Search

Post-COVID-19 syndrome is a complex of different symptoms, which results in a multisystemic impairment after the suffering from COVID-19 infection. The aim of the study was to reveal the clinical, laboratory, and gut disorders in patients with post-COVID-19 syndrome (n = 39) before and after taking part in the 14-day complex program of rehabilitation. A complete blood count, coagulation test, blood chemistry, biomarkers, and metabolites in serum samples, and gut dysbiosis were revealed in patients on the day of admission and after 14-day rehabilitation, in comparison with the variables of healthy volunteers (n = 48) or with reference ranges. On the day of discharge, patients noted an improvement in respiratory function, general well-being, and mood. At the same time, the levels of some metabolic (4-hydroxybenzoic, succinic, fumaric acids) and inflammatory (interleukin-6) variables, which were increased on admission, did not reach the level of healthy people during the rehabilitation program. Taxonomy disbalance was observed in patients’ feces, namely, a high level of total bacterial mass, a decrease in the number of Lactobacillus spp., and an increase in pro-inflammatory microorganisms. The authors suggest that the post-COVID-19 rehabilitation program should be personalized, considering the patient’s state together with not only the baseline levels of biomarkers, but also with the individual taxonomy of the gut microbiota.

Pharmaceutical salt formation is the most preferred and effective method to enhance the physicochemical properties of APIs. The aim of the study was to design and synthesize a series of new salts to improve the solubility of Imatinib (IM). Two stable salts with malonic acid (S1) and citric acid (S5), one metastable salt with fumaric acid (S2), two unstable salts with citric acid (S3, S4) were obtained for the first time. Single crystal and powder X-ray diffraction, Fourier transform infrared, differential scanning calorimetry, and thermogravimetric analysis were used to characterize the novel salts. The solubility and stability of the solid were also evaluated, and three salts (S1, S2, S5) had a more than 20 folds of solubility and a faster dissolution rate improved as compared to the pure drug in water and pH 6.8 buffer, respectively.

The present work investigates the effects of cis and trans butenedioic acid isomers (maleic acid and fumaric acid) on the crystallinity and pharmaceutical behavior of lumefantrine. Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), attenuated total reflectance infrared spectroscopy (ATR-IR), solid-state nuclear magnetic resonance spectroscopy (ss-NMR), and single-crystal X-ray diffraction (SC-XRD) studies were employed. Lumefantrine–fumaric acid crystallized as a salt in the monoclinic space group P21/c. In comparison, DSC and PXRD showed the formation of a co-amorphous solid with maleic acid. Complete proton transfer with a strong ionic interaction led to crystalline salt formation with the trans isomer, whereas weaker/fewer hydrogen bonds with the cis isomer of butenedioic acid led to a co-amorphous salt. The in vitro dissolution of both salts resulted in a similar 2.6–2.7-fold improvement in dissolution rate when compared to that of the crystalline lumefantrine. The crystalline and co-amorphous salts were stable under accelerated stability conditions (40 ± 2 °C and 75 ± 5% RH) for one month.

Metal–organic frameworks (MOFs) have attracted extensive attention for the development of colorimetric detection methods due to their ease of modification and high density of active sites. However, most of the reported colorimetric sensors based on MOFs show only a single nanozyme activity. Herein, the bifunctional enzyme activities of a hexagonal prism Cu MOF with fumaric acid as the ligand (Cu FMA), namely laccase-like activity under alkaline conditions (pH = 8) and peroxidase-like activity under acidic conditions (pH = 4), were verified. The specificity of Cu FMA at different pH values may be due to the presence of the Cu+ active center introduced by the weak reducibility of FMA. At pH = 8, Cu+ active centers are beneficial for dissociating the H–O bonds of phenolic compounds for the laccase system. In contrast, the dissociation of H–O is weakened at pH = 4, which prompts the breaking of the O–O bonds of H2O2 as a Fenton-like reaction for the peroxidase system. Based on the dual enzyme activities, Cu FMA sensors exhibit outstanding detectability for epinephrine and glucose with linear ranges of 2.7–54.6 μM and 0.01–0.8 mM and detection limits of 1.1 μM and 2.28 × 10−7 M, respectively. The Cu FMA colorimetric sensor can be applied for detecting and measuring glucose and epinephrine in human serum samples. This work paves the way for Cu MOFs to be used as the basis for rational regulation of the activity of dual nanozymes and for multifunctional applications under completely independent conditions.

Species in the fungal genus Rhizopus are able to convert simple sugars into primary metabolites such as fumaric acid, lactic acid, citric acid, and, to a lesser extent, malic acid in the presence of specific carbon and nitrogen sources. This ability has been linked to plant pathogenicity. Rhizopus stolonifer causes hull rot disease in almonds, symptoms of which have been previously associated with the fungus’s production of fumaric acid. Six isolates of R. stolonifer taken from infected almond hulls were grown in artificial media amended with one of four carbon sources (glucose, fructose, sucrose, and xylose) and two nitrogen sources (asparagine and ammonium sulphate) chosen based on almond hull composition and used in industry. Proton nuclear magnetic resonance (1H NMR)–based metabolomics identified that R. stolonifer could metabolise glucose, fructose, sucrose, and to a lesser extent xylose, and both nitrogen sources, to produce three metabolites, i.e., fumaric acid, lactic acid, and ethanol, under in vitro conditions. Sugar metabolisation and acid production were significantly influenced by sugar source and isolates, with five isolates depleting glucose most rapidly, followed by fructose, sucrose, and then xylose. The maximum amounts of metabolites were produced when glucose was the carbon source, with fumaric acid produced in higher amounts than lactic acid. Isolate 19A–0069, however, preferred sucrose as the carbon source, and Isolate 19A–0030 produced higher amounts of lactic acid than fumaric acid. This is the first report, to our knowledge, of R. stolonifer producing lactic acid in preference to fumaric acid. Additionally, R. stolonifer isolate 19–0030 was inoculated into Nonpareil almond fruit on trees grown under high– and low–nitrogen and water treatments, and hull compositions of infected and uninfected fruit were analysed using 1H NMR–based metabolomics. Glucose and asparagine content of uninfected hulls was influenced by the nitrogen and water treatments provided to the trees, being higher in the high–nitrogen and water treatments. In infected hulls, glucose and fructose were significantly reduced but not sucrose or xylose. Large amounts of both fumaric and lactic acid were produced, particularly under high–nitrogen treatments. Moreover, almond shoots placed in dilute solutions of fumaric acid or lactic acid developed leaf symptoms very similar to the ‘strike’ symptoms seen in hull rot disease in the field, suggesting both acids are involved in causing disease.

