Plant-based yogurts are rapidly emerging in the food market due to veganism, health and environmental issues. The aim of this work is the profiling of fatty acids (FAs) and phenolic compounds in plant-based yogurts from the Greek market. A fast liquid chromatography-high resolution mass spectrometry (LC-HRMS) method is applied for the determination of free fatty acids (FFAs) in plant-based yogurts, and a conventional gas chromatography-mass spectrometry method (GC-MS) for total FA composition. A UHPLC-Orbitrap MS method is employed for the determination of phenolic compounds too. Seven plant-based yogurts, including almond-, soy-, coconut-, and oat-based products, were analyzed. Regarding oat, almond, and soy yogurts, the major constituents were linoleic, oleic, palmitic and stearic acids in both FFAs and total FAs, while in coconut yogurts, lauric and myristic acids were also prominent, amounting to 73.8 % of total FAs and 20.1 % of FFAs. Bioactive saturated hydroxy FAs were detected in plant-based yogurts for the first time, with 6-hydroxypalmitic and 12-hydroxystearic acids being the most abundant. The phenolic profile in the tested samples was consistent with the phenolic composition of the raw ingredients used in the products, while a suspect screening approach enabled the semi-quantification of avenanthramides A, B, and C in oat-based yogurt.

The diverse synthetic applications offered by the — so far not widely explored — excited-state catalysis has intensified the need for development of new EnT catalysts. Herein, we uncover the high efficiency of an unrecognized class, aromatic aldehydes, as EnT photocatalysts. Structure-catalytic efficiency relationship studies on a wide range of common, commercially available and cheap aromatic aldehydes led to the discovery that several aldehydes, for example biphenyl-4-carboxaldehyde, 1-naphthaldehyde and 2-methoxy-1-naphthaldehyde, are highly efficient catalysts for [2+2] cycloadditions and isomerizations under UVA irradiation. To explore the theoretical underpinnings of this catalysis, computational studies combined with principal component analysis suggested that both energy factors and aromaticity/antiaromaticity of ground and excited states contribute to the overall outcome. A wide substrate scope for cyclobutanes/cyclobutenes construction by the addition of alkenes/alkynes to N -arylmaleimides along with dimethyl fumarate isomerization and the dimerization of cinnamates to truxinates demonstrated the wide potential of aromatic aldehydes, expanding the EnT photocatalyst-space.

The SARS-CoV-2 main protease (Mpro), an enzyme essential for viral replication and lacking a human homologue, has emerged as a highly attractive target for the development of novel antiviral agents. Although several Mpro inhibitors have been developed — some receiving regulatory approval — their use is sometimes limited by drug-drug interactions. In this study, we designed and synthesized peptidomimetic SARS-CoV-2 Mpro inhibitors incorporating a novel thiazolyl 4-carboxylate ketone warhead, previously employed by our group in the development of cytosolic phospholipase A2 inhibitors. The synthesized compounds were evaluated for their in vitro inhibitory potency against SARS-CoV-2 Mpro, and a highly potent Mpro inhibitor (GK730) was identified (IC50 5.75 nM). The melting temperature of the Mpro-GK730 complex revealed high stability, consistent with the high inhibitory potency. The X-ray crystal structures of inhibitors GK729 and GK730 bound to Mpro were determined, providing insights into the binding interactions and mechanism of action. Studies on the host cell proteases cathepsin B and L showed that GK730 did not inhibit cathepsin B, while exhibited weak inhibition of cathepsin L. Furthermore, GK730 demonstrated an EC50 value of 5.70 μM against a wild-type SARS-CoV-2 strain in Vero E6 cells and minimal cytotoxicity (CC50 value greater than 100 μM).

