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Royal jelly (RJ) is a bee product produced by the mandibular and hypopharyngeal glands of worker honeybees which has attracted special attention because of its numerous pharmacological activities and its applications to dermatology and cosmetics. In 2020, we demonstrated a liquid chromatography–high resolution mass spectrometry (LC–HRMS) method for the determination of seven medium-chain FFAs in RJ samples. The aim of the present work was to extend our studies on FA profiling of RJ, exploring the presence of common long-chain saturated, mono-unsaturated and poly-unsaturated free FAs in RJ samples using this LC–HRMS method. Among twenty common FAs studied by a targeted approach, palmitic acid, stearic acid and oleic acid were found at concentrations higher than the rest of the FAs (the concentrations of these three acids ranged from 37.4 to 48.0, from 17.7 to 24.0 and from 9.4 to 11.1 mg/100 g of fresh RJ, respectively). The high mass accuracy of LC–HRMS allowed the application of a suspect approach, which enabled the exploration of various C9 and C11 FAs, as well as hydroxylated C12 FAs. Nonenoic acid was indicated as the most abundant among these acids. In addition, for the first time, the presence of a variety of regio-isomers of hydroxymyristic, hydroxypalmitic and hydroxystearic acids was demonstrated in RJ samples. [ABSTRACT FROM AUTHOR]

Fatty acids (FAs) play pleiotropic roles in living organisms, acting as signaling molecules and gene regulators. They are present in plants and foods and may affect human health by food ingestion. As a consequence, analytical methods for their determination in biological fluids, plants and foods have attracted high interest. Undoubtedly, mass spectrometry (MS) has become an indispensable technique for the analysis of FAs. Due to the inherent poor ionization efficiency of FAs, their chemical derivatization prior to analysis is often employed. Usually, the derivatization of the FA carboxyl group aims to charge reversal, allowing detection and quantification in positive ion mode, thus, resulting in an increase in sensitivity in determination. Another approach is the derivatization of the double bond of unsaturated FAs, which aims to identify the double bond location. The present review summarizes the various classes of reagents developed for FA derivatization and discusses their applications in the liquid chromatography-MS (LC-MS) analysis of FAs in various matrices, including plasma and feces. In addition, applications for the determination of eicosanoids and fatty acid esters of hydroxy fatty acids (FAHFAs) are discussed. [ABSTRACT FROM AUTHOR]

Phenolic compounds are plant secondary metabolites, one of the most common and widespread groups of substances in plants, as well as a major group of phytochemicals present in medicinal and aromatic plants. The phytochemical composition of the hydroalcoholic extracts from S. raeseri, S. scardica and S. syriaca was determined by LC-MS/MS-QTOF analysis. A total amount of 23 secondary metabolites were identified, including 17 flavonoids (Fs), 4 phenylethanoid glycosides (PEGs), 1 phenolic acid (PA) and 1 fatty acid (FA). Among the three species, the constituents that have been detected in all of nine samples were: verbascocide/isoverbascoside (PEG), apigenin 7-O- glucoside (F), isoscutellarein 7-O-[6″-O-acetyl]-allosyl(1→2)-glucoside (F) and apigenin 7-(4″-p-coumaroylglucoside) (F). This study contributes to the phytochemical characterization of the Sideritis spp. by providing a comparative study of bioactive compounds present in three different Sideritis species, S. raeseri, S. scardica and S. syriaca, which are widely used as a herbal medicine in Mediterranean region and Balkan Peninsula. [ABSTRACT FROM AUTHOR]

Abstract Phospholipase A 2 (PLA 2) enzymes are involved in various inflammatory pathological conditions including arthritis, cardiovascular and autoimmune diseases. The regulation of their catalytic activity is of high importance and a great effort has been devoted in developing synthetic inhibitors. We summarize the most important small-molecule synthetic PLA 2 inhibitors developed to target each one of the four major types of human PLA 2 (cytosolic cPLA 2 , calcium-independent iPLA 2, secreted sPLA 2, and lipoprotein-associated LpPLA 2). We discuss recent applications of inhibitors to understand the role of each PLA 2 type and their therapeutic potential. Potent and selective PLA 2 inhibitors have been developed. Although some of them have been evaluated in clinical trials, none reached the market yet. Apart from their importance as potential medicinal agents, PLA 2 inhibitors are excellent tools to unveil the role that each PLA 2 type plays in cells and in vivo. Modern medicinal chemistry approaches are expected to generate improved PLA 2 inhibitors as new agents to treat inflammatory diseases. [ABSTRACT FROM AUTHOR]

Broccoli (Brassica oleracea L. var. italica Plenck) is a widely consumed vegetable, very popular due to its various nutritional and bioactive components. Since studies on the lipid components of broccoli have been limited so far, the aim of the present work was the study of free fatty acids (FFAs) present in different broccoli parts, aerial and underground. The direct determination of twenty-four FFAs in broccoli tissues (roots, leaves, and florets) was carried out, using a liquid chromatography–high-resolution mass spectrometry (LC-HRMS) method in a 10 min single run. Linolenic acid was found to be the most abundant FFA in all different broccoli parts in quantities ranging from 0.76 to 1.46 mg/g, followed by palmitic acid (0.17–0.22 mg/g) and linoleic acid (0.06–0.08 mg/g). To extend our knowledge on broccoli's bioactive components, for the first time, the existence of bioactive oxidized fatty acids, namely hydroxy and oxo fatty acids, was explored in broccoli tissues adopting an HRMS-based lipidomics approach. 16- and 2-hydroxypalmitic acids were detected in all parts of broccoli studied, while ricinoleic acid was detected for the first time as a component of broccoli. [ABSTRACT FROM AUTHOR]