Active pharmaceutical ingredients (API) with unfavorable physicochemical properties and stability present a significant challenge during their processing into final dosage forms. Cocrystallization of such APIs with suitable coformers is an efficient approach to mitigate the solubility and stability concerns. A considerable number of cocrystal-based products are currently being marketed and show an upward trend. However, to improve the API properties by cocrystallization, coformer selection plays a paramount role. Selection of suitable coformers not only improves the drug’s physicochemical properties but also improves the therapeutic effectiveness and reduces side effects.Numerous coformers have been used till date to prepare pharmaceutically acceptable cocrystals. The carboxylic acid-based coformers, such as fumaric acid, oxalic acid, succinic acid, and citric acid, are the most commonly used coformers in the currently marketed cocrystal-based products. Carboxylic acid-based coformers are capable of forming the hydrogen bond and contain smaller carbon chainwith the APIs. This review summarizes the role of coformers in improving the physicochemical and pharmaceutical properties of APIs, and deeply explains the utility of afore-mentioned coformers in API cocrystal formation. The review concludes with a brief discussion on the patentability andregulatory issues related to pharmaceutical cocrystals.

Ecuador is the world’s fifth largest cocoa producer, generating hundreds of tons of residues from this fruit annually. This research generates value from the residual (cocoa pod husk) by using it as raw material to obtain pectin, which is widely used in the food and pharmaceutical industries. Extraction of three different organic acids with GRAS status (safe for use), the citric, malic and fumaric acids, was studied. In addition, two other factors, temperature (70–90 °C) and extraction time (60–90 min), were explored in a central composite design of experiments. We determined the conditions of the experiments where the best yields were garnered for citric acid, malic acid and fumaric acid, along with a ~86 min extraction time. The temperature did not show a significant influence on the yield. The pectin obtained under optimal conditions was characterised, showing the similarity with commercial pectin. However, the equivalent weight and esterification degree of the pectin obtained with fumaric acid led us to classify it as having a high equivalent weight and a low degree of esterification. In these regards, it differed significantly from the other two acids, perhaps due to the limited solubility of fumaric acid.

Fumaric acid is one of the most promising biorefinery platform chemicals, fruit residues being a very suitable raw material for its production in second generation biorefineries. In particular, apple pomace is a plentiful residue from the apple juice industry, with apple being the second largest fruit crop in the world, with a production that increased from 46 to 86 Mtons in the 1994–2021 period. With a global apple juice production of more than 4.5 Mtons, a similar amount of apple pomace is produced yearly. In this work, apple pomace hydrolysate has been obtained by enzymatic hydrolysis and further characterized for its content in sugars, phenolics and nitrogen using different analytic methods, based on HPLC and colorimetric techniques. Previous to the use of this hydrolysate (APH), we studied if the addition of fructose to the usual glucose-rich broth could lead to high fumaric acid yields, titers and productivities. Afterwards, APH fermentation was performed and improved using different nitrogen initial amounts, obtaining production yields (0.32 gFumaric acid/gconsumed sugar) similar to those obtained with synthetic media (0.38 gFumaric acid/gconsumed sugar). Kinetic modelling was employed to evaluate, explain, and understand the experimental values and trends of relevant components in the fermentation broth as functions of the bioprocess time, proposing a suitable reaction scheme and a non-structured, non-segregated kinetic model based on it.

BACKGROUND/AIM Carbon-ion radiotherapy has strong antitumor effects in X-ray-resistant tumors. However, the mechanisms underlying the strong antitumor effect, especially on metabolic alterations, are not fully elucidated. This study aimed to determine the effect of therapeutic carbon ions on metabolic alterations in cancer cells. MATERIALS AND METHODS Five human cancer cell lines were used in this study. The change in 333 metabolite levels in response to carbon ions was analyzed using gas chromatography-mass spectrometry. RESULTS Fifty-two metabolites were commonly detected in all cell lines. The levels of five metabolites significantly changed in four or more cell lines. Three of the five metabolites (i.e., 2-ketoglutaric acid, fumaric acid and 2-hydroxyglutaric acid) were associated with the TCA cycle. TCA cycle intermediates and the downstream oncometabolite 2-hydroxyglutaric acid were up-regulated by carbon ions. CONCLUSION We demonstrated for the first time that TCA cycle intermediates and 2-hydroxyglutaric acid are up-regulated after carbon-ion irradiation.

The human Dietary Approaches to Stop Hypertension-Sodium Trial has shown that β-aminoisobutyric acid (BAIBA) may prevent the development of salt-sensitive hypertension (SSHT). However, the specific antihypertensive mechanism remains unclear in the renal tissues of salt-sensitive (SS) rats. In this study, BAIBA (100 mg/kg/day) significantly attenuated SSHT via increased nitric oxide (NO) content in the renal medulla, and it induced a significant increase in NO synthesis substrates (L-arginine and malic acid) in the renal medulla. BAIBA enhanced the activity levels of total NO synthase (NOS), inducible NOS, and constitutive NOS. BAIBA resulted in increased fumarase activity and decreased fumaric acid content in the renal medulla. The high-salt diet (HSD) decreased fumarase expression in the renal cortex, and BAIBA increased fumarase expression in the renal medulla and renal cortex. Furthermore, in the renal medulla, BAIBA increased the levels of ATP, ADP, AMP, and ADP/ATP ratio, thus further activating AMPK phosphorylation. BAIBA prevented the decrease in renal medullary antioxidative defenses induced by the HSD. In conclusion, BAIBA's antihypertensive effect was underlined by the phosphorylation of AMPK, the prevention of fumarase's activity reduction caused by the HSD, and the enhancement of NO content, which in concert attenuated SSHT in SS rats.

Aegle marmelos (Bilva) is being used in Ayurveda for the treatment of several inflammatory disorders. The plant is a member of a fixed dose combination of Dashamoola in Ayurveda. However, the usage of roots/root bark or stems is associated with sustainability concerns. Bael (Aegle marmelos (L.) Corr.) is an important medicinal plant of India. Leaves, fruits, stem and roots of A. marmelos have been used in ethno medicine to exploit its' medicinal properties including astringent, antidiarrheal antidysenteric, demulcent, antipyretic and anti-inflammatory activities. Compounds purified from bael have been proven to be biologically active against several major diseases including cancer, diabetes and cardiovascular diseases. Preclinical studies indicate the therapeutic potential of crude extracts of A. marmelos in the treatment of many microbial diseases, diabetes and gastric ulcer. This review covers the biological activities of some isolated chemical constituents of A. marmelos and preclinical studies on some crude extracts and pure compounds to explore novel bioactive compounds for therapeutic application. Aegle marmelos (L.) is a seasonal fruit that contains significant amounts of bioactives like, phenolic acids (gallic acids, 2,3-dihydroxy benzoic acid, chlorogenic acid, p-coumaric acid, vanillic acid), flavonoid (rutin), organic acids (oxalic acid, tartaric acid, malic acid, lactic acid, acetic acid, citric acid, propionic acid, succinic acid, fumaric acid), vitamin C, vitamin B group (thiamine, niacin, pyridoxine, pantothenic acid, biotin, cobalamins, riboflavin), tocopherols (α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol), carotenes (α-carotene, β-carotene, γ-carotene, δ-carotene) and also rich in essential minerals (potassium, calcium, phosphorus, sodium, iron, copper, manganese). Hence the use of aegle plays important role as anti-inflammatory.

This study aims to determine ovarian cancer (OC) patients with platinum resistance for alternative treatment protocols by using metabolomic methodologies. Urine and serum samples of platinum-resistant and platinum-sensitive OC were analyzed using GC-MS. After data processing of GC-MS raw data, multivariate analyses were performed to interpret complex data for biologically meaningful information and to identify the biomarkers that cause differences between two groups. The biomarkers were verified after univariate, multivariate, and ROC analysis. Finally, metabolomic pathways related to group separations were specified. The results of biomarker analysis showed that 3,4-dihydroxyphenylacetic acid, 4-hydroxybutyric acid, L-threonine, D- mannose, and sorbitol metabolites were potential biomarkers in urine samples. In serum samples, L-arginine, linoleic acid, L-glutamine, and hypoxanthine were identified as important biomarkers. R2Y, Q2, AUC, sensitivity and specificity values of platinum-resistant and sensitive OC patients’ urine and serum samples were 0.85, 0.545, 0.844, 91.30%, 81.08 and 0.570, 0.206, 0.743, 77.78%, 74.28%, respectively. In metabolic pathway analysis of urine samples, tyrosine metabolism and fructose and mannose metabolism were found to be statistically significant (p

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.

Mushrooms contain a variety of secondary metabolites, including various phenolic compounds, which have been shown to act as excellent antioxidants. In this study, the contents of total phenolic, flavonoids and tannins of mushrooms methanolic extracts were evaluated by colorimetric assays to ranges of 277.36±0.66 to 420.86±0.90 mg (GAE)/100g DW; 31.99±0.90 to 90.90±0.07mg (QE)/100g DW and 150.61±0.16 to 220.47±1.01mg (TAE)/100g DW respectively. HPLC-profiles of methanolic extracts indicated that the individual phenolic compounds found to the samples of the species of mushrooms that are Lentinus squarrosulus and Auricularia politrich revealed us that gallic acid, catechin, acid ρ-hydroxybenzoїc, acid ellagique and naringerin were presented to the level of the two species. With respect to organic acids, the results showed that citric acid and fumaric acid was the major organic acid in all the samples of both mushrooms species. The methanolic extracts of the two mushrooms exhibited the high DPPH radical scavenging activities ranging from 34.10±1.12 to 58.95±0.52%. These data indicated that these mushrooms could constitute a potential good source of natural antioxidant for the local population.

Escherichia coli JM109 (pGV3-SBA) can assimilate starch by fusing the starch-digesting enzyme α-amylase from Streptococcus bovis NRIC1535 to an OprI′ lipoprotein anchor on the cell membrane. This study shows microbial fuel cells (MFCs) development using this recombinant type of E. coli and starch as fuel. We observed the current generation of MFCs with E. coli JM109 (pGV3-SBA) for 120 h. During this period, it consumed 7.1 g/L of starch. A mediator in the form of anthraquinone-2,6-disulfonic acid disodium salt at 0.2, 0.4, and 0.8 mM was added to the MFCs. The highest maximum-current density (271 mA/m2) and maximum-power density (29.3 mW/m2) performances occurred in the 0.4 mM mediator solution. Coulomb yields were calculated as 3.4%, 3.0%, and 3.5% in 1.0, 5.0, and 10.0 g/L of initial starch, respectively. The concentrations of acetic acid, succinic acid, fumaric acid, and ethanol as metabolites were determined. In particular, 38.3 mM of ethanol was produced from 7.1 g/L of starch. This study suggests the use of recombinant E. coli which can assimilate starch present in starch-fueled MFCs. Moreover, it proposes the possibility of gene recombination technology for using wide variety of biomass as fuel and improving MFC's performance.

The traditional two-step cultivation mode for fungal cultivation is commonly divided into the seed stage (usually 24 to 48 h) and the production stage (usually 96 to 144 h). The use of two stages prolongs the total production cycle and generates excess wastewater. In this work, an efficient and environmentally friendly one-step fermentation method was applied for the production of fumaric acid by immobilized Rhizopus arrhizus in a stirred-tank reactor. The nitrogen source content and the agitation speed of the reactor were optimized as the two critical factors in the one-step fermentation process; the fumaric acid production of 51 g/L with a yield of 0.42 g/g glucose was comparable with the product from the traditional two-step fermentation process. Furthermore, the total production cycle was shortened to 96 h, and the amount of wastewater was reduced due to the avoidance of the seed culture process. Thus, utilization of the one-step fermentation method to produce fumaric acid was shown to be preferable feasibility and environmental-friendliness. This is a promising method for industrial production of fumaric acid and other high-value biochemicals by fungus.

The filamentous fungi Rhizopus oryzae are well known for their ability to hydrolyze plant polysaccharides. Representatives of this species are widely used for the production of various products, such as organic acids (lactic acid, fumaric acid), ethanol, and hydrolytic enzymes (glucoamylases, polygalacturonases). Various carbon sources such as pentose and hexose sugars are used for the synthesis of R. oryzae exoproducts. Expensive plant sugarcontaining raw materials are used in the lactic acid production by the microbiological method, which significantly increases the final cost of the product. The article demonstrates the possibility of using cheaper by-products of pulp and paper production such as sulphite liquors as an alternative source of carbon for microbiological synthesis of lactic acid. Sulphite liquors contain a large amount of carbohydrates – products of incomplete hydrolysis of cellulose such as hemicelluloses, mono- and oligomeric sugars. The composition of sulfite liquors allows us to consider them as a potential substrate for the synthesis of lactic acid by using different microorganisms. The paper considers the dependence of the lactic acid yield on the composition of the nutrient medium based on sulfite liquor and the cultivation method of the fungus R. oryzae F-1030. As additional sources of nitrogen and phosphorus, (NH4)2SO4 and KH2PO4 were introduced to the nutrient medium. The fungus R. oryzae F-1030 was cultivated by two methods: the semicontinuous culture method, when the nutrient medium was completely replaced after depletion of the reducing sugars in it; the batch culture method, when the lack of reducing sugars in the medium was compensated by the addition of concentrated sulfite liquor. Since the nutrient medium based on sulfite liquor contains the products of incomplete cellulose hydrolysis and xylans, the xylanase and cellulase activities of the fungus R. oryzae F-1030 were measured in order to determine its absorption degree of carbohydrates, contained in the nutrient medium. It was found that it is more expedient to use the semicontinuous method for the fungus R. oryzae F-1030 cultivation on a nutrient medium based on sulfite liquor in order to obtain more synthesized lactic acid. The addition of mineral sources of nitrogen and phosphorus has practically no effect on the final yield of lactic acid.For citation: Mingazova L.A., Kryakunova E.V., Kanarskaya Z.A., Kanarsky A.V. Applying Sulfite Liquors as a Nutrient Medium for Cultivation of Lactic Acid Producer Rhizopus oryzae F-1030. Lesnoy Zhurnal [Russian Forestry Journal], 2021, no. 5, pp. 163–173. DOI: 10.37482/0536-1036-2021-5-163-173Acknowledgements: The work was carried out using the equipment of the Center for Collective Use “Ecology, Biotechnology and Processes for Producing Environmentally Friendly Energy Carriers” of the Volga State University of Technology.

A series of aliphatic poly(carbonate-co-ester)s (PBCFs) were successfully synthesized via melt polycondensation of 1,4-butanediol (BD) and dimethyl carbonate (DMC) in the presence of biobased fumaric acid (FA). The prepared unsaturated copolymers had weight-average molecular weights (Mw) in the 4.98 × 104 to 8.82 × 104 g·mol−1 range and from 1.56 to 1.83 polydispersities. They all had random microstructures. The physical properties of the novel poly(carbonate-co-ester)s, such as melting temperature (Tm) and melting enthalpy (∆Hm), varied widely depending on their composition. The stiff fumaric acid units in the poly(butylene carbonate) (PBC) chain caused an increase in the glass transition temperature (Tg) and thermal stability. Furthermore, PBCF10 to PBCF20 (with fumaric acid unit content of

Palladium(I) coordination polymers with unsaturated dicarboxylic acids, {[cis-Pd(C4H2O4)(H2O)]·(H2O)}n (I) (maleic acid), {[cis-Pd(C5H4O4)(H2O)]·2H2O}n (II) (citraconic acid), and {[trans-Pd(C4H2O4)(H2O)]·(H2O)}n (III) (fumaric acid) with stable paramagnetic centers in the polymer matrix were synthesized for the first time. According to IR and ESR spectroscopy data (determining the number of paramagnetic centers) and results of thermogravimetric analysis, the building blocks of I–III are, at least, tetranuclear Pd(I) clusters, in which palladium atoms are linked by bridging carboxylate groups. Each carboxylate group is coordinated via only one O atom, while the second O atom is linked to the nearest palladium atom of the neighboring cluster, thus giving a multidimensional coordination polymer. The coordination sphere of each Pd(I) atom in the cluster is completed by a water molecule and Pd–Pd bond. Heating of I–III results in the loss of solvation water molecules as the first stage. Above 100°C, the onset of removal of the coordinated water molecules is accompanied by complete decomposition of the complexes. On treatment of I with CH3CN in methanol, redox reaction takes place, in which complex I disproportionates to give Pd(II) complex and Pd(0) to give [Pd(HOOC–CH–CH(CH3O)(CH3CN)2] (IV) (CIF file CCDC no. 2039147).

In a narrowing beam-walking test, on the 21st day after the occlusion of the middle cerebral artery, it was found that the succinic salt of diethylaminoethanol fumaric ester (PDES), at doses of 10 and 75 mg/kg, led to a statistically signifi cant decrease in the severity of sensorimotor defi cit of the anterior and posterior contralateral limbs of male rats under the conditions of cerebral ischemia. The test substance at a dose of 10 mg/kg reduced the volume of ischemic damage to the cerebral cortex of rats by 1.5 times. In terms of neuroprotective activity, the effect of the succinic salt of diethylaminoethanol fumaric ester at a dose of 10 mg/kg is comparable to that of Citicoline at a dose of 500 mg/kg.

This work aims to develop a new enzymatic method for analysing fumaric acid in wines. Fumaric acid is a very effective lactic acid bacteria inhibitor that is widely used in the food industry as an additive (E297). Using it to inhibit malolactic fermentation has recently been authorized by the International Organisation of Vine and Wine (OIV). However, the official analytical method for fumaric acid involves the classical HPLC method for organic acids, which is overly complicated for use in wineries. This research proposes a very simple and efficient enzymatic method that allows the simultaneous determination of L-malic acid and fumaric acid. The method uses a commercial enzymatic kit for L-malic acid and adds a supplementary step in which the fumarase enzyme is added to transform fumaric acid into L-malic acid. The results obtained show that this method could be used in different media (synthetic solution, white wine, red wine and white grape juice). This article also proposes a modification of the enzymatic method to be applied when the L-malic acid concentration of the sample is very high.

To understand fumaric acid sludge (FAS) systematically and comprehensively and find out how to utilize it, we conducted a series of characterization analyses on FAS. Fourier transform infrared (FT-IR) Spectra shows that the main component of FAS is fumaric acids and also contains a small amount of silicate. The nuclear magnetic resonance hydrogen (1H-NMR) spectrum also shows that fumaric acid accounted for a large proportion of FAS. The X-ray diffraction (XRD) shows that the main phase in FAS is fumaric acid, and there is also a small amount of Kaliophilite. After gas chromatography and mass spectrometry (GC-MS) and pyrolysis gas chromatography and mass spectrometry (Py-GC-MS) analysis, it indicates that the possible volatiles and pyrolysis products in FAS are fumaric acid, maleic acid, maleic anhydride, phthalic acid, etc. In the test of Liquid chromatography and mass spectrometry (LC-MS), we determined the contents of phthalic acid, fumaric acid, and maleic acid in FAS. The detailed mass content of each component in FAS is as follows: phthalic acid is about 0.10–0.15%; maleic anhydride is about 0.40–0.80%; maleic acid is about 18.40–19.0%; fumaric acid is about 55.00–56.90%; succinic anhydride is about 0.06–0.08%; acrylic acid is about 0.06–0.08%; malic acid is about 0.90–1.00%; acetic acid is about 0.10–0.20%; silicate is about 0.25–0.30%; phthalic anhydride is about 0.20–0.30%; water is about 24.30–24.80%. The filtrate loss reducer (PAAF) used in oilwell drilling fluids synthesized by FAS not only has excellent temperature and complex saline resistance, the API filtration loss (FL) was only 13.2 mL/30 min in the complex saline based mud, but is also cost-effective.

Background and objectives: Cancer remains a global problem of health, and has been recorded as one of the causes of death after heart disease Natural products from plants, the environment and microorganisms are leveraged for the purpose of fighting cancer. Actinobacteria have been recognized as main sources of bioactive natural products as early as in the 1950s, for which about half of the secondary metabolites revealed, including enzymes, antibiotics, immunosuppressive, and anti-tumour agents Materials and methods:The methods of this study included isolated and identification of bacteria from soil samples and identified by morphology characters and biochemical test. Subjected extract of actinomycetes to HPLC purification then collected purified fractions then analyzed by GC-mass. After the fractions were mixed with liposome nanoparticals which tested activity on HT29 colon cancer cell line. Results: The results of identification of bacterial isolates showed the colonies growing on a SNA medium were morphologically identified where the colonies were well-growth and had a gray color, not producing dyes in the medium. The results of the biochemical tests indicated that isolates were amylase, catalase, and gelatinase producing isolates and non-lipase producing, non H2S production and consuming urea, while the carbon consumption test indicated the isolates' ability to consume starch, glucose and sucrose respectively. While The results of preparative HPLC revealed that 4 fractions analytical HPLC with (50 % HPLC-grade acetonitrile) at 254 nm and cycling up was employed to increase the separation efficiency. The chemical composition of the HPLC fractions using GC-MS showed the identification of many components example ( Hexadeconic acid , Octadecanoic acid,ethyl ester and Fumaric acid). The results of In vitro anti-tumor cytotoxicity showed that all four nano purified fractions were applied on HT 29 colon cancer cells and exhibited significantly differences compared with control.

Kefir is an acidic-alcoholic fermented milk that can provide probiotic benefits, such as intestinal microecological balance regulation, antibacterial activity, and anti-inflammatory activity. In this study, Lactobacillus fermentum grx08 isolated from longevous people was used to further improve the health properties of kefir. L. fermentum grx08 and kefir grains obtained from Xinjiang, People's Republic of China, were mixed at ratios of 1:1, 5:1, and 25:1 as starters. The six gram-positive and gram-negative foodborne pathogens were able to grow in the supernatant of kefir but not in the supernatant of kefir with L. fermentum grx08. With increasing amounts of inoculated L. fermentum grx08, the antibacterial activity of the mixed fermented kefir gradually increased. The contents of lactic acid, fumaric acid, and malic acid in the mixed fermented milk were significantly increased by adding L. fermentum grx08 (P < 0.05), while the content of acetic acid decreased with the increase of L. fermentum grx08 and the content of citric acid was unaffected. This study suggests that the addition of L. fermentum grx08 shortened the fermentation time, improved the acidity, and retained the quality of fermented milk. Moreover, the antibacterial properties of kefir is enhanced by increasing the production of certain acids. HIGHLIGHTS

Lamivudine (3TC) is a drug in the antiretroviral class used to treat AIDS / HIV. Featuring two chiral centers, 3TC has two pairs of diastereomers, of which cis - (−) is the first option, as it has biological activity and is not cytotoxic. Due to the great demand for this compound, several synthetic routes were developed for its production. Among them, the enantioselective synthesis of lamivudine from L-menthyl-glyoxylate, which uses L-menthol as a chiral auxiliary, stands out. L-menthyl-glyoxylate is obtained by reacting menthol with some carboxyl derivatives, such as glyoxyl acid, maleic anhydride and fumaric acid. The present work aims to produce this basic component (L-menthyl glyoxylate) using alternative batch and continuous flow methodologies. The synthesis was carried out in two ways: a) from the esterification of menthol with maleic anhydride followed by ozonolysis of dimenthyl maleate and hydration; and b) starting from the esterification of menthol with fumaric acid to synthesize dimenthyl fumarate, followed by ozone and hydration. For all stages, conversions and selectivity above 90% were observed. The ozonolysis of dimenthyl maleate was transposed to continuous flow conditions resulting in conversion and selectivity above 99%. Thus, the work allowed the development of an alternative process to synthesize L-menthyl-glyoxylate, from the use of domestic ozone generator for the reaction of ozonolysis.

Biomass, as renewable energy source, is of importance to investigate to extend the conversion yield by microorganism. Because of lignocellulosic structure, biomass must be pretreated with a process, frequently inorganic acid has to be used with a problem of hazardous byproducts. Organic acid pretreatment is an efficient alternative to be investigated. Sugar beet pulp, as an agro-industrial residue of microorganism, can be utilized by pretreatment, which is usually a costly process. Pretreatment with organic acids creates a great opportunity to convert the process into more economic and effective. Moreover, pressure conditions significantly increase the yield of biodegradable sugar content. In this study, different organic acids of maleic, fumaric, oxalic, and acetic acid pretreatment was investigated to pretreatment of sugar beet pulp, which came vast amount from factories, under pressure and non-pressure conditions via Box–Behnken method to estimate optimum point of acid ratio (1, 3, 5%), time (10, 27.5, 45 min), and solid ratio factors (3, 6.5, 10%) for highest degradation. Results were also evaluated economically. As a result of the experiments, it was observed that acetic acid gave the best result with 409.16 g/L total sugar concentration than the other organic acids. The highest TS concentration of maleic, oxalic, and fumaric acid were 97.26, 97.85, and 91.37 g/L, respectively, under pressure. According to economical evaluation, owing to lower market price and highest TS formation yield, pretreatment cost of acetic acid pretreatment was found averagely 1.51 $/gTS under pressure conditions. Supplementary Information The online version contains supplementary material available at 10.1007/s10163-021-01276-7.

Macrophage-mediated inflammation drives autoimmune and chronic inflammatory diseases. Treatment with anti-inflammatory agents can be an effective strategy to reduce this inflammation; however, high concentrations of these agents can have immune-dampening and other serious side effects. Synergistic combination of anti-inflammatory agents can mitigate dosing by requiring less drug. Multiple anti-inflammatory agents were evaluated in combination for synergistic inhibition of macrophage inflammation. The most potent synergy was observed between dexamethasone (DXM) and fumaric acid esters (e.g., monomethyl fumarate (MMF)). Furthermore, this combination was found to synergistically inhibit inflammatory nuclear factor κB (NF-κB) transcription factor activity. The optimal ratio for synergy was determined to be 1:1, and DXM and MMF were conjugated by esterification at this molar ratio. The DXM-MMF conjugate displayed improved inhibition of inflammation over the unconjugated combination in both murine and human macrophages. In the treatment of human donor monocyte-derived macrophages, the combination of DXM and MMF significantly inhibited inflammatory gene expression downstream of NF-κB and overall performed better than either agent alone. Further, the DXM-MMF conjugate significantly inhibited expression of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome-associated genes. The potent anti-inflammatory activity of the DXM-MMF conjugate in human macrophages indicates that it may have benefits in the treatment of autoimmune and inflammatory diseases.

Organic acids, e.g, citric acid, fumaric acid, lactic acid, malic acid, pyruvic acid and succinic acid, have important role in the food industry and are potential raw materials for the sustainable chemical industry. Their fermentative production based on renewable raw materials requires innovatively designed downstream processing to maintain low environmental impact and resource efficiency throughout the production process. The application of bipolar membranes offers clean and effective way to generate hydrogen ions required for free acid production from its salt. The water dissociation reaction inside the bipolar membrane triggered by electric field plays key role in providing hydrogen ion for the replacement of the cations in organic acid salts. Combined with monopolar ion-exchange membranes in a bipolar membrane electrodialysis process, material flow can be separated beside the product stream into additional reusable streams, thus minimizing the waste generation. This paper focuses on bipolar membrane electrodialysis applied for organic acid recovery from fermentation broth.

The hydrolysis of lignocellulosic biomass opens an array of bioconversion possibilities for producing fuels and chemicals. Microbial fermentation is particularly suited to the conversion of sugar rich hydrolysates to biochemicals. Rhizopus oryzae ATCC 20344 was employed to produce fumaric acid from glucose, xylose and a synthetic lignocellulosic hydrolysate (glucose-xylose mixture) in batch and continuous fermentations. A novel immobilised biomass reactor was used to investigate the co-fermentation of xylose and glucose. Ideal medium conditions and a substrate feed strategy were then employed to optimise for the production of fumaric acid. The batch fermentation of the synthetic hydrolysate at the optimal conditions (urea feed rate 0.625 mg L−1 h−1 and pH 4) produced a fumaric acid yield of 0.439 g g−1. A specific substrate feed rate (0.164 g L−1 h−1) which negated ethanol production and selected for fumaric acid was determined. Using this feed rate in a continuous fermentation a fumaric acid yield of 0.735 g g−1 was achieved; a 67.4 % improvement. Metabolic analysis helped to determine a continuous synthetic lignocellulosic hydrolysate feed rate that selected for fumaric acid production, while achieving co-fermentation of glucose and xylose, avoiding the undesirable carbon catabolite repression. This work demonstrates the viability of fumaric acid production from lignocellulosic hydrolysate; the process developments discovered will pave the way for an industrially viable process.

Current studies on the reactive extraction of fumaric acid with Amberlite LA-2 from aqueous phases with different viscosities using three solvents highlighted the influences of rheological properti...

Tuning the structural defects of graphite carbon nitride (g-C3N4) is an effective strategy to modify its band structure and promote charge separation, but it is still limited by complex and harsh p...

With an unsupervised GC–MS metabolomics approach, polar metabolite changes of the microalgae Coccomyxa melkonianii SCCA 048 grown under standard conditions for seven weeks were studied. C. melkonianii was sampled at the Rio Irvi River, in the mining site of Montevecchio-Ingurtosu (Sardinia, Italy), which is severely contaminated by heavy metals and shows high concentrations of sulfates. The partial-least-square (PLS) analysis of the GC–MS data indicated that growth of C. melkonianii was characterized by an increase of the levels of threonic acid, myo-inositol, malic acid, and fumaric acid. Furthermore, at the sixth week of exponential phase the lipid fingerprint of C. melkonianii was studied by LC-QTOF-MS. C. melkonianii lipid extract characterized through an iterative MS/MS analysis showed the following percent levels: 61.34 ± 0.60% for triacylglycerols (TAG); 11.55 ± 0.09% for diacylglyceryltrimethyl homoserines (DGTS), 11.34 ± 0.10% for sulfoquinovosyldiacylglycerols (SQDG) and, 5.29 ± 0.04% for lysodiacylglyceryltrimethyl homoserines (LDGTS). Noteworthy, we were able to annotate different fatty acid ester of hydroxyl fatty acid, such as FAHFA (18:1_20:3), FAHFA (18:2_20:4), FAHFA (18:0_20:2), and FAHFA (18:1_18:0), with relevant biological activity. These approaches can be useful to study the biochemistry of this extremophile algae in the view of its potential exploitation in the phycoremediation of polluted mining areas.

The aimof the study was to research the qualitative composition and to investigate the quantitative content of some carboxylic acids in the herbal mixtures with established hypoglycemic, hypolipidemic and antioxidant activity in previous studies in vivo. Materials and methods.Studies of carboxylic acid content in the herbal mixtures were performed by HPLC analysis using Agilent Technologies 1200 liquid chromatograph (USA). Identification and quantitative analysis were performed using standard solutions of carboxylic compounds (tartaric, pyruvic, isocitric, citric, succinic and fumaric acids). Conclusions. HPLC analysis of five samples of the herbal mixture with antidiabetic activity showed the presence of six carboxylic acids. The dominant acid in all samples was isocitric acid. Among the most important for the prevention and treatment of diabetes, high levels of succinic and fumaric acids have been identified and established. The obtained data indicate a correlation between the phytochemical composition of the studied herbal mixtures and their pharmacodynamics, which was previously established

It is well known that chloride ions could affect the oxidation kinetics and mechanism of contaminant based on SO4•− in the wastewater. Here, the degradation of an organic acid, fumaric acid (FA), was investigated in the presence of chloride (0–300 mM) by the Fe(II)/peroxymonosulfate (Fe(II)/PMS) system. A negative impact of chloride was observed on the rates of FA degradation. The degree of inhibitory effect was higher in Fe(II)/PMS addition order. Some chlorinated byproducts were identified during the FA oxidation process in the presence of Cl− by the ultraperformance liquid chromatography and quadrupole-time of flight mass spectrometer (UPLC-QTOF-MS). With the increasing content of Cl−, an accumulation of adsorbable organic halogen (AOX), an increase in acute toxicity, and an inhibition of mineralization were observed. According to the results of kinetic modeling, the production and transformation of oxidative species were dependent on Cl− dosage and reaction time. SO4•− was supposed to be the main radical for FA degradation with Cl− concentration below 5 mM, whereas Cl2•− was primarily responsible for the depletion of FA at [Cl−] > 5 mM. A possible degradation pathway of FA was discussed. This study reveals the potential environmental risk of organic acid and is necessary to explore useful strategies for ameliorating the treatment of chloride-rich wastewater.

Naftopidil (NAF), an α1-adrenoceptor antagonist, is administered as a treatment for benign prostatic hyperplasia; however, according to the Biopharmaceutical Classification System (BCS IV), it is a poorly-soluble drug that exhibits poor permeability. We aimed to increase the dissolution (%) of NAF by adding chitosan to a polymer-free formulation. Compared to the formulation prepared using Flivas®, at 60 min, the solid dispersion (SD) formulation containing NAF, fumaric acid, chitosan, and US2® in a 1:1:2:1 weight ratio improved the dissolution (%) of NAF in distilled water, pH 1.2 media, pH 4.0 and pH 6.8 buffers by 27.2-, 1.2-, 1.1- and 6.5-fold, respectively. The physicochemical properties of the SD1 formulation were also found to be altered, including its thermal properties, crystal intensity, and chemical interaction. As a result, the hydrogen bonding that occurs between NAF and fumaric acid was identified as a major factor in the increase in NAF dissolution (%). Further, chitosan was observed to contribute to the stability of NAF and SD1, which was assessed over a 3-month period. To our knowledge, this is the first study to employ a polymer-free system to improve the solubilization of NAF.

Enzymatic synthesis of l-alanine has the advantages of less byproducts, strong stereoselectivity, and high catalytic efficiency. Aspartate 4-decarboxylase (ASD) is used industrially in DL-aspartic acid resolution and l-alanine production because it catalyzes the decarboxylation of l-aspartic acid. In this study, the ASD gene from Acinetobacter radioresistens (ArASD) was cloned, and its enzymatic properties were analyzed. ArASD is a dodecamer and has the highest enzyme activity ever reported to date. The optimal conditions for ArASD catalysis are 50°C and pH 4.5. Site-directed mutagenesis was used to improve ArASD stability under acidic conditions to compensate for its weak acid resistance, and the variant N35D with higher catalytic ability was obtained. The conversion by N35 recombinant cells of l-aspartic acid to l-alanine was 92.5% at pH 4.5% and 99.9% at pH 6.0, whereas that of the wild-type recombinant cells was 29.7% and 31.4%, respectively. Aspartase from Escherichia coli (AspA) was employed with ArASD to construct a dual-enzyme system that catalyzes fumaric acid to l-alanine, and the conversion reached 97.1% using recombinant cells harboring the dual-enzyme system. This study explored the enzymatic properties of ArASD and an effective strategy for the acidic resistance modification of ASD. Moreover, the strain expressing the ArASD variant and AspA engineered in this study has great potential application for the l-alanine production industry, especially in the case of high optical purity requirements.

Producing more than one structure from the same set of metal and ligand precursors will grant structural diversity in metal-organic framework (MOF) systems. One of the biggest obstacles of getting structural diversity for the late transition metals is that the coordination mode is pretty much fixed by nature. Herein, we show that two different coordination modes to Cu(II) are possible for flexible ligands containing hydrophilic terminal groups through solvent guidance. It is demonstrated that trans,trans-muconic acid (H2muco) ligands coordinate to Cu(II) to form Cu(II) muconate MOFs having a 1D chain structure and a 2D plane structure in water-rich and DMF-rich water-DMF mixed solvent systems, respectively. It is suggested that the interaction between ligands and solvent is responsible for the selective coordination. A similar result was observed from the attempts using the fumaric acid ligand. Our results provide a new direction to obtain diverse secondary building units for the construction of diverse MOFs.

A simple and reliable high-performance liquid chromatography method was developed to determine the enantiomeric impurity of tenofovir disoproxil fumarate, an orally bioavailable prodrug of tenofovir, commonly used for the treatment of human immunodeficiency virus and hepatitis B. Tenofovir disoproxil and its enantiomer, were completely separated on a Chiralpak IC column (3 μm, 100 × 4.6 mm, i.d.). The chiral separation was achieved using a mobile phase containing n-hexane, ethanol, methanol, and triethylamine 65/25/10/0.1 (v/v/v/v) at a flow rate of 0.6 mL/min. Ideally, the reversal of enantiomer elution order was achieved on the Chiralpak IC column, to allow the elution of the minor enantiomeric impurity before the major component. Moreover, the proposed method was able to discriminate the active ingredient from the related substances available in the tenofovir disoproxil fumarate raw materials. These compounds were isolated and structurally elucidated by MS and nuclear magnetic resonance. Based on the spectral data, the structures of related substances were confirmed as tenofovir isoproxil monoester and fumaric acid. The high-performance liquid chromatography method was optimized by the design of experiment approach and successfully validated following the International Conference on Harmonization guideline. Proposed method was effectively applied for the quantification of enantiomeric impurity in tenofovir disoproxil fumarate raw materials.

The experimental lipophilicity of fumaric acid (FA) and maleic acid (MA) using the traditional shake-flask method in an n-octanol–water system using reversed-phase thin-layer chromatography (RP-TLC) was determined. Experimental partition coefficients (logPexp) were equal to −0.65 and 0.63 for MA and FA, respectively. The chromatographic lipophilicity (RMW) of the FA and MA was evaluated using reversed-phase thin-layer chromatography on RP8F254s, RP18WF254, and CNF254s plates with a mixture of an organic solvent (methanol or dioxane) and water as the mobile phase. All applied chromatographic conditions were appropriate to determine the lipophilicity of the tested MA and FA. Topological indices derived from distance matrices allowed for the development of a new method for the evaluation of the lipophilicity of MA and FA. All methods applied in this work indicate that MA is less lipophilic than FA. The methods used in this work to determine lipophilicity are of particular importance in the aspect of studying cis- and trans-configuration compounds, because generally available computer programs based on various algorithms (Virtual Computational Chemistry Laboratory and Molinspiration Cheminformatics) indicate that fumaric acid and maleic acid have identical logP values.

Fumaric aciduria resulting from fumarate hydratase deficiency is a rare inherited disorder of the Krebs tricarboxylic acid cycle that is characterized by neurologic manifestations, a spectrum of brain abnormalities, and the excretion of fumaric acid in urine. We describe a 3 year old Sri Lankan boy who was referred at age 10 months with poor weight gain and hypotonia for further laboratory investigations. In addition to global developmental delay, there were noticeable dysmorphic features with a prominent forehead, low-set ears, micrognathia, and hypertelorism with persistent neutropenia. Urine organic acid assay revealed a massive elevation of fumaric acid on 2 occasions. Molecular analysis revealed a homozygous likely pathogenic missense variant, NM000143.3:c.1048C>T p. (Arg350Trp), in the FH gene, confirming the biochemical diagnosis. Our patient was the first patient in Sri Lanka molecularly diagnosed with fumaric aciduria. This case study highlights the importance of performing organic acid assays in children presenting with neurologic manifestations especially when these are suspected to have a metabolic basis.

Significant advances have been made in unknown metabolite identification and expansion of the number of quantifiable metabolites in human plasma, serum, and whole blood using NMR spectroscopy. However, reliable quantitation of metabolites is still a challenge. A major bottleneck is the lack of a suitable internal standard that does not interact with the complex blood sample matrix and also does not overlap with metabolite peaks apart from exhibiting other favorable characteristics. With the goal of addressing this challenge, a comprehensive investigation of fumaric and maleic acids as potential internal standards was made along with a comparison with the conventional standards, TSP (trimethylsilylpropionic acid) and DSS (trimethylsilylpropanesulfonic acid). Both fumaric acid and maleic acid exhibited a surprisingly high performance with a quantitation error

Current study was conducted to figure out the effects of some organic acids as either individually or in combinations at varying levels (Fumaric Acid (Fu), Malic Acid (Ma), Formic Acid (Fo), Fu + Ma, Fu + Fo, Fo + Ma and Fu + Ma + Fo) on volatile fatty acids (VFA) and methane mitigating of some legume forages such as alfalfa (Medicago polymorphia), clover (Trifolium repens) and vetch (Vicia villosa). Graded 100 ml syringes were used in gas production test. Gas volume was measured and sampled at 3, 6, 12, 24, 48, 72 and 96 h of incubation times, headspace produced methane was sampled at 24 h and the VFA profile was assessed at the end of the experiment. Obtained data were analyzed by exploiting SAS package program. Effects of legume forage × organic acid interactions and legume forages on the amounts of gas production determined at different incubation times and the amounts of methane production measured at 24 h of incubation were found significant (p 0.05). Reduction in Acetic Acid percentage was discovered for samples treated with Formic Acid (P

Furfural is an alternative feedstock and has been used for the production of maleic acid (MA) and fumaric acid (FA) by an oxidation process. Deep eutectic solvents (DESs) were used as the green solvents while sodium chlorate was used as an oxidant and vanadium pentoxide was used as the catalyst at 70–90 ℃ under atmospheric pressure. It was found that several acidic DESs are valid, such as acetic acid/choline chloride (AA/ChCl) and propionic acid/choline chloride (PA/ChCl), and AA/ChCl DES was selected as the solvent for the conversion. The optimal DES is AA/ChCl, and the effect of the amount of oxidant, time, and temperature on the yield of the MA and FA has been systematically studied, and the conversion of furfural can reach 100% while the yield of the MA and FA reached 66.5% under reaction temperature of 80 ℃ for 12 h, which provides a new green route to synthesis valuable monomers from furfural.

The γ-butyrolactone and δ-valerolactone structural units are present in different natural products with significant pharmacological properties. Fumaric acid ester-based drugs are used for the treatment of psoriasis and, more recently, multiple sclerosis. We synthesized different γ-butyrolactone and δ-valerolactone derivatives where the fumarate moiety is forced into a lactone ring in search of strategies to maintain the anti-inflammatory activity of fumaric acid esters limiting the side effects and enhancing the bioavailability. The structures of all synthesized compounds obtained were identified on the basis of their spectral data. The toxicity profile as well as the neuroprotective properties of the synthesized derivatives were evaluated in human neuroblastoma SH-SY5Y cell line. All tested fumaric esters presented lower cytotoxicity and higher neuroprotective properties, in comparison to dimethyl fumarate. Pre-treatment of cells with at least seven compounds for 24 h lead to a significantly neuroprotection against H2O2-induced cell damage. Our results demonstrate that SH-SY5Y cells are suitable cellular model to evaluate the neuroprotective role of fumaric acid esters, and support further evaluation of BG-12 derivatives aimed at decreasing cytotoxicity and limiting the side effects for improvement of treatments for multiple sclerosis and psoriasis.

In present study, effects of foliar GA3 treatments on phenolic compounds, organic acids, vitamin C content and agro-morphological characteristics of 5 strawberry cultivars were investigated. Principle component analysis was also performed to assess the variations in and relationships between bioactive compounds contents of cultivars treated with GA3. Although they varied depending on cultivars, the highest organic acid contents were generally determined in fruits treated with 50 ppm GA3. Both GA3 treatments increased vitamin C contents in ‘Albion’ and ‘Aromas’ but decreased in ‘Seascape’ fruits. GA treatment caused significant change in some phenolic compounds content. While 100 ppm GA3 treatment significantly increased catechin content of ‘Albion’ and ‘Aromas’, it decreased catechin content of ‘Seascape’ fruits. Results of PCA analysis showed that ‘Sweet Ann’ differ from other cultivars by poor ascorbic and fumaric acid content. ‘Albion’ and ‘Honeoye’ differ from other cultivars by high p-coumaric and low ellagic acid contents.

Background Fumaric acid esters (FAEs) are used to treat chronic plaque psoriasis. Fumarate is a crucial component of the Krebs cycle and mitochondrial function. Proximal tubule cells have high energy demands and rely on aerobic respiration. Proximal tubular dysfunction can cause renal Fanconi syndrome and acute kidney injury. We sought to better understand the mechanism for this in the context of FAE therapy. Methods We describe a case series of 10 patients with FAE-associated Fanconi syndrome. Patients were diagnosed and managed at a tertiary renal tubular disorder clinic, with examination of serum and urine biochemistry. Five patients had a renal biopsy with examination of the specimens by electron microscopy. Results The median age was 36.5 years [interquartile range (IQR) 32.25–54.25]. The median dose of FAE was 720 mg/day (IQR 390–720). There was low molecular weight proteinuria: the median urinary retinol-binding protein (RBP) at presentation was 8385 μg/mL (IQR 2793–14 600) and the RBP:creatinine ratio was 710 (IQR 390–2415). All patients had hyperphosphaturia [median fractional excretion of phosphate 24.2% (IQR 20.8–26.9), normal range Conclusions We document for the first time that FAE-associated renal Fanconi syndrome is associated with mitochondrial damage visible on electron microscopy. This effect may be ameliorated by antagonism of the organic anion transporter with probenecid.

Atrazine (ATZ) and ametryn (AMT) are poorly soluble s-triazine herbicides widely used worldwide as the main weed control (WC) method in crops. Herein, we report the highly soluble multicomponent crystals of these s-triazine herbicides, which were fabricated with the aim to provide safer and more eco-friendly formulations. The crystallization of ATZ with fumaric acid yielded hydrated (ATZ–H2Fum·H2O) and dehydrated (ATZ–H2Fum) cocrystals with an herbicide : acid ratio of 2 : 1, whereas the combination of AMT with nitric and trifluoracetic acids resulted in the formation of two 1 : 1 salts (AMT–NO3 and AMT–TFA, respectively). All solid forms were characterized in terms of their structural (single-crystal/powder X-ray diffraction and infrared spectroscopy), and physicochemical properties (thermal stability, phase transition, and solubility). Similarities between the crystal arrangements of these compounds could be seen in the formation of 1D-chains by the association of the s-triazine herbicide molecules and the ionizable portion of coformers. Thus, the crystal structures featured hydrophilic domains, breaking the original hydrophobic packing of the pure herbicides and, hence, increasing significantly the melting point and modifying the solubility compared to the parent forms. The new crystals ATZ–H2Fum, AMT–NO3, and AMT–TFA were 6-fold, 22-fold, and 14-fold, respectively, more soluble than their corresponding pure forms. The implication of these findings complies with enhanced sustainability in the crop production, whereby the herbicidal formulation utilizes highly soluble compounds, which could decrease the presence of undissolved solids or adjuvants, and thereby, reduce the dosage needed for WC.

In industry, L-alanine is biosynthesized using fermentation methods or catalyzed from L-aspartic acid by aspartate β-decarboxylase (ASD). In this study, a triple-enzyme system was developed to biosynthesize L-alanine from cis-butenedioic anhydride, which was cost-efficient and could overcome the shortcomings of fermentation. Maleic acid formed by cis-butenedioic anhydride dissolving in water was transformed to L-alanine via fumaric acid and L-asparagic acid catalyzed by maleate isomerase (MaiA), aspartase (AspA) and ASD, respectively. The enzymatic properties of ASD from different origins were investigated and compared, as ASD was the key enzyme of the triple-enzyme cascade. Based on cofactor dependence and cooperation with the other two enzymes, a suitable ASD was chosen. Two of the three enzymes, MaiA and ASD, were recombinant enzymes cloned into a dual-promoter plasmid for overexpression; another enzyme, AspA, was the genomic enzyme of the host cell, in which AspA was enhanced by a T7 promoter. Two fumarases in the host cell genome were deleted to improve the utilization of the intermediate fumaric acid. The conversion of whole-cell catalysis achieved 94.9% in 6 h, and the productivity given in our system was 28.2 g (L h)−1, which was higher than the productivity that had been reported. A catalysis-extraction circulation process for the synthesis of L-alanine was established based on high-density fermentation, and the wastewater generated by this process was less than 34% of that by the fermentation process. Our results not only established a new green manufacturing process for L-alanine production from cis-butenedioic anhydride but also provided a promising strategy that could consider both catalytic ability and cell growth burden for multi-enzyme cascade catalysis.

Chemobiocatalytic selective transformation is an attractive yet challenging task, due to the incompatibility issues between different types of catalysts. In this work, one-pot, multi-step cascades integrating biocatalysis with organo-, base- and photocatalysis in a plug-and-play fashion were constructed for the controllable synthesis of eight C4 chemicals from furfural. Furfural was converted to 5-hydroxy-2(5H)-furanone (HFO) by sequential biocatalytic oxidation and photooxygenation in phosphate buffer, in >90% yields. Ring opening and concurrent isomerization of HFO to fumaric semialdehyde (FSA) were readily realized under mild conditions by a weakly basic resin (e.g., DVB resin). The versatile intermediate FSA could be oxidized to fumaric acid (FA) using a laccase–2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO) system, which was further upgraded to amino acids including L-aspartic acid (L-Asp) and β-alanine (β-Ala) by whole-cell catalysis. Notably, amino acids were obtained from biobased furfural in a one-pot, four-step process with yields of up to 75%, without the isolation of any intermediates. Besides, the scale-up synthesis of L-Asp was demonstrated. This work demonstrates the great potential of the combination of chemo- and biocatalysis for selective furfural valorization.