Phospholipase A2 (PLA2) constitutes a superfamily of enzymes that hydrolyze the sn-2 fatty acyl chain of glycerophospholipids. Polyunsaturated fatty acids (PUFAs) are preferentially attached at the sn-2 position of glycerophospholipids and are easily truncated by oxidation. The truncated-oxidized phospholipids (tr-oxPLs) trigger various cellular responses, and PLA2s may play a critical role in the metabolism of the tr-oxPLs by removing the oxidized sn-2 chain. In the present study, we demonstrated using an in vitro lipidomics assay that Group VIA calcium-independent PLA2 (GVIA iPLA2) showed high activity toward phosphatidylcholine with a 9-oxononanoyl chain, but not with an azelaoyl chain on the sn-2 position. We conducted molecular dynamics simulations which revealed that the hydrophilicity of the sn-2 acyl chain critically affects the binding of the substrate in the active site. Based on the unique specificity of GVIA iPLA2 toward tr-oxPLs, we synthesized an oxidatively modified inhibitor (GK766) for GVIA iPLA2, aiming for improvement of its selectivity and/or potency. As we expected, the modified inhibitor improved its selectivity of GVIA iPLA2 compared to the unmodified inhibitor (GK187), although the inhibitory effect became somewhat weaker. More importantly, we demonstrated that GK766 induces cell death by ferroptosis more effectively than GK187 using an erythroleukemia cell line. In the present study, we have further defined the unique substrate specificity of GVIA iPLA2 toward tr-oxPLs and its molecular mechanism. Furthermore, we have developed a novel specificity-based inhibitor that induces ferroptosis demonstrating that using substrate selectivity helps in developing more effective therapeutics.

The development of novel methods for the synthesis of substituted benzoxazoles is of wide interest, since such heterocyclic compounds exhibit various bioactivities. We report herein an efficient photochemical protocol for the oxidative cyclization of glycine derivatives to produce 2-substituted benzoxazoles bearing ester or amide moieties. Cheap and commercially available 1,8-dihydroxyanthraquinone serves as the organocatalyst in the presence of a nonprecious salt (CuI), while Kessil LED 427 nm is the source of irradiation. An extended substrate scope proves the generality of the method, which operates under mild conditions and in line with the principles of green chemistry. Direct infusion-high resolution mass spectrometry studies supported the proposal of the reaction mechanism. Furthermore, ease derivatization of selected benzoxazole 2-carboxylates/carboxamides demonstrates their utility as versatile intermediates for the synthesis of a wide range of compounds, thereby highlighting the value and broader applicability of the new photochemical protocol.

BACKGROUND:Lactate dehydrogenase A (LDHA) can regulate tumorigenesis and cancer progression. Nevertheless, whether the regulation of LDHA is involved in the development of gemcitabine resistance in PDAC has not yet been fully elucidated. Increasing studies have shown that cancer acquired drug resistance led to treatment failure is highly attributed to the cancer stem cell (CSC) properties. Therefore, we aim to demonstrate the functions and regulatory mechanisms of LDHA on cancer stem cell (CSC) properties and gemcitabine resistance in PDAC. METHODS:We investigate the metabolite profiles by liquid chromatography-mass spectrometry between gemcitabine-resistant PDAC and parental PDAC cells. Additionally, gain-of-function and loss-of-function experiments were conducted to examine the roles of LDHA on CSC properties and gemcitabine resistance in the gemcitabine-resistant PDAC and parental PDAC cells. To investigate regulators involved in LDHA-mediated gemcitabine resistance and CSC of pancreatic cancer cells, we further used a combination of the miRNA microarray results and software predictions and confirmed that miR-4259 is a direct target of LDHA by luciferase assay. Furthermore, we constructed serial miR-4259 promoter reporters and searched for response elements using the TESS 2.0/TFSEARCH software to find the transcription factor binding site in the promoter region of miR-4259. RESULTS:We observed that elevated LDHA expression significantly correlates with recurrent pancreatic cancer patients following gemcitabine treatment and with CSC properties. We further identify that FOXO3a-induced miR-4259 directly targets the 3'untranslated region of LDHA and reduced LDHA expression, leading to decreased gemcitabine resistance and a reduction in the CSC phenotypes of pancreatic cancer. CONCLUSION:Our results demonstrated that LDHA plays a critical role in cancer stemness and gemcitabine resistance of pancreatic cancer, and indicate that targeting the FOXO3a/miR-4259/LDHA pathway might serve as a new treatment for pancreatic cancer patients with a poor response to gemcitabine chemotherapy.

Inhibitors of cytosolic phospholipase A2 (GIVA cPLA2) have received great attention, since this enzyme is involved in a number of inflammatory diseases, including cancer and auto-immune and neurodegenerative diseases. Traditionally, the effects of GIVA cPLA2 inhibitors in cells have been studied by determining the inhibition of arachidonic acid release. However, although to a lesser extent, GIVA cPLA2 may also hydrolyze glycerophospholipids, releasing other free fatty acids (FFAs), such as linoleic acid or oleic acid. In the present work, we applied a liquid chromatography–high-resolution mass spectrometry method to study the levels of intracellular FFAs, after treating cells with selected GIVA cPLA2 inhibitors. Six inhibitors belonging to different chemical classes were studied, using SH-SY5Y neuroblastoma cells as a model. This lipidomic approach revealed that treatment with each inhibitor created a distinct intracellular FFA profile, suggesting not only inhibitory potency against GIVA cPLA2, but also other parameters affecting the outcome. Potent inhibitors were found to reduce not only arachidonic acid, but also other long-chain FAs, such as adrenic or linoleic acid, even medium-chain FAs, such as caproic or caprylic acid, suggesting that GIVA cPLA2 inhibitors may affect FA metabolic pathways in general. The downregulation of intracellular FFAs may have implications in reprogramming FA metabolism in neurodegenerative diseases and cancer.