A mild photocatalytic manifold for the synthesis of γ-lactones has been developed. Utilizing Ru(bpy)3Cl2 as the photocatalyst, a cheap and reproducible synthetic protocol for γ-lactones has been introduced. Mechanistic studies revealed the successful monitoring of photocatalytic reactions and radical intermediates via high-resolution mass spectrometry. [ABSTRACT FROM AUTHOR]

The aim of this work was to study the chromatographic behavior of polar artificial sweeteners on three hydrophilic interaction liquid chromatography (HILIC) columns: Kinetex HILIC (unbounded silica, core shell), ZIC HILIC (sulfoalkylbetain) and TSKgel Amide-80 (amide). The studied analytes were dipeptides (aspartame, neotame, advantame, alitame), sulfamates (acesulfame, saccharin, cyclamate), and sugars (sucralose, neohesperidin dihydrochalcone). Critical parameters such as the mobile phase pH, buffer concentration, column temperature, and organic modifier were studied for the investigation of the retention mechanism. Partition and adsorption models were also used. The retention mechanism of dipeptides seems to be partition for the aqueous layer and weak electrostatic interactions or hydrogen bonds. For the sulfamates, on Kinetex and ZIC HILIC columns, it is likely that partitioning to the aqueous layer is combined with the ERLIC phenomena at pH 5.5. For the TSKgel Amide, the partition and the hydrogen bonds formed between the analytes and carbamoyl groups of the stationary phase play an important role in the retention mechanism. For sucralose, partition seems to be the predominant mechanism in every column, while, for neohesperidin dihydrochalcone, both partition to aqueous layer and hydrogen bonding seems to contribute to the retention. This is also the first report of a method for the chromatographic determination of advantame, a new sweetener. [ABSTRACT FROM AUTHOR]

Broccoli is a rich source of bioactive compounds. Among them, sulforaphane and indole-3-carbinol have attracted a lot of attention, since their consumption is associated with reduced risk of cancer. In this work, the development of an efficient and direct method for the simultaneous determination of sulforaphane and indole-3-carbinol in broccoli using UPLC–HRMS/MS is described. The correlation coefficient, and limits of detection (LOD) and quantification (LOQ) were 0.993, 0.77 mg/L and 2.35 mg/L for sulforaphane and 0.997, 0.42 mg/L, 1.29 mg/L for indole-3-carbinol, respectively. The content of sulforaphane and indole-3-carbinol varied between 72 ± 9–304 ± 2 mg and 77 ± 1–117 ± 3 mg per 100 g of fresh florets, respectively. Taking into consideration the differences in cultivar, geography, season and environmental factors, the results agreed with values published in the literature using other techniques. [ABSTRACT FROM AUTHOR]

A novel and efficient metal-free catalyzed hydroacylation of dialkyl azodicarboxylates is reported. Graphite flakes were found to be the most efficient catalyst among other carbon-based materials to promote this reaction. This unprecedented catalytic activity can be expanded into a wide substrate scope of aliphatic aldehydes bearing various functional groups, leading to the corresponding products in good to excellent yields. [ABSTRACT FROM AUTHOR]

Calcium-independent phospholipase A 2 (GVIA iPLA 2 ) has recently attracted interest as a medicinal target. The number of known GVIA iPLA 2 inhibitors is limited to a handful of synthetic compounds (bromoenol lactone and polyfluoroketones). To expand the chemical diversity, a variety of 2-oxoamides based on dipeptides and ether dipeptides were synthesized and studied for their in vitro inhibitory activity on human GVIA iPLA 2 and their selectivity over the other major intracellular GIVA cPLA 2 and the secreted GV sPLA 2 . Structure-activity relationship studies revealed the first 2-oxoamide derivative (GK317), which presents potent inhibition of GVIA iPLA 2 ( X I (50) value of 0.007) and at the same time significant selectivity over GIVA cPLA 2 and GV sPLA 2 . [ABSTRACT FROM AUTHOR]

Among the various phytochemicals, which are present in Lamiaceae plants, carnosic acid and carnosol stand out. Carnosic acid is a phenolic diterpene carrying two phenolic hydroxyl groups and a carboxyl group, while carnosol carries a lactone moiety in addition to phenolic hydroxyls. Both these phenolic diterpenes exhibit interesting biological properties, such as antioxidant, anticancer, anti-inflammatory and neuroprotective activities. In this review, we summarize the existing analytical methods for the determination of carnosic acid and carnosol, primarily in plants, but also in foods and biological samples. Due to the biological importance of carnosic acid and carnosol, a variety of analytical methods, including high-performance liquid chromatography–ultra violet (HPLC–UV), liquid chromatography–mass spectrometry (LC–MS) and capillary electrophoresis (CE), were developed for their determination. In addition, we discuss the extraction methods applied for their isolation from plants and in brief the bioactivities of these phytochemicals. [ABSTRACT FROM AUTHOR]

The development of light‐mediated methods for synthetic applications is increasingly attracting high interest. We present herein a new photochemical protocol for the synthesis of hydroxamic acids, which constitute an important class of medicinal agents, mainly due to their anticancer properties. The method is mediated by UVA‐light or sunlight and its key point is the generation of a charge transfer complex by the interaction of 4‐dimethylaminopyridine with a halomethane. Various carboxylic acids were directly coupled with O‐protected hydroxylamines, upon irradiation with either LED 370 nm or solar light. A detailed study of the mechanism was carried out by the employment of direct infusion–high resolution mass spectrometry (DI‐HRMS), providing experimental evidence for the formation of various activated species, which may lead to the desired product. The light‐mediated protocol was applied in the synthesis of the drugs Vorinostat and Bufexamac. [ABSTRACT FROM AUTHOR]

[Display omitted] • Comparative GC–MS, FTIR and Raman spectroscopic studies of Pistacia vera oils. • Chemometric differentiation of Pistacia vera oils of two consecutive harvest periods. • FTIR spectroscopy-based chemometric discrimination of the oils was most successful. Pistacia vera oil is a rich source of unsaturated fatty acids, whose presence is associated with high quality and nutritional value. According to the literature, fatty acid oil composition is not constant every harvest year, but varies mainly depending on climate conditions. Therefore, the knowledge of oil composition in fatty acids is necessary to assess both its quality and its nutritional value. Twenty-two samples (11 samples from the harvest year 2017 and 11 samples from 2018) of the Greek variety "Aegina" were collected from four different Greek regions, from producers following the same cultivation and post-harvest cares. Extraction oil yields were found to be similar (61.7% w/w, 2017; 60.8% w/w, 2018). A reduction of the saturated fatty acids content was determined in 2018 (mean values 12.2% w/w against 13.8% w/w in 2017) by Gas Chromatography-Mass Spectrometry, accompanied by an increase of the unsaturated ones (mean values 87.9% w/w against 86.2% w/w in 2017). These results indicate that the harvest year 2018 may be considered superior to 2017 in terms of quality and nutritional value and may be correlated with an increased mean rain rate in 2018 and a slight decrease of the mean temperature. Fourier transform infrared (FTIR) and Raman spectroscopic studies of the oils were also performed. Three chemometric models were developed for the two consecutive harvest years of pistachio oil and the discrimination was based on GC–MS analysis, FTIR and Raman spectroscopic data combined with cross-validation techniques and comparison among them. The most successful chemometric model was that based on FTIR spectroscopy, which has the advantage of speed, simplicity and economy. Such a chemometric model may help in estimating the quality of Pistacia vera oils. [ABSTRACT FROM AUTHOR]

Consumption of cruciferous vegetables (Brassicaceae) has been associated with prevention of chronic non-communicable diseases. Unlike other plant species, they are able to accumulate the essential micronutrient selenium and synthesize seleno-compounds with additional health benefits. Biofortification of cruciferous vegetables could be a solution to combat selenium deficiency and a means to enhance their health-promoting properties. However, biofortification leads to alterations of plant metabolism from micro- and macronutrients to various types of phytochemicals. This systematic review presents factors controlling selenium addition has on nutrients and phytochemicals of cruciferous vegetables. Selenium compounds of Brassicaceae and their possible cancer-preventive properties are also presented. Literature research was performed using four known databases by keywords such as cruciferous vegetables names and selenium biofortification. Over 90 references, mainly from the last decade, have been reviewed. Findings suggest that selenium biofortification affects differently the contents of nutrients and phytochemicals and therefore the biofortification process for each crop should be designed accordingly taking into account selenium toxicity. [ABSTRACT FROM AUTHOR]

A liquid chromatography–high resolution mass spectrometry (LC-HRMS) method for the direct determination of various saturated hydroxy fatty acids (HFAs) in milk was developed for the first time. The method involves mild sample preparation conditions, avoids time-consuming derivatization procedures, and permits the simultaneous determination of 19 free HFAs in a single 10-min run. This method was validated and applied in 17 cow milk and 12 goat milk samples. This work revealed the existence of various previously unrecognized hydroxylated positional isomers of palmitic acid and stearic acid in both cow and goat milk, expanding our knowledge on the lipidome of milk. The most abundant free HFAs in cow milk were proven to be 7-hydroxystearic acid (7HSA) and 10-hydroxystearic acid (10HSA) (mean content values of 175.1 ± 3.4 µg/mL and 72.4 ± 6.1 µg/mL in fresh milk, respectively). The contents of 7HSA in cow milk seem to be substantially higher than those in goat milk. [ABSTRACT FROM AUTHOR]

Fatty acid esters of hydroxy fatty acids (FAHFAs) constitute a class of recently identified novel lipids exhibiting anti-diabetic and anti-inflammatory effects. Due to their high biological significance, a tremendous effort has been devoted to the development of analytical methods for the detection and quantitation of FAHFAs during the last five years. The analysis of FAHFAs is very challenging due to the great number of possible regio-isomers arising from the great number of possible combinations of FAs with HFAs, and the low abundancies of FAHFAs in biological samples. The aim of this review article is to summarize all the cutting-edge analytical methodologies for the determination of FAHFAs in biological samples, plant tissues and food matrices, with emphasis on extraction and analysis steps. All the analytical methodologies rely on the use of liquid chromatography–mass spectrometry (LC-MS), providing high sensitivity due to the MS detection. Powerful and robust analytical methodologies may highly contribute in studying FAHFAs levels under various biomedical conditions, and facilitate our understanding of the role of these lipid species in physiological and pathological conditions. [ABSTRACT FROM AUTHOR]

The determination of free fatty acids (FFAs) in milk is of importance for quality control, legislative purposes, authentication and product development. We present herein a liquid chromatography–high resolution mass spectrometry method for the direct determination of FFAs in milk. The method involves mild sample preparation, avoids time-consuming derivatization and allows the direct quantification of twenty-two FFAs in a 10-min single run. It was validated and applied in thirteen cow milk and seven goat milk samples. Saturated fatty acids C16:0, C18:0 and unsaturated C18:1 (n-9) were found to be the major components of milk FFAs at concentrations of 33.1 ± 8.2 μg/mL, 16.5 ± 5.3 μg/mL and 14.8 ± 3.8 μg/mL, respectively, in cow milk and at concentrations of 22.8 ± 1.8 μg/mL, 12.7 ± 2.8 μg/mL and 13.3 ± 0.3 μg/mL, respectively, in goat milk. Other saturated and unsaturated FFAs were found in significantly lower quantities. Saturated fatty acids C6:0, C8:0 and C10:0 were found in higher quantities in goat milk than in cow milk. The levels of the important (for human health) odd-chain FFAs C15:0 and C17:0 were estimated in cow and goat milk. [ABSTRACT FROM AUTHOR]

2-Oxoesters constitute an important class of potent and selective inhibitors of human cytosolic phospholipase A2 (GIVA cPLA2) combining an aromatic scaffold or a long aliphatic chain with a short aliphatic chain containing a free carboxylic acid. Although highly potent 2-oxoester inhibitors of GIVA cPLA2 have been developed, their rapid degradation in human plasma limits their pharmaceutical utility. In an effort to address this problem, we designed and synthesized two new 2-oxoesters introducing a methyl group either on the α-carbon to the oxoester functionality or on the carbon carrying the ester oxygen. We studied the in vitro plasma stability of both derivatives and their in vitro inhibitory activity on GIVA cPLA2. Both derivatives exhibited higher plasma stability in comparison with the unsubstituted compound and both derivatives inhibited GIVA cPLA2, however to different degrees. The 2-oxoester containing a methyl group on the α-carbon atom to the oxoester functionality exhibits enhancement of the metabolic stability and retains considerable inhibitory potency. [ABSTRACT FROM AUTHOR]

In the present review, we discuss the occurrence of ellagitannins (ETs) and ellagic acid (EA) and methods for their isolation from plant materials. We summarize analytical methods, including high-performance liquid chromatography–ultraviolet (HPLC–UV) and liquid chromatography–mass spectrometry (LC–MS), for the determination of ETs, EA and their bioactive metabolites urolithins (Uros) in samples of plant and food origin, as well as in biological samples, such as plasma, urine and feces. In addition, the current interest in the bioactivities of Uros is discussed in brief. [ABSTRACT FROM AUTHOR]

The epoxidation of alkenes has altered and reshaped the way scientists think in modern organic synthesis. Herein, a novel, sustainable and eco‐friendly protocol for the epoxidation of alkenes is reported, utilizing hydrogen peroxide as the green oxidant and, for the first time, hydroxamic acid derivatives as the organocatalyst. The presented methodology is very effective, leading to good to high yields for the oxidation of a variety of olefins, while various functional groups are well tolerated. Mechanistic studies utilizing direct infusion high resolution mass spectrometry (DI‐HRMS) provide strong evidence for the mechanism of the organocatalytic oxidation. [ABSTRACT FROM AUTHOR]

Auxins are signaling molecules involved in multiple stages of plant growth and development. The levels of the most important auxin, indole-3-acetic acid (IAA), are regulated by the formation of amide and ester conjugates with amino acids and sugars. In this work, IAA and IAA amide conjugates with amino acids bearing a free carboxylic group or a methyl ester group, along with some selected IAA metabolites, were studied in positive and negative electrospray ionization (ESI) modes, utilizing high-resolution mass spectrometry (HRMS) as a tool for their structural analysis. HRMS/MS spectra revealed the fragmentation patterns that enable us to identify IAA metabolites in plant extracts from eight vegetables of the Brassicaceae family using a fast and reliable ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QToF-MS) method. The accurate m/z (mass to charge) ratio and abundance of the molecular and fragment ions of the studied compounds in plant extracts matched those obtained from commercially available or synthesized compounds and confirmed the presence of IAA metabolites. [ABSTRACT FROM AUTHOR]

The development of novel methodologies for the functionalization of saturated heterocycles is highly desirable. Herein, we report a cheap and efficient photochemical method for the C−H functionalization of saturated O‐heterocycles, as well as the deconstructive ring‐cleavage of S‐heterocycles, employing hypervalent iodine alkynylation reagents (ethynylbenziodoxolones, EBX). This photochemical alkynylation is performed utilizing phenylglyoxylic acid as the photoinitiator, leading to the corresponding products in good to high yields, under household fluorescent light bulb irradiation. When O‐heterocycles were employed, the expected α‐C−H alkynylation took place. In contrast, oxidative ring‐opening to form a thioalkyne and an aldehyde was observed with S‐heterocycles. Preliminary mechanistic experiments are presented to give first insights into this puzzling divergent reactivity. [ABSTRACT FROM AUTHOR]

Parkinson's disease is biochemically characterized by the deposition of aberrant aggregated α‐synuclein in the affected neurons. The aggregation properties of α‐synuclein greatly depend on its affinity to bind cellular membranes via a dynamic interaction with specific lipid moieties. In particular, α‐synuclein can interact with arachidonic acid (AA), a polyunsaturated fatty acid, in a manner that promotes the formation of α‐helix enriched assemblies. In a cellular context, AA is released from membrane phospholipids by phospholipase A2 (PLA2). To investigate the impact of PLA2 activity on α‐synuclein aggregation, we have applied selective PLA2 inhibitors to a SH‐SY5Y cellular model where the expression of human wild‐type α‐synuclein is correlated with a gradual accumulation of soluble oligomers and subsequent cell death. We have found that pharmacological and genetic inhibition of GIVA cPLA2 resulted in a dramatic decrease of intracellular oligomeric and monomeric α‐synuclein significantly promoting cell survival. Our data suggest that alterations in the levels of free fatty acids, and especially AA and adrenic acid, promote the formation of α‐synuclein conformers which are more susceptible to proteasomal degradation. This mechanism is active only in living cells and is generic since it does not depend on the absolute quantity of α‐synuclein, the presence of disease‐linked point mutations, the expression system or the type of cells. Our findings indicate that the α‐synuclein‐fatty acid interaction can be a critical determinant of the conformation and fate of α‐synuclein in the cell interior and, as such, cPLA2 inhibitors could serve to alleviate the intracellular, potentially pathological, α‐synuclein burden. [ABSTRACT FROM AUTHOR]

The recent discovery of a novel class of endogenous lipids, named Fatty Acid esters of Hydroxy Fatty Acids (FAHFAs), that present antidiabetic and anti‐inflammatory activities, has attracted the interest on hydroxy fatty acids (HFAs) and their derivatives. We present herein the development of a convenient and general methodology for the asymmetric synthesis of HFAs and FAHFAs. The enantioselective organocatalytic synthesis of asymmetric terminal epoxides starting from monoprotected α,ω‐diols and their subsequent ring opening by a Grignard reagent are the key‐steps for our methodology, allowing the introduction of the hydroxy group at different positions of the long chain by proper selection of the starting diol and the Grignard reagent. MacMillan's third generation imidazolidinone organocatalyst has been employed for the epoxide formation, ensuring products in high enantiomeric purity. Furthermore, an approach for the synthesis of deuterated HFAs and FAHFAs was developed, leading to deuterated derivatives, which can be useful in biological studies and in mass spectrometry studies as internal standards. Convenient enantioselective synthesis of bioactive hydroxy fatty acids and fatty acid esters of hydroxy fatty acids was developed, based on the organocatalytic synthesis of chiral epoxides. [ABSTRACT FROM AUTHOR]

(1) Background: The essential oils (EOs) of Sideritis L. have attracted great interest due to their pharmacological activities and potential applications in the cosmetic and perfume industries. The aim of this work was to study the EO chemical composition of three of the most popular, in Greece, mountain tea species: namely, these include Sideritis scardica, Sideritis raeseri, and Sideritis syriaca. (2) Methods: The EOs were obtained from the aerial parts of three Sideritis species that were cultivated in various regions of Greece by hydrodistillation, and the chemical composition was studied by gas chromatography–mass spectrometry (GC-MS) analysis. (3) Results: The EOs of the Sideritis species—S. scardica (SSC1, SSC2, SSC3), S. raeseri (SR1, SR2, SR3), and S. syriaca (SS1, SS2, SS3)—were analyzed by GC-MS, and they showed both qualitatively and quantitatively high variation in their chemical composition. (4) Conclusions: The EOs of S. scardica and S. raeseri from three different regions of Greece, and the S. syriaca from three different localities of Crete Island in Southern Greece, showed high chemical variability. Although 165 different components were found to be present in the nine samples through GC-MS analysis, only 7 (1-octen-3-ol, linalool, trans-pinocarveol, p-mentha-1,5-dien-8-ol, α-terpineol, myrtenol, and verbenone) were common components in the nine EOs, which were identified to be highly variable in different percentages among the samples. Even the EOs of SS1 and SS2, which were cultivated nearby, showed different GC profiles. The composition variation observed might be attributed to differentiations in the soil and climatic conditions. [ABSTRACT FROM AUTHOR]

Autotaxin (ATX) catalyzes the hydrolysis of lysophosphatidylcholine (LPC) generating the lipid mediator lysophosphatidic acid (LPA). Both ATX and LPA are involved in various pathological inflammatory conditions, including fibrosis and cancer, and have attracted great interest as medicinal targets over the past decade. Thus, the development of novel potent ATX inhibitors is of great importance. We have developed a novel class of ATX inhibitors containing the zinc binding functionality of hydroxamic acid. Such novel hydroxamic acids that incorporate a non-natural δ-amino acid residue exhibit high in vitro inhibitory potency over ATX (IC50 values 50–60 nM). Inhibitor 32, based on δ-norleucine, was tested for its efficacy in a mouse model of pulmonary inflammation and fibrosis induced by bleomycin and exhibited promising efficacy. The novel hydroxamic ATX inhibitors provide excellent tools for the study of the role of the enzyme and could contribute to the development of novel therapeutic agents for the treatment of fibrosis and other chronic inflammatory diseases. [ABSTRACT FROM AUTHOR]

In recent years, the development of light‐mediated methods for synthetic applications has attracted high interest, because such methods constitute alternative approaches for the production of valuable chemical products. We study herein a photochemical protocol for the synthesis of Weinreb amides and morpholine amides from carboxylic acids. Various carboxylic acids were directly coupled to N,O‐dimethylhydroxylamine, upon irradiation with either LED 370 nm or sunlight in the presence of 4‐dimethylaminopyridine and bromotrichloromethane, providing Weinreb amides in moderate to high yields. Similarly, morpholine amides were obtained in satisfactory to high yields under sunlight or LED 370 nm irradiation. Thus, the versatile building blocks Weinreb amides and morpholine amides may be efficiently synthesized directly from carboxylic acids by light‐mediated approaches, without the need of coupling reagents or pre‐activation of carboxylic acids. [ABSTRACT FROM AUTHOR]

The direct amide bond formation between a carboxylic acid and an amine still constitutes a challenging reaction for both academia and industry. We demonstrate herein that several pairs of amines (halogen bond acceptors) and organohalogen sources may be used for the photochemical amidation reaction under either UVA or sunlight irradiation. Our studies led to the identification of pyridine‐CBr4 as an efficient agent to perform amide synthesis under LED 370 nm irradiation, avoiding super‐stoichiometric quantities. An extended substrate scope was demonstrated, showing that the widely used amino and carboxyl protecting groups are compatible with this photochemical protocol, while a number of industrially interesting products and bioactive compounds were synthesized. Direct infusion‐high resolution mass spectrometry studies suggest an unprecedented type of carboxylic acid activation mode upon irradiation, involving the generation of a symmetric anhydride, an active ester with pyridine N‐oxide and a mixed anhydride with hypobromous acid. [ABSTRACT FROM AUTHOR]

An organocatalytic and environmentally friendly approach for the selective oxidation of substituted anilines was developed. Utilizing a 2,2,2-trifluoroacetophenone-mediated oxidation process, substituted anilines can be transformed into azoxybenzenes, while a simple treatment with MeCN and H2O2 leads to the corresponding nitro compounds, providing user-friendly protocols that can be easily scaled up. Various substitution patterns and functional groups were tolerated leading to products in high to excellent yields. Mechanistic studies utilizing HRMS provide clear evidence for the distinct mechanistic intermediates that are involved. This study constitutes an indirect proof excluding the involvement of a dioxirane intermediate in the green organocatalytic oxidation, utilizing 2,2,2-trifluoroacetophenone as the catalyst. [ABSTRACT FROM AUTHOR]

An organocatalytic linchpin catalysis approach was envisaged to convert simple aldehydes into enantioenriched 2-oxopiperazines. A four-step reaction sequence (chlorination, oxidation, substitution, and cyclization) was developed and led to different substitution patterns in high yields and selectivities. The reaction mechanism was studied, and the previously elusive epoxy lactone intermediate was identified by HRMS. [ABSTRACT FROM AUTHOR]

Cytosolic GIVA phospholipase A 2 (GIVA cPLA 2 ) initiates the eicosanoid pathway of inflammation and thus inhibitors of this enzyme constitute novel potential agents for the treatment of inflammatory diseases. Traditionally, GIVA cPLA 2 inhibitors have suffered systemically from high lipophilicity. We have developed a variety of long chain 2-oxoamides as inhibitors of GIVA PLA 2 . Among them, AX048 was found to produce a potent analgesic effect. We have now reduced the lipophilicity of AX048 by replacing the long aliphatic chain with a chain containing an ether linked aromatic ring with in vitro inhibitory activities similar to AX048. [ABSTRACT FROM AUTHOR]

[Display omitted] • Rapid LC-HRMS method for the simultaneous determination of 63 free fatty acids (common FAs, SHFAs and SOFAs) in yogurt samples in a 10-min run. • Application in 26 cow and 7 sheep yogurt samples from the Greek market. • Detailed study of SHFA and SOFA levels in yogurt for the first time. • Different concentrations of 6 common FAs and 5 oxidized FAs allowed the discrimination between cow and sheep yogurt samples by PCA. Yogurt is a fermented dairy product of high nutritional value, very popular in many parts of the world. Free fatty acids (FFAs), which are formed during fermentation, may cause changes in organoleptic properties of yogurt, and thus, the determination of FFAs is of importance. We present a liquid chromatography–high resolution mass spectrometry (LC-HRMS) method, which allows the simultaneous determination of a large set of common and uncommon FFAs in yogurt samples, avoiding any derivatization step. Twenty-five common saturated and unsaturated FAs, together with 21 saturated hydroxy fatty acids (SHFAs) and 17 saturated oxo fatty acids (SOFAs), were analyzed in 26 cow and 7 sheep Greek yogurt samples. A detailed analysis of bioactive SHFAs and SOFAs was carried out in yogurt samples for the first time. Differences at the concentrations of six common FAs and five oxidized FAs between the cow and sheep samples were observed. Based on these FAs, Principal Component Analysis (PCA) allows the discrimination of cow from sheep yogurt samples. [ABSTRACT FROM AUTHOR]

The development of inhibitors for phospholipase A2 (PLA2) is important in elucidating the enzymes implication in various biological pathways. PLA2 enzymes are an important pharmacological target implicated in various inflammatory diseases. Computational chemistry, organic synthesis, and in vitro assays were employed to develop potent and selective inhibitors for group VIA calcium-independent PLA2. A set of fluoroketone inhibitors was studied for their binding mode with two human cytosolic PLA2 enzymes: group IVA cPLA2 and group VIA iPLA2. New compounds were synthesized and assayed toward three major PLA2s. This study led to the development of four potent and selective thioether fluoroketone inhibitors as well as a thioether keto-1,2,4-oxadiazole inhibitor for GVIA iPLA2, which will serve as lead compounds for future development and studies. The keto-1,2,4-oxadiazole functionality with a thioether is a novel structure, and it will be used as a lead to develop inhibitors with higher potency and selectivity toward GVIA iPLA2. [ABSTRACT FROM AUTHOR]

The development of green and sustainable methods for the conversion of aldehydes to carboxylic acids is of high academic and industrial interest. We demonstrate herein a practical and efficient light-promoted oxidation of aldehydes, utilising atmospheric oxygen as the sole oxidant. The transformation is promoted by either sunlight or LED 370 nm irradiation, without the use of a catalyst. A solvent mixture of acetone and water proved to be the most effective solvent medium. A wide range of aliphatic or aromatic aldehydes were successfully employed, providing the corresponding carboxylic acids in high to excellent yields. A mechanism was proposed based on direct infusion-high resolution mass spectrometry (DI-HRMS) studies, suggesting a solvent-assisted oxidative transformation. The method is green, sustainable and operationally simple under very mild conditions. [ABSTRACT FROM AUTHOR]

Cruciferous vegetables are characterized by the presence of sulfur-containing secondary plant metabolites known as glucosinolates (GLS). The consumption of cruciferous vegetables such as broccoli, cabbage, rocket salad, and cauliflower has been related to the prevention of non-communicable diseases. Their beneficial effects are attributed to the enzymatic degradation products of GLS, e.g., isothiocyanates and indoles. Owing to these properties, there has been a shift in the last few years towards the research of these compounds and a wide range of methods for their extraction and analytical determination have been developed. The aim of this review is to present the sample preparation and extraction procedures of isothiocyanates and indoles from cruciferous vegetables and the analytical methods for their determination. The majority of the references that have been reviewed are from the last decade. Although efforts towards the application of eco-friendly non-conventional extraction methods have been made, the use of conventional solvent extraction is mainly applied. The major analytical techniques employed for the qualitative and quantitative analysis of isothiocyanates and indoles are high-performance liquid chromatography and gas chromatography coupled with or without mass spectrometry detection. Nevertheless, the analytical determination of isothiocyanates presents several problems due to their instability and the absence of chromophores, making the simultaneous determination of isothiocyanates and indoles a challenging task. [ABSTRACT FROM AUTHOR]

Nervous system malignancies are characterized by rapid progression and poor survival rates. These clinical observations underscore the need for novel therapeutic insights and pharmacological targets. To this end, here, we identify the orphan nuclear receptor NR5A2/LRH1 as a negative regulator of cancer cell proliferation and promising pharmacological target for nervous system-related tumors. In particular, clinical data from publicly available databases suggest that high expression levels of NR5A2 are associated with favorable prognosis in patients with glioblastoma and neuroblastoma tumors. Consistently, we experimentally show that NR5A2 is sufficient to strongly suppress proliferation of both human and mouse glioblastoma and neuroblastoma cells without inducing apoptosis. Moreover, short hairpin RNA-mediated knockdown of the basal expression levels of NR5A2 in glioblastoma cells promotes their cell cycle progression. The antiproliferative effect of NR5A2 is mediated by the transcriptional induction of negative regulators of the cell cycle, CDKN1A (encoding for p21cip1), CDKN1B (encoding for p27kip1) and Prox1. Interestingly, two well-established agonists of NR5A2, dilauroyl phosphatidylcholine (DLPC) and diundecanoyl phosphatidylcholine, are able to mimic the antiproliferative action of NR5A2 in human glioblastoma cells via the induction of the same critical genes. Most importantly, treatment with DLPC inhibits glioblastoma tumor growth in vivo in heterotopic and orthotopic xenograft mouse models. These data indicate a tumor suppressor role of NR5A2 in the nervous system and render this nuclear receptor a potential pharmacological target for the treatment of nervous tissue-related tumors. [ABSTRACT FROM AUTHOR]

3-Hydroxy fatty acids have attracted the interest of researchers, since some of them may interact with free fatty acid receptors more effectively than their non-hydroxylated counterparts and their determination in plasma provides diagnostic information regarding mitochondrial deficiency. We present here the development of a convenient and general methodology for the asymmetric synthesis of 3-hydroxy fatty acids. The enantioselective organocatalytic synthesis of terminal epoxides, starting from long chain aldehydes, is the key-step of our methodology, followed by ring opening with vinylmagnesium bromide. Ozonolysis and subsequent oxidation leads to the target products. MacMillan's third generation imidazolidinone organocatalyst has been employed for the epoxide formation, ensuring products in high enantiomeric purity. Furthermore, a route for the incorporation of deuterium on the carbon atom carrying the hydroxy group was developed allowing the synthesis of deuterated derivatives, which may be useful in biological studies and in mass spectrometry studies. In addition, the synthesis of fatty γ-lactones, corresponding to 4-hydroxy fatty acids, was also explored. [ABSTRACT FROM AUTHOR]

Sunlight or LED 370 nm irradiation mediates the direct coupling of carboxylic acids to I N,O i -dimethylhydroxylamine or morpholine in the presence of 4-dimethylaminopyridine and bromotrichloromethane, providing the corresponding amides in satisfactory to high yields. A Photochemical Protocol for the Synthesis of Weinreb and Morpholine Amides from Carboxylic Acids Cover Feature: (Eur. J. Org. B The Cover Feature b illustrates the photochemical conversion of carboxylic acids to Weinreb and morpholine amides. [Extracted from the article]

[Display omitted] • Corinthian currant consumption leads to polar phenol detection in rat brain. • Isoquercetin was detected in Corinthian currant for the first time. • Isoquercetin brain content was higher in the Corinthian currant supplemented rats. • Optimized raw brain SPE extraction resulted in polar phenol detection by UPLC-HRMS. • Rat hippocampus content of four polar phenols was higher after currant consumption. This study aimed to validate a rapid and selective bioanalytical method, using UHPLC-Orbitrap MS, for the determination of brain polar phenolics and to apply it in rats that orally consumed Corinthian currant for 38 days. Corinthian currant, is a dried vine fruit rich in polar phenolics that potentially penetrate the brain. During method optimization fresh and lyophilized tissues were comparatively studied along with different solid-phase extraction cartridges; satisfactory recoveries (>80%) for almost all analytes were attained using fresh tissues and Oasis® HLB cartridges. Brain regional levels in phenol concentrations were then determined; isoquercetin showed higher concentrations in frontal cortex, hippocampus and cerebellum (14.0 ± 5.5, 6.6 ± 2.0, and 2.9 ± 1.3 ng/g tissue, respectively); rutin and gallic acid in cerebellum and isorhamnetin, quercetin and rutin in hippocampus of the Corinthian currant supplemented rat group compared to the control. This is the first study investigating polar phenolics' accumulation in rat brain after Corinthian currant supplementation. [ABSTRACT FROM AUTHOR]

Autoimmune β-cell death leads to type 1 diabetes, and with findings that Ca(2+)-independent phospholipase A2β (iPLA2β) activation contributes to β-cell death, we assessed the effects of iPLA2β inhibition on diabetes development. Administration of FKGK18, a reversible iPLA2β inhibitor, to NOD female mice significantly reduced diabetes incidence in association with 1) reduced insulitis, reflected by reductions in CD4(+) T cells and B cells; 2) improved glucose homeostasis; 3) higher circulating insulin; and 4) β-cell preservation. Furthermore, FKGK18 inhibited production of tumor necrosis factor-α (TNF-α) from CD4(+) T cells and antibodies from B cells, suggesting modulation of immune cell responses by iPLA2β-derived products. Consistent with this, 1) adoptive transfer of diabetes by CD4(+) T cells to immunodeficient and diabetes-resistant NOD.scid mice was mitigated by FKGK18 pretreatment and 2) TNF-α production from CD4(+) T cells was reduced by inhibitors of cyclooxygenase and 12-lipoxygenase, which metabolize arachidonic acid to generate bioactive inflammatory eicosanoids. However, adoptive transfer of diabetes was not prevented when mice were administered FKGK18-pretreated T cells or when FKGK18 administration was initiated with T-cell transfer. The present observations suggest that iPLA2β-derived lipid signals modulate immune cell responses, raising the possibility that early inhibition of iPLA2β may be beneficial in ameliorating autoimmune destruction of β-cells and mitigating type 1 diabetes development. [ABSTRACT FROM AUTHOR]

Autoimmune β-cell death leads to type 1 diabetes, and with findings that Ca2+-independent phospholipase A2b (iPLA2β) activation contributes to β-cell death, we assessed the effects of iPLA2β inhibition on diabetes development. Administration of FKGK18, a reversible iPLA2β inhibitor, to NOD female mice significantly reduced diabetes incidence in association with 1) reduced insulitis, reflected by reductions in CD4+ T cells and B cells; 2) improved glucose homeostasis; 3) higher circulating insulin; and 4) β-cell preservation. Furthermore, FKGK18 inhibited production of tumor necrosis factor-α (TNF-α) from CD4+ T cells and antibodies from B cells, suggesting modulation of immune cell responses by iPLA2b-derived products. Consistent with this, 1) adoptive transfer of diabetes by CD4+ T cells to immunodeficient and diabetes-resistant NOD.scid mice was mitigated by FKGK18 pretreatment and 2) TNF-α production from CD4+ T cells was reduced by inhibitors of cyclooxygenase and 12- lipoxygenase, which metabolize arachidonic acid to generate bioactive inflammatory eicosanoids. However, adoptive transfer of diabetes was not prevented when mice were administered FKGK18-pretreated T cells or when FKGK18 administration was initiated with T-cell transfer. The present observations suggest that iPLA2βb-derived lipid signals modulate immune cell responses, raising the possibility that early inhibition of iPLA2b may be beneficial in ameliorating autoimmune destruction of β-cells and mitigating type 1 diabetes development. [ABSTRACT FROM AUTHOR]