactors allowed for an improved yield and productivity. [ABSTRACT FROM AUTHOR]

As the national flower of Korea, the Hibiscus syriacus L. (Rose of Sharon) is symbolic in its abundance and is a prominent feature of Korean culture. H. syriacus has played an important role in Korea, not only as an ornamental plant but also as an essential ingredient in folk remedies through its various parts. This study aimed to characterize the nutritional and biochemical composition of each plant unit of H. syriacus "Wonhwa." The units are namely: the petals, leaves, roots, and sprouts from its seeds. According to the results each unit produced, the sprouts had the highest content of amino acids and fatty acids which adhere to the requirements of nutritionally excellent food ingredients. The petals produced high quantities of glucose, sucrose, and fumaric acid, with the highest antioxidant activity among the four units. The main bioactive compounds detected in H. syriacus extracts in the four units were o‐coumaric acid, p‐coumaric acid, schaftoside, isoschaftoside, apigenin‐6‐C‐glucoside‐7‐o‐glucoside, and kaempferol‐3‐O‐galactoside‐7‐O‐rhamnoside. Overall, the highest number of bioactive compounds, 2 phenolic acids and 22 flavonoids, were identified in the petals. These results suggest the possibility of excellent pharmacological activity in the petals. [ABSTRACT FROM AUTHOR]

Summary: Inventions into chitosan oligosaccharide (COS) derivatives over recent decades have hugely broadened their application in food safety. Herein, monomethyl fumaric acid (MFA) was grafted on the OH position of COS to synthesise new COS‐O‐MFA derivatives and evaluated their in vitro antibacterial properties. The degrees of substitution (DS) of the derivatives yielded almost 15% with the range of 0.093 to 0.260. The in vitro antibacterial properties of the new COS‐O‐MFA1‐3 derivatives against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) were significantly enhanced concerning COS. Based on the finding, the introduction of MFA and increasing DS have a great impact on the enhancement of antibacterial properties of the COS‐O‐MFA1‐3 derivatives. This work proves that COS‐O‐MFA1‐3 derivatives can be potential novel antibacterial agents and also open up a new avenue to improve their antibacterial attributes. [ABSTRACT FROM AUTHOR]

Mushrooms and truffles are attracting attention as a new generation of biotherapeutics. In the current study, isolation, phenolic and organic acid composition, and antioxidant, cytotoxic, anticholinesterase activities of truffle Reddellomyces parvulosporus were examined. Four known compounds (brassicasterol (1), ergosterol peroxide (2), fumaric acid (3) and mannitol (4)) were isolated with the combination of chromatographic techniques. Fumaric acid (54.74 ± 0.85 µg g−1) was found as the major compound by HPLC‐DAD. All isolated compounds were bioassayed for antioxidant, cytotoxic, anticholinesterase, anti‐tyrosinase, anti‐urease, anti‐α‐glucosidase and anti‐α‐amylase activities. Compound 1 indicated notable cytotoxic activity on MCF‐7 (IC50: 38.08 ± 0.75 µg mL−1) and compound 3 on H1299 (IC50: 62.37 ± 0.75 µg mL−1). Also, compounds 1 (84.55 ± 1.14%) and 2 (84.90 ± 0.10%) showed higher anti‐urease activity than thiourea (78.57 ± 0.22%), while compound 2 (66.31 ± 0.08%) displayed near‐standard anti‐BChE activity. Also, being the first to emphasise the potential of R. parvulosporus as a natural food additive, this study evidenced its medicinal importance by revealing bioactive compounds and properties. [ABSTRACT FROM AUTHOR]

Aim: We recently proposed miR‐142‐3p as a molecular player in inflammatory synaptopathy, a new pathogenic hallmark of multiple sclerosis (MS) and of its mouse model experimental autoimmune encephalomyelitis (EAE), that leads to neuronal loss independently of demyelination. MiR‐142‐3p seems to be unique among potential biomarker candidates in MS, since it is an inflammatory miRNA playing a dual role in the immune and central nervous systems. Here, we aimed to verify the impact of miR‐142‐3p circulating in the cerebrospinal fluid (CSF) of MS patients on clinical parameters, neuronal excitability and its potential interaction with disease modifying therapies (DMTs). Methods and Results: In a cohort of 151 MS patients, we found positive correlations between CSF miR‐142‐3p levels and clinical progression, IL‐1β signalling as well as synaptic excitability measured by transcranial magnetic stimulation. Furthermore, therapy response of patients with 'low miR‐142‐3p' to dimethyl fumarate (DMF), an established disease‐modifying treatment (DMT), was superior to that of patients with 'high miR‐142‐3p' levels. Accordingly, the EAE clinical course of heterozygous miR‐142 mice was ameliorated by peripheral DMF treatment with a greater impact relative to their wild type littermates. In addition, a central protective effect of this drug was observed following intracerebroventricular and ex vivo acute treatments of EAE wild type mice, showing a rescue of miR‐142‐3p‐dependent glutamatergic alterations. By means of electrophysiology, molecular and biochemical analysis, we suggest miR‐142‐3p as a molecular target of DMF. Conclusion: MiR‐142‐3p is a novel and potential negative prognostic CSF marker of MS and a promising tool for identifying personalised therapies. [ABSTRACT FROM AUTHOR]

A new resolution method of racemic amlodipine has been developed. The racemic compound is reacted in a suitable solvent with 0.25‐mol equivalent of (R,R)‐tartaric acid. After the decomposition of the diastereomeric salt, the remaining racemic fraction is precipitated with half‐equivalent of fumaric acid, and the pure amlodipine enantiomer is obtained. A quarter equivalent of the same resolving agent, (R,R)‐tartaric acid has been also added to the mother liquor to obtain the other enantiomer. The advantage of this method is that both of the enantiomers of amlodipine could be obtained with high enantiomeric excess with the same resolving agent. The racemic excess can also be isolated and re‐resolved. Achiral reagents (urea and thiourea) have been added to the resolving agent. These neutral additives are incorporated as co‐crystals in the structure of the diastereomeric salts. The used solvate‐former solvents and achiral additives are structurally similar, and their presence can enable the fractional separation of the diastereomers. In addition, the racemate, the enantiomers, and some intermediate salts with high diastereomeric excess obtained in the resolution process of amlodipine have been also subjected to thermal (DSC, TG/DTA‐EGA‐MS, and ‐FTIR), analytical (FTIR spectroscopic), and structural (XRD) comparisons, which indicate that the key‐intermediate crystalline diastereomeric salts—as solvates and co‐crystals—inherit a kind of structural similarity from their related additives—solvents (DMF, DMAA, and DMSO) or (thio)ureas, respectively. [ABSTRACT FROM AUTHOR]

BACKGROUND: The objective of the study was to evaluate the physicochemical characteristics and shelf‐life of corn tortilla stored at room temperature (25 °C) using aw modifiers (propylene glycol and glycerol) and pH modifiers (fumaric acid and sodium benzoate) as preservatives combined with calcium hydroxide. Detection thresholds were used to determine the maximum preservative concentration and calcium hydroxide. Physicochemical characterization and sensory evaluation were used to determine the stability and sensory shelf‐life of tortillas. RESULTS: Control, calcium hydroxide, calcium hydroxide + fumaric acid, calcium hydroxide + glycerol, calcium hydroxide + propylene glycol, and calcium hydroxide + sodium benzoate treatments had rounded half‐lives of 1, 2, 1, 2, 2, and 2 days respectively. Glycerol combined with calcium hydroxide resulted in tortillas with lower pH variations over time. Mold presence was the critical attribute causing tortilla rejection. CONCLUSION: The use of aw modifiers had a better effect in preserving corn tortilla, as the concentration of pH modifiers at detection threshold levels was not able to reach an optimum performance when combined with calcium hydroxide. © 2021 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Aim: To create and validate a prediction model to identify patients with type 2 diabetes (T2D) at high risk of new-onset heart failure (HF), including those treated with a sodium-glucose cotransporter-2 (SGLT2) inhibitor., Methods: A prediction model was developed from the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE), a trial in T2D patients with albuminuria or cardiovascular disease. We included 5081 patients with baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) measurement and no history of HF. The model was developed using Cox regression and validated externally in the placebo arm of the Canagliflozin Cardiovascular Assessment Study (CANVAS), which included 996 participants with T2D and established cardiovascular disease or high cardiovascular risk, and in patients treated with canagliflozin., Results: ALTITUDE participants (mean age 64 ± 9.8 years) had a median serum NT-proBNP level of 157 (25th-75th percentile 70-359) pg/mL. Higher NT-proBNP level, troponin T (TnT) level and body mass index (BMI) emerged as significant and independent predictors of new-onset HF in both cohorts. The model further contained urinary albumin-to-creatinine ratio, glycated haemoglobin, age, haematocrit, and use of calcium channel blockers. A prediction model including these variables had a C-statistic of 0.828 (95% confidence interval [CI] 0.801-0.855) in ALTITUDE and 0.800 (95% CI 0.720-0.880) in CANVAS. The C-statistic of this model increased to 0.847 (95% CI 0.792-0.902) in patients after 1 year of canagliflozin treatment., Conclusion: In patients with T2D, higher NT-proBNP level, TnT level and BMI are independent and externally validated predictors of new-onset HF, including patients using an SGLT2 inhibitor. This newly developed model may identify patients at high risk of new-onset HF, contributing to early recognition and possibly prevention., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

The article discusses Japan's emergency approval system for drugs and vaccines during the COVID-19 pandemic. Previously, pharmaceutical companies in Japan could only import approved drugs from overseas, but a new emergency approval system was implemented in May 2022 to encourage domestic production. The first domestically produced oral COVID-19 medication, ensitrelvir fumaric acid (Xocoba), was granted emergency approval in November. However, there are concerns about the limited clinical data and the government's contract with the manufacturer before approval. The article questions whether Japan's regulatory policy prioritizes citizens' health or domestic company profits and suggests a need for evidence-based regulatory science. [Extracted from the article]

Background: In a phase 3 clinical study, patients from Germany with moderate to severe psoriasis who were naïve to systemic treatment and received risankizumab had greater and more rapid disease improvements compared with those who received fumaric acid esters (FAEs). Objective: To evaluate patient‐reported outcomes (PROs) in patients treated with risankizumab compared with FAEs. Methods: Adult patients were randomized 1:1 to receive either risankizumab 150 mg subcutaneous injections at weeks 0, 4 and 16 or FAEs (Fumaderm®) provided according to the prescribing label. PRO secondary endpoints assessed were Psoriasis Symptom Scale (PSS), Dermatology Life Quality Index (DLQI), 36‐Item Short Form Health Survey, version 2 (SF‐36v2), Patient Benefit Index (PBI), Hospital Anxiety and Depression Scale (HADS), Patient Global Assessment (PtGA) and European Quality of Life 5 Dimensions 5 Level (EQ‐5D‐5L). PROs were assessed at weeks 0, 16 and 24. Results: Sixty patients each were randomized to receive risankizumab or FAEs. A significant PSS improvement was observed with risankizumab vs. FAEs at weeks 16 and 24 for total and psoriasis‐associated redness, itching and burning scores (P < 0.001). DLQI scores were significantly lower (reflecting better health‐related quality of life) with risankizumab vs. FAEs, with least squares (LS) mean differences of −7.4 and −7.6 at weeks 16 and 24, respectively (both P < 0.001). Patients randomized to risankizumab also had larger improvements in SF‐36 Physical and Mental Component Summary scores, HADS anxiety and depression scores, PtGA, and EQ‐5D‐5L index and visual analogue scale scores (all P ≤ 0.002) at weeks 16 and 24 compared with FAEs. PBI was significantly higher, indicating greater benefit, with risankizumab vs. FAEs, with an LS mean difference of 1.1 and 1.3 at weeks 16 and 24, respectively (both P < 0.001). Conclusions: Risankizumab provides significant benefits over FAEs in improving PROs across several dimensions in patients with moderate to severe psoriasis. [ABSTRACT FROM AUTHOR]

The commercially available partially bio‐based poly(butylene succinate) (PBS) and poly(butylene succinate‐co‐adipate) (PBSA) are subjected to prolonged and multiple extrusion cycles to investigate their thermal behavior. Empirically, both PBS and PBSA form branches at 190°C, with PBS possessing a higher tendency for branching than PBSA as studied by rheology and size exclusion chromatography (SEC). In each case, the branching is favored by fumaric acid moieties, making both PBS and PBSA susceptible to accelerated thermal oxidation. Indeed, the NMR signal attributed to fumaric acid disappears upon thermal processing of PBS and PBSA. Presumably, the bio‐based succinic acid used contains minor quantities of fumaric acid, yet still sufficient to cause this surprising processing behavior. The branching of both polymers is suppressed by stabilizers such as phenolic antioxidants, as proven by rheology and SEC. This is complemented by nuclear magnetic resonance (NMR), revealing that the fumaric acid signal is still well‐resolved in the stabilized processed samples. [ABSTRACT FROM AUTHOR]

Perovskite solar cells (PSCs) have debuted as the photovoltaic devices with the most potential and progress is being made at an unprecedented pace. Meanwhile, additive engineering is continuously pushing the power conversion efficiency (PCE) and device stability to higher levels by passivating defects and regulating crystallization behaviors. Considering the scalable fabrication of PSCs in the following stage, seeking green additives for optimizing perovskites is extremely valuable and paramount. Herein, we pioneer a green additive engineering method using fumaric acid (FMAC) to optimize the three‐cation perovskites to obtain highly efficient PSCs. FMAC not only optimizes crystallization behaviors to endow the perovskite films with a large grain size and few grain boundaries, but also forms a strong interaction with Pb2+/I− of the perovskites, thereby stabilizing the [PbI6]4− octahedral framework of the perovskite crystal lattices and effectively passivating the surface defects. On this basis, FMAC improves the photoelectric properties of perovskites and in particular, suppresses the nonradiative recombination. Consequently, the PCE of PSCs incorporating FMAC rises to 20.48%, exceeding that (19.18%) of the pristine device. In addition, FMAC also enhances the stability of PSCs. Therefore, we provide a significant strategy using a green additive to enhance the photovoltaic performance of PSCs. [ABSTRACT FROM AUTHOR]

Background: Brodalumab is a fully human monoclonal immunoglobulin IgG2 antibody that binds to the human IL‐17 receptor subunit A and by that inhibits the biologic action of IL‐17A, IL‐17F, IL‐17C and IL‐17E. Therapy with fumaric acid esters (FAE) is a well established and widely used first‐line systemic treatment for subjects with moderate‐to‐severe plaque psoriasis. Objectives: To compare brodalumab to FAE in terms of clinical efficacy, patient‐reported outcomes and safety in subjects with moderate‐to‐severe plaque psoriasis who were naïve to systemic treatment. Methods: Eligible subjects were randomized 1 : 1 to 210 mg brodalumab injections or oral FAE according to product label in this 24‐week, open‐label, assessor‐blinded, multi‐centre, head‐to‐head phase 4 trial. The primary endpoints were having PASI75 and having sPGA score of 0 or 1 (sPGA 0/1). Subjects with missing values for the primary endpoints were considered non‐responders. Results: A total of 210 subjects were randomized. 91/105 subjects completed brodalumab treatment and 58/105 subjects completed FAE treatment. At Week 24, significantly more subjects in the brodalumab group compared to the FAE group had PASI75 (81.0% vs. 38.1%, P < 0.001) and sPGA 0/1 (64.8% vs. 20.0%, P < 0.001). In the brodalumab group, the median time to both PASI75 and to PASI90 was significantly shorter than in the FAE group (4.1 weeks vs. 16.4 weeks, and 7.4 weeks vs. 24.4 weeks, respectively, P < 0.0001 for both). The rate of adverse events was lower in subjects treated with brodalumab compared to subjects treated with FAE (616.4 vs. 1195.8 events per 100 exposure years). No new safety signals were detected for brodalumab. Conclusions: Brodalumab was associated with rapid and significant improvements in signs and symptoms of moderate‐to‐severe plaque psoriasis, with a superior efficacy profile to what was observed with FAE in systemic‐naïve subjects over 24 weeks. [ABSTRACT FROM AUTHOR]

Background: The effect of adalimumab and fumaric acid esters (FAE) on the cardiovascular risk associated with psoriasis has only been investigated scarcely in randomized controlled studies. Objective: The aim of this prospective, randomized controlled head‐to‐head trial was to compare the influence of adalimumab and FAE on cardiovascular disease markers in psoriasis patients. Methods: Sixty‐five patients with moderate to severe plaque psoriasis were randomly assigned to adalimumab or FAE treatment for 6 months. Cardiovascular haemodynamic parameters [flow‐mediated dilation (FMD), nitro‐glycerine mediated dilation (NMD) and carotid intima–media thickness (CIMT), blood pressure] were assessed at baseline (v0) and after 6 months (v6). Cutaneous disease severity, inflammatory and lipid cardiovascular risk markers were analysed at baseline(v0), after 3 (v3) and 6 months (v6). Results: After 6 months of treatment FMD in the adalimumab group increased significantly [v0 5.9% (6.4% SD), v6 8.0% (4.8% SD), P = 0.048) but not in the FAE group. (v0 7.0% (4.1% SD), v6 8.4% (6.1% SD), P = 0.753]. This was paralleled by a significant decrease of high sensitive C‐reactive protein (hsCRP) in the adalimumab group in comparison to the FAE group (v0: 0.39 mg/dL (0.38 SD), v6: 0.39 mg/dL (0.48 SD), P = 0.043). No significant changes were observed in any other haemodynamic parameters. FAE, however, additionally decreased total cholesterol (P = 0.046) and apolipoprotein B (P = 0.041) levels compared to adalimumab. Mean Psoriasis Area and Severity Index (psoriasis area severity score) reduction was greater but not significant (P = 0.116) under adalimumab treatment compared to FAE treatment [−71.1% (29.9 SD) vs. −54.6% (45.7%)]. Conclusion: In our study, both treatments were documented to exert effects on the cardiovascular system. While adalimumab showed anti‐inflammatory effects and improved FMD, FAE interacted favourably with the cholesterol metabolism. [ABSTRACT FROM AUTHOR]

Two new metal coordination complexes, namely, poly[aqua(μ6‐benzene‐1,2,4,5‐tetracarboxylic acid‐κ8O1:O1,O2:O2′:O4:O4,O5:O5′)(μ‐but‐2‐enedioato‐κ2O1:O4)potassium(I)], [K2(C4H2O4)(C10H6O8)(H2O)2]n or [K2(fum)(H4btec)(H2O)2]n, (1), and poly[aqua(μ8‐2,5‐dicarboxybenzene‐1,4‐dicarboxylato‐κ12O1:O1′,O2:O2,O2′:O2′:O4:O4′,O5:O5,O5′:O5′)(μ‐ethanedioato‐κ4O1,O2:O1′,O2′)strontium(II)], [Sr2(C2O4)(C10H4O8)(H2O)2]n or [Sr2(ox)(H2btec)(H2O)2]n, (2) (H4btec = benzene‐1,2,4,5‐tetracarboxylic acid, H2btec = 2,5‐dicarboxybenzene‐1,4‐dicarboxylate, fum = fumarate and ox = oxalate), have been obtained under hydrothermal conditions by reacting the different alkali and alkaline earth metal salts with H4btec, fumaric acid (H2fum) and oxalic acid (H2ox). Complexes (1) and (2) were structurally characterized by single‐crystal X‐ray diffraction, IR and UV–Vis spectroscopy, powder X‐ray diffraction (PXRD) and thermogravimetic analysis–differential scanning calorimetry (TGA–DSC). Complex (1) displays a two‐dimensional (2D) layer with the K+ ion in a distorted pentagonal bipyramidal geometry and exhibits a uninodal 6‐connected hxl/Shubnikov plane net (3,6) with {36.46.53} topology. Complex (2) displays a three‐dimensional (3D) network structure, in which the Sr2+ ion is in a distorted monocapped square antiprism geometry. The framework possess a binodal (5,8)‐connected net with the Schläfli symbol {32.410.58.64.74}{32.46.52}2. The 3D Hirshfeld surfaces and 2D fingerprint plots show that the main interactions are the O...H/H...O intermolecular interactions. Moreover, the thermal decompositions of (1) and (2) in the temperature range 303–1273 K revealed that they both decompose in three steps and transform to the corresponding metal oxide. [ABSTRACT FROM AUTHOR]

Poly(propylene fumarate) (PPF) was crosslinked with vinyl phosphonic acid (VPA) and vinyl phosphonic acid diethyl ester (VPES) to prepare biodegradable and biocompatible polymers with a network structure. Intended for this purpose, the PPF pre‐polymer was synthesized through a polycondensation reaction of propylene glycol and fumaric acid in an excess of propylene glycol. The PPF pre‐polymer was then thermally cured with various ratios of VPA and VPES in the presence of benzoyl peroxide initiator via radical polymerization. Complete cure of PPF/VPA and PPF/VPES copolymers was confirmed by differential scanning calorimetry, crosslink density was determined via swelling experiments, and thermomechanical properties and thermal degradation profiles were characterized by dynamic mechanical and thermogravimetric analyses, respectively. Various compositions of the PPF/VPA and PPF/VPES copolymers exhibited compressive modulus values in the wide range 10–836 MPa and compressive strength values in the range 14–119 MPa. The equilibrium water content of the PPF/VPA and PPF/VPES copolymers ranged from 4 to 20.5 wt%. Biodegradation rate of the polymers in buffer solution at 37 °C, examined via both weight loss and pH measurements, was significantly influenced by the co‐monomer and initiator compositions. Combining the results of these studies indicated that PPF/VPA and PPF/VPES copolymers show potential for applications as bone tissue engineering scaffolds. Moreover, just varying PPF and co‐monomer ratio and initiator amount provides adjustable and controllable characteristics of the end product. © 2020 Society of Industrial Chemistry [ABSTRACT FROM AUTHOR]

Fumaric acid was reacted with the binary superacidic systems HF/SbF5 and HF/AsF5. The O,O'‐diprotonated [C4H6O4]2+([MF6]–)2 (M = As, Sb) and the O‐monoprotonated [C4H5O4]+[MF6]– (M = As, Sb) species are formed depending on the stoichiometric ratio of the Lewis acid to fumaric acid. The colorless salts were characterized by low‐temperature vibrational spectroscopy. In case of the hexafluoridoantimonates single‐crystal X‐ray structure analyses were carried out. The [C4H6O4]2+([SbF6]–)2 crystallizes in the monoclinic space group C2/c with four formula units per unit cell and [C4H5O4]+[SbF6]– crystallizes in the triclinic space group P1 with one formula unit per unit cell. The protonation of fumaric acid does not cause a notable change of the C=C bond length. The experimental data are discussed together with quantum chemical calculations of the cations [C4H6O4· 4 HF]2+ and [C4H6O4· 2 H2CO · 2 HF]2+. [ABSTRACT FROM AUTHOR]

BACKGROUND: The preparation of maleic acid from the oxidation of renewable furfural has attracted significant attention, but research regarding the direct transformation of biomass‐derived sugar to maleic acid is rare. The research regarding the direct transformation of xylose to maleic acid would further promote its industrial applications. RESULTS: The direct synthesis of maleic acid from xylose was investigated based on a sustainable system of deep eutectic solvents (DESs). Four DESs were screened to evaluate their abilities for the dehydration of xylose. Hydrogen peroxide (H2O2) was then loaded to realize the oxidation of furfural without the separation of intermediates. A good maleic acid yield of 20.8%, along with 5.0% of fumaric acid, based on the xylose content were obtained under the initial xylose loading of 50 mM, a tin(IV) chloride (SnCl4)–xylose molar ratio of 4:1, in a monophase choline chloride (ChCl)–formic acid (Fa) (molar ratio of 1:6) system at 120 °C for 2 h. Then, 4 mL of H2O2 per mmol furfural was loaded for a further 10 min at 120 °C. CONCLUSION: This ChCl–Fa–SnCl4–H2O2 system possesses a higher oxidation selectivity to maleic acid with no furanone and succinic acid. Moreover, it was interesting that ChCl and SnCl4 could be recovered through natural recrystallization. © 2019 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Background: Psoriasis is a chronic inflammatory skin disease associated with quality of life (QoL) impairment. BRIDGE was a randomized, double‐blind, phase III study comparing the efficacy and safety of dimethylfumarate (DMF) with a fixed combination of fumaric acid esters (FAE) or placebo for the treatment of moderate‐to‐severe psoriasis. Objectives: This post hoc analysis investigated treatment effect on QoL overall and by patient subgroups categorized by disease severity. Week 8 efficacy responses were also investigated as possible predictors of Week 16 Dermatology Life Quality Index (DLQI) outcomes. Methods: Patients were randomized to receive a maximum daily dose of 720 mg of DMF, FAE (gradual up‐titration) or placebo for 16 weeks. Psoriasis Area Severity Index, Body Surface Area, Physician's Global Assessment and DLQI were assessed at baseline, Weeks 8 and 16. DLQI 0‐1 indicated 'no effect on patient life'. Associations between baseline severity, Week 16 DLQI and Week 8 efficacy (as observed cases) were also examined. Results: At baseline, 671 patients were included in the full analysis set (267 randomized to DMF, 273 to FAE and 131 to placebo). DMF was superior to placebo (P < 0.001) and not significantly different to FAE regarding Week 16 DLQI outcomes (P > 0.05). Baseline disease severity did not impact DLQI outcomes at Week 16. In DMF‐ and FAE‐treated patients, Week 8 PASI 50/75 responders reported better DLQI responses at Week 16 vs non‐responders (P < 0.05). Week 8 PASI ≤ 3 and/or PGA 0‐1 responders were also more likely to report DLQI 0‐1 at Week 16 vs non‐responders (P < 0.05). Conclusion: Dimethylfumarate significantly improved DLQI outcomes vs. placebo and was not affected by baseline disease severity. Efficacy responses (PASI 50/75, PASI ≤3 and PGA 0‐1) as early as Week 8 were predictive of QoL outcomes at Week 16 in DMF‐ and FAE‐treated patients. [ABSTRACT FROM AUTHOR]

Background: Several treatment options are currently available for the treatment of psoriasis. Objective: To explore the main associations between patients' characteristics and systemic treatments prescribed for psoriasis in a large group of patients observed in real‐life clinical practice. Methods: This was a retrospective analysis of baseline data collected within the Swiss Dermatology Network for Targeted Therapies registry in Switzerland between March 2011 and December 2017. Semantic map analysis was used in order to capture the best associations between variables taking into account other covariates in the system. Results: A total of 549 patients (mean age 46.7 ± 14.7 years) were included in the analysis. Conventional therapies such as retinoids and methotrexate were associated with no previous systemic therapies for psoriasis, a moderate quality of life (QoL) at therapy onset and older age (≥60 years). Fumaric acid derivatives were associated with mild psoriasis (psoriasis area severity index < 10) and long disease duration (≥20 years). On the other side, cyclosporine and psoralen and ultraviolet A/ultraviolet B treatments were linked to a more severe condition, including impaired QoL, hospitalization and inability to work. Regarding biological therapies, both infliximab and adalimumab were connected to the presence of psoriatic arthritis, severe disease condition and other comorbidities, including chronic liver or kidney diseases and tuberculosis. Etanercept, ustekinumab and secukinumab were all connected to a complex history of previous systemic treatments for psoriasis, moderate disease condition, overweight and university education. Conclusions: The analysis shows multifaceted associations between patients' characteristics, comorbidities, disease severity and systemic treatments prescribed for psoriasis. In particular, our semantic map indicates that comorbidities play a central role in decision‐making of systemic treatments usage for psoriasis. Future studies should further investigate specific connections emerging from our data. [ABSTRACT FROM AUTHOR]

Dimethylfumarate (DMF) has long been used as part of a fixed combination of fumaric acid esters (FAE) in some European countries and is now available as an oral monotherapy for psoriasis. The present investigation determined whether DMF and its main metabolite monomethylfumarate (MMF) interact with hepatic cytochrome P450 (CYP) enzymes and the P-glycoprotein (P-gp) transporter, and was performed as part of DMF's regulatory commitments. Although referred to in the available product labels/summary of product characteristics, the actual data have not yet been made publicly available. In vitro inhibition experiments using CYP-selective substrates with human liver microsomes showed 50% inhibitory concentrations (IC50) of >666 μmol/L for DMF and >750 μmol/L for MMF. MMF (≤250 μmol/L; 72 hours) was not cytotoxic in cultured human hepatocyte experiments and mRNA expression data indicated no CYP induction by MMF (1-250 μmol/L). DMF (≤6.66 mmol/L) showed moderate- to-high absorption (apparent permeability [Papp] ≥2.3-29.7 x 10-6 cm/s) across a Caucasian colon adenocarcinoma (Caco-2) cell monolayer, while MMF (≤7.38 mmol/L) demonstrated low-to-moderate permeability (Papp 1.2-8.9 x 10-6 cm/s). DMF was not a substrate for P-gp (net efflux ratios ≤1.22) but was a weak inhibitor of P-gp at supratherapeutic concentrations (estimated IC50 relative to solvent control of 1.5 mmol/L; [3H]digoxin efflux in Caco-2 cells). This inhibition is unlikely to be clinically relevant. MMF was not a substrate or inhibitor of P-gp. Thus, DMF and MMF should not affect the absorption, distribution, metabolism or excretion of coadministered drugs that are CYP and P-gp substrates. [ABSTRACT FROM AUTHOR]

Dietary vitamin A status affects energy metabolism. The present study explored the effect of all‐trans retinoic acid (ATRA) on the expression levels of molecules and metabolites of brown adipocytes. Chronic ATRA treatment was initiated during the early stage (days 0‐8) or late stage (days 8‐12) of adipogenesis. Treatment with ATRA during the early and late stage of adipogenesis resulted in an increase in the expression level of Ucp1 and Cidea, genes highly expressed in brown adipocytes, on day 8 and day 12, respectively, whereas expression of Pgc‐1α, another gene expressed during brown adipogenesis, was unaffected by ATRA. Non‐targeted metabolomic analyses indicated that the pathways related to the glucose metabolism were affected by ATRA, irrespective of the differentiation stage. Cellular levels of glucose 6‐phosphate, fructose 6‐phosphate, citric acid, and succinic acid decreased after ATRA treatment on days 8 and 12. In contrast, glucose level was higher in ATRA‐treated cells on day 8, but it was lower on day 12. ATRA decreased the cellular level of aconitic acid, fumaric acid, and malic acid on day 12 but not on day 8. Furthermore, ATRA increased the expression level of Hxk2 and downregulated the expressions of G6pdh and Pfkl/Pfkp on day 8 but not on day 12. Together, the results indicate that the chronic treatment with ATRA stimulated the formation of activated brown adipocytes, eventually leading to alterations in the levels of cellular metabolites related to glucose metabolism. Significance of the study: Significance of the study treatment with all‐trans retinoic acid (ATRA) during the early and late stage of adipogenesis increased the expression of Ucp1 and Cidea, genes highly expressed in brown adipocytes, on day 8 and day 12. Cellular levels of glucose 6‐phosphate, fructose 6‐phosphate, citric acid, and succinic acid decreased after ATRA treatment on days 8 and 12. In contrast, glucose level was higher in ATRA‐treated cells on day 8, but it was lower on day 12. The present results indicate that ATRA stimulated the formation of activated brown adipocytes, eventually leading to alterations in the levels of cellular metabolites related to glucose metabolism. [ABSTRACT FROM AUTHOR]

Background: Plaque psoriasis has significant impact on patients' quality of life. Topical therapy is considered the treatment mainstay for mild‐to‐moderate disease according to guidelines. Calcipotriol/betamethasone dipropionate (Cal/BD) [0.005%/0.05%] aerosol foam is indicated for psoriasis vulgaris treatment in adults. Cal/BD foam trials demonstrated improved efficacy and similar safety in this population. Psoriasis treatment is complicated by the broad range of disease presentation, variability and therapeutic options; particularly decisions on transition from topical to non‐biologic systemic treatment are difficult. Assessing comparative effectiveness of treatment options provides meaningful value to treatment decisions. Objective: To compare efficacy of Cal/BD foam individual patient data from pooled trials with efficacy of non‐biologic systemic treatments based on aggregated patient characteristics and treatment outcomes. Methods: Individual data from four Cal/BD foam trials in 749 psoriasis patients were pooled to conduct matching‐adjusted indirect comparisons. Literature review identified non‐biologic systemic treatment trials where methods, populations and outcomes align with Cal/BD foam trials. Of 3090 screened publications, four studies of apremilast, methotrexate, acitretin or fumaric acid esters (FAE) were included. Results: After baseline matching, patients treated with 4 weeks of Cal/BD foam had greater Physician's Global Assessment 0/1 response compared to those treated with 16 weeks of apremilast (52.7% vs. 30.4%; P < 0.001). Patients treated with Cal/BD foam had significantly greater Psoriasis Area and Severity Index (PASI) 75 response at Week 4 compared to 16 weeks of apremilast treatment (51.1% vs. 21.6%; P < 0.001). Cal/BD foam patients demonstrated significantly greater PASI 75 response improvements at Week 4 vs. 12 weeks of methotrexate (50.8% vs. 33.5%; P < 0.001) or acitretin (50.9% vs. 31.7%; P = 0.009), and comparable response to FAE (42.4% vs. 47.0%; P = 0.451). Conclusions: Despite recent treatment advances, unmet needs for psoriasis patients remain. Cal/BD foam offers improved efficacy in baseline matched psoriasis patients compared to apremilast, methotrexate or acitretin, and comparable efficacy to FAE. [ABSTRACT FROM AUTHOR]

Background: Fumaric acid esters (FAEs) are used to treat psoriasis and are known to cause lymphopenia in roughly 60% of the patients. Much remains to be elucidated about the biological effects of FAEs on lymphocytes. Objective: To evaluate the influence of long‐term FAE (Fumaderm®) treatment on peripheral blood CD4+ and CD8+ T cells, CD19+ B cells and CD56+ natural killer (NK) cells in psoriasis. Methods: In this single‐centre retrospective observational subcohort study, we obtained leucocyte and lymphocyte subset counts before initiating FAE therapy in 371 psoriasis patients (mean age, 47.8 years; 63.3% males) and monitored them during treatment (mean treatment duration, 2.9 years). Multiparametric flow cytometry was used for immunophenotyping. Results: FAEs significantly reduced the numbers of CD4+ T, CD8+ T, CD19+ B and CD56+NK cells. Among lymphocyte subsets, the mean percentage reduction from baseline was always highest for CD8+ T cells, with a peak of 55.7% after 2 years of therapy. The risk of T‐cell lymphopenia increased significantly with the age of the psoriasis patients at the time that FAE therapy was initiated. It was significantly decreased for the combination therapy with methotrexate and folic acid (vitamin B9) supplementation. Supporting evidence was found suggesting that T‐cell lymphopenia enhances the effectiveness of FAE therapy. Conclusions: Monitoring distinct T‐cell subsets rather than just absolute lymphocyte counts may provide more meaningful insights into both the FAE treatment safety and efficacy. We therefore suggest optimizing pharmacovigilance by additionally monitoring CD4+ and CD8+ T‐cell counts at regular intervals, especially in patients of middle to older age. Thus, further prospective studies are needed to establish evidence‐based recommendations to guide dermatologists in the management of psoriasis patients who are taking FAEs and who develop low absolute T‐cell counts. [ABSTRACT FROM AUTHOR]

The synthesis of unprecedented benzimidazole‐fused thiazocines, thiazonines, and thiazecines having an exocyclic double bond is reported. The process proceeds through an 8‐, 9‐, or 10‐exo‐dig cyclocarbopalladation followed by reduction. The scope and limitations were established and showed the importance of the precursor structure for the success of the reaction. A competition between the exo‐dig and the endo‐dig cyclization was observed for two substrates bearing an N‐homopropargyl chain, the endo‐cyclization leading to rarely encountered 10‐ and 11‐membered N,S‐heterocycles with a trans‐endocyclic double bond. X‐ray structures of three products were obtained by co‐crystallization with fumaric acid and show the twisted structures of these molecules. Benzimidazole‐fused medium‐sized N,S‐heterocycles (8 to 10 ring atoms) having an exocyclic double bond were synthesized by using exo‐dig Pd‐catalyzed reductive cyclizations. In the case of two substrates bearing an N‐homopropargyl chain, a competing endo‐dig cyclocarbopalladation occurred, leading to rarely encountered 10‐ and 11‐membered N,S‐heterocycles with an endocyclic double bond. [ABSTRACT FROM AUTHOR]

In this paper, fumaric acid (FA) which was a new type of environmental and low‐cost flame retardant was applied for thermoplastic polyurethane elastomer (TPU). The flame‐retardant properties of TPU were tested using limiting oxygen index, cone calorimeter test, smoke density test, and thermogravimetric/Fourier transform infrared spectroscopy. It has been proved that FA could improve the difficulty of the ignition of the sample; the limiting oxygen index value of the sample (FA‐4) increased by 29.7% when 2.0 wt% FA was added to TPU. The cone calorimeter test showed that FA can greatly reduce heat release and smoke production during the combustion process of TPU composites. For example, compared with the pure TPU, the peak heat release rate and total smoke release of the sample (FA‐4) with 2.0 wt% FA were decreased by 50.8% and 51.5% respectively. The results of smoke density test showed that the luminous flux of the samples contained 0.5 wt% FA was increased by 79.2% compared with the pure TPU. The TG results revealed that the sample of FA‐4 had higher char residue content compared with the sample of TPU. The results of thermogravimetric/Fourier transform infrared spectroscopy proved that FA could decrease the initial decomposition temperature for TPU composites and increase the release of CO2 and H2O. All results of test illustrated that FA had good flame‐retardant effect on TPU. [ABSTRACT FROM AUTHOR]

The metabolic consequences of mitophagy alterations due to age-related stress in healthy aging brains versus neurodegeneration remain unknown. Here, we demonstrate that ceramide synthase 1 (CerS1) is transported to the outer mitochondrial membrane by the p17/PERMIT transporter that recognizes mislocalized mitochondrial ribosomes (mitoribosomes) via 39-FLRN-42 residues, inducing ceramide-mediated mitophagy. P17/PERMIT-CerS1-mediated mitophagy attenuated the argininosuccinate/fumarate/malate axis and induced d-glucose and fructose accumulation in neurons in culture and brain tissues (primarily in the cerebellum) of wild-type mice in vivo. These metabolic changes in response to sodium-selenite were nullified in the cerebellum of CerS1to/to (catalytically inactive for C18-ceramide production CerS1 mutant), PARKIN-/- or p17/PERMIT-/- mice that have dysfunctional mitophagy. Whereas sodium selenite induced mitophagy in the cerebellum and improved motor-neuron deficits in aged wild-type mice, exogenous fumarate or malate prevented mitophagy. Attenuating ceramide-mediated mitophagy enhanced damaged mitochondria accumulation and age-dependent sensorimotor abnormalities in p17/PERMIT-/- mice. Reinstituting mitophagy using a ceramide analog drug with selenium conjugate, LCL768, restored mitophagy and reduced malate/fumarate metabolism, improving sensorimotor deficits in old p17/PERMIT-/- mice. Thus, these data describe the metabolic consequences of alterations to p17/PERMIT/ceramide-mediated mitophagy associated with the loss of mitochondrial quality control in neurons and provide therapeutic options to overcome age-dependent sensorimotor deficits and related disorders like amyotrophic lateral sclerosis (ALS)., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

The aim of this study was to develop an environmentally safe and efficient method for β‐alanine production using a dual‐enzyme cascade route with L‐aspartase (AspA) from E. coli and L‐aspartate‐α‐decarboxylase (PanD) from Corynebacterium glutamicum. Poor cooperativity in this system due to the divergent catalysis efficiencies of AspA and PanD led to an imbalance between the two reactions. To address this issue, we employed ribosome binding site regulation and gene duplication to coordinate the expression levels of AspA and PanD. Finally, we achieved β‐alanine production of 80.4±1.6 g L−1 with a conversion rate of 95.3±1.6 % in a 5‐L bioreactor. The dual‐enzyme cascade reported herein represents a promising strategy to meet industrial requirements for large‐scale β‐alanine production in the future. Unblocking bottlenecks! A dual‐enzyme cascade reaction for the generation of β‐alanine from fumaric acid, employing the enzymes AspA and PanD, is developed. Limited by poor cooperativity between the two enzymes, imbalance of the pathways became a bottleneck when producing β‐alanine in whole‐cell system. It was eliminated by RBS regulation of the aspA gene and duplication of the panD gene, well fine‐tuned the activity ratio of AspA to PanD. [ABSTRACT FROM AUTHOR]

Abstract: Fumaric acid esters (FAEs) are a group of small molecules that were first investigated for the treatment of psoriasis in 1959. The first fumarate‐based drug – Fumaderm® – was approved in Germany in 1994 for severe psoriasis and then in 2008, the label was expanded to include moderate psoriasis. Fumaderm is a combination of different FAEs: dimethyl fumarate (DMF), which is regarded as the main active component, plus calcium, magnesium and zinc salts of monoethyl fumarate (MEF). FAEs are the most frequently used first‐line systemic psoriasis treatment in Germany, with an overall treatment experience comprising more than 220 000 patient‐years. FAEs have demonstrated good, sustained clinical efficacy with an acceptable safety profile for the long‐term treatment of patients with moderate‐to‐severe psoriasis. Indeed, the European S3‐Guideline on the systemic treatment of Psoriasis vulgaris recommends FAEs for induction and long‐term treatment. Until recently, FAEs were only licensed (for the psoriasis indication) in Germany, but were imported to many other European countries, such as The Netherlands, UK, Ireland, Austria and Italy, for the treatment of psoriasis. In 2017, the European Medicines Agency (EMA) approved Skilarence®, a new oral formulation of DMF, for the treatment of adult patients with moderate‐to‐severe chronic plaque psoriasis in need of systemic therapy. Skilarence only contains DMF and is the first FAE for the treatment of psoriasis that has been approved by the EMA. This approval has given rise to a new oral treatment option for patients with moderate‐to‐severe plaque psoriasis across Europe. Here, we report the results of an expert meeting which was convened to deliver clinician‐agreed consensus and real‐world guidance on the clinical use of DMF in moderate‐to‐severe chronic plaque psoriasis. Guidance on appropriate patient selection, DMF dosage considerations, monitoring and side‐effect management is offered based upon available evidence and collective real‐world clinical experience. [ABSTRACT FROM AUTHOR]

Background: Fumaric acid esters (FAEs) are an established systemic treatment for moderate‐to‐severe psoriasis. However, the long‐term clinical safety and effectiveness of continuous FAE monotherapy and combination therapy have not been established. Objective: To examine the long‐term safety and effectiveness of FAEs as monotherapy and in combination with phototherapy or methotrexate in patients with psoriasis treated at a single centre in Germany. Methods: This monocentric, retrospective observational study, with a follow‐up period of up to 32.5 years, included 859 patients: 626 received FAE monotherapy, 123 received FAEs with concomitant phototherapy and 110 received FAEs with methotrexate. Results: Approximately half of patients (49.0%) reported adverse events (566 total events), most of which involved the gastrointestinal tract. Serious adverse events were reported in 2.3% of patients, but none were deemed to have a causal relationship with any of the treatment regimens. Adverse events leading to treatment discontinuation were observed in 12.9% of patients. A median duration of 1 year was observed in all three treatment subcohorts (P = 0.70) from initiation of FAE treatment to a 50% response rate, where response was defined as achieving a cumulative static Physician's Global Assessment (PGA) score of 'light' and at least a 2‐point reduction in baseline PGA. A 50% response rate for the cumulative Psoriasis Area and Severity Index 75 was achieved in the FAE monotherapy subcohort after a median of 3 years of treatment, in the FAEs + phototherapy subcohort after 6.7 years and in the FAEs + methotrexate subcohort after 8.1 years (P = 0.001). Conclusion: According to our data, FAEs as monotherapy or in combination with phototherapy or methotrexate are safe and beneficial for long‐term clinical use. However, multicentre, randomized controlled trials are required to establish the clinical value of monotherapy versus combination therapy and the optimal treatment duration. [ABSTRACT FROM AUTHOR]

Abstract: Timothy, red clover and white clover from two cuts and two stages of maturity and whole crops (WC) of barley, wheat and maize from three stages of maturity were analysed for individual plant organic acids (OAs) before and after ensiling in mini‐silos. Total OA levels, as previously reported, were generally lower in WC (14–70 g/kg dry matter) in comparison with leys (51–98 g/kg dry matter). Succinic, shikimic and fumaric acid levels were very low in all samples, while quinic, malonic, malic and citric acid constituted >90% of total OAs in all samples except maize. Maize had lower total OA levels than any other species but was the only one containing detectable levels of oxalic and aconitic acid. The sum of oxalic and aconitic acid decreased, however, from 89% to 35% of total OAs from early to late maturity, while there was a parallel increase in citric acid with increasing harvest date. Total OA level was unaffected in the ley crops by maturity, cut and species (p > .1), but among WC, wheat was higher than maize (p < .05) and also higher at early, than late maturity (p < .01). Silage total OA levels were lower than in parent crops (p < .001). Individual OA levels decreased by 38%–56% from ensiling, except for oxalic acid, which was unaffected, and succinic acid, which increased >7‐fold. Excluding succinic acid, which is also a fermentation product, average loss during ensiling was 44%. [ABSTRACT FROM AUTHOR]