Gemcitabine resistance (GR) remains a major clinical challenge in the treatment of pancreatic cancer and often develops within weeks of therapy, largely due to the persistence of cancer stem cells (CSCs). In our previous study, we demonstrated that eicosapentaenoic acid (EPA), a well-known dietary fatty acid with antioxidant and anti-tumor properties, inhibited the growth of KRAS-mutant pancreatic cancer cells by suppressing STAT3 phosphorylation. In this study, we established gemcitabine-resistant murine pancreatic ductal adenocarcinoma (PDAC) cells, designated Panc02-GR, and confirmed that these cells exhibit enhanced tumorigenicity and elevated expression of CSC markers. We investigated the effects of three naturally occurring hydroxy stearic acids (HSAs), commonly found in dairy products, on Panc02-GR cells. These compounds significantly reduced cell viability and downregulated the expression of STAT3, Sox2, and c-Myc at the transcriptional level. Proteomic analysis revealed that HSAs suppressed the expression of mitochondrial proteins associated with Complex I and III of the electron transport chain, the tricarboxylic acid (TCA) cycle, and mitochondrial ribosomal components. Among them, 7-R-hydroxystearic acid (7RHSA) most prominently repressed mitochondrial complex subunit proteins, suggesting that HSAs inhibit pancreatic CSCs by disrupting mitochondrial biogenesis and metabolism. These findings support the potential of hydroxy stearic acids as promising therapeutic agents against gemcitabine-resistant pancreatic cancer.

Eicosanoids are key players in inflammatory diseases and cancer. Targeting their production by inhibiting Group IVA cytosolic phospholipase A2 (cPLA2α) offers a promising approach for cancer therapy. In this study, we synthesize a second generation of thiazolyl ketone inhibitors of cPLA2α starting with compound GK470 (AVX235) and test their in vitro and cellular activities. We identify a more potent and selective lead molecule, GK420 (AVX420), which we test in parallel with AVX235 and a structurally unrelated compound, AVX002 for inhibition of cell viability across a panel of cancer cell lines. From this, we show that activity of polycomb group repressive complex 2 is a key molecular determinant of sensitivity to cPLA2α inhibition, while resistance depends on antioxidant response pathways. Consistent with these results, we show that elevated intracellular reactive oxygen species and activating transcription factor 4 target gene expression precede cell death in AVX420-sensitive T-cell acute lymphoblastic leukemia cells. Our findings imply cPLA2α may support cancer by mitigating oxidative stress and inhibiting tumor suppressor expression and suggest that AVX420 has potential for treating acute leukemias and other cancers that are susceptible to oxidative cell death.

Synthetic photochemistry is an alternative, green and sustainable approach in organic synthesis, offering the possibility for the discovery of novel reactivities. Carboxylic acids are abundant and widely used as suitable radical precursors for light-mediated processes, providing access to products that are not accessible via conventional methods. Herein, we report a green, cheap, metal-free, photochemical decarboxylative protocol for the 1,4-radical conjugate addition (Giese reaction) using thioxanthone, a commercially available organic molecule, or a thioxanthone-triflic acid (TfOH) complex, as the photocatalyst, under LED 427 nm irradiation. A wide range of carboxylic acids, amino acids and Michael acceptors has been tested, affording the desired products in good to high yields.

Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) have emerged as extraordinary bioactive lipids, exhibiting diverse bioactivities, from the enhancement of insulin secretion and the optimization of blood glucose absorption to anti-inflammatory effects. The intricate nature of FAHFAs’ structure reflects a synthetic challenge that requires the strategic introduction of ester bonds along the hydroxy fatty acid chain. Our research seeks to create an effective methodology for generating varied FAHFA derivatives. Our primary approach centers on a photochemical hydroacylation reaction, merging terminal alkenes, either ω-alkenoic acids or ω-alkenyl alcohols, with commercially available aldehydes. This transformative, environmentally friendly process, orchestrated by phenylglyoxylic acid as the photoinitiator, serves as the linchpin in establishing a practical and relatively simple method for constructing a library of racemic FAHFAs. The ketones produced by the photochemical reactions are easily converted to hydroxy derivatives, which are coupled with caproic, palmitic, or oleic acid, providing a large set of FAHFAs, which broaden our ability for future structure–activity relationship studies.

Light-mediated processes have received significant attention, since they have re-surfaced unconventional reactivity platforms, complementary to conventional polar chemistry. gamma-Lactones and cyclopropanes are prevalent moieties, found in numerous natural products and pharmaceuticals. Among various methods for their synthesis, light-mediated protocols are coming to the spotlight, although these are contingent upon the use of photoorgano- or metal-based catalysts. Herein, we introduce a novel photochemical activation of iodo-reagents via the use of cheap sodium ascorbate or ascorbic acid to enable their homolytic scission and addition onto double bonds. The developed protocol was applied successfully to the formal [3+2] cycloaddition for the synthesis of gamma-lactones, traditional atom transfer radical addition (ATRA) reactions and the one-pot two-step conversion of alkenes to cyclopropanes. In all cases, the desired products were obtained in good to high yields, while the reaction mechanism was thoroughly investigated. Depending on the nature of the iodo-reagent, a halogen or a hydrogen-bonded complex is formed, which initiates the process. Photochemistry: A direct and mild photochemical synthesis of lactones, cyclopropanes and ATRA products, utilizing sodium ascorbate or ascorbic acid as the halogen/hydrogen bonding mediator and irradiation at 370 nm, 390 nm or 427 nm LED as the irradiation source. A variety of iodo-reagents were activated via halogen or hydrogen bonding and reacted successfully with a number of alkenes without the use of an external photocatalyst, leading to products in good to excellent yields (up to 95 % yield).** image

Plastic pollution constitutes an evergrowing urgent environmental problem, since overaccumulation of plastic waste, arising from the immense increase of the production of disposable plastic products, overcame planet's capacity to properly handle them. Chemical upcycling of polystyrene constitutes a convenient method for the conversion of plastic waste into high-added value chemicals, suggesting an attractive perspective in dealing with the environmental crisis. We demonstrate herein a novel, easy-to-perform organocatalytic photoinduced aerobic protocol, which proceeds via synergistic indirect hydrogen atom transfer (HAT) catalysis under LED 390 nm Kessil lamps as the irradiation source. The developed method employs a BrCH2CN-thioxanthone photocatalytic system and was successfully applied to a variety of everyday-life plastic products, leading to the isolation of benzoic acid after simple base-acid work up in yields varying from 23-49 %, while a large-scale experiment was successfully performed, suggesting that the photocatalytic step is susceptible to industrial application. Upcycling of plastic waste constitutes an excellent solution to the rising problem of plastic waste treatment. Synergistic HAT catalysis from thioxanthone and bromoacetonitrile is introduced for the photochemical aerobic upcycling of polystyrene plastics into benzoic acid. image

Hydroxy fatty acids (HFAs) constitute a class of lipids, distinguished by the presence of a hydroxyl on a long aliphatic chain. This study aims to expand our insights into HFA bioactivities, while also introducing new methods for asymmetrically synthesizing unsaturated and saturated HFAs. Simultaneously, a procedure previously established by us was adapted to generate new HFA regioisomers. An organocatalytic step was employed for the synthesis of chiral terminal epoxides, which either by alkynylation or by Grignard reagents resulted in unsaturated or saturated chiral secondary alcohols and, ultimately, HFAs. 7-(S)-Hydroxyoleic acid (7SHOA), 7-(S)-hydroxypalmitoleic acid (7SHPOA) and 7-(R)- and (S)-hydroxymargaric acids (7HMAs) were synthesized for the first time and, together with regioisomers of (R)- and (S)-hydroxypalmitic acids (HPAs) and hydroxystearic acids (HSAs), whose biological activity has not been tested so far, were studied for their antiproliferative activities. The unsaturation of the long chain, as well as an odd-numbered (C17) fatty acid chain, led to reduced activity, while the new 6-(S)-HPA regioisomer was identified as exhibiting potent antiproliferative activity in A549 cells. 6SHPA induced acetylation of histone 3 in A549 cells, without affecting acetylated α-tubulin levels, suggesting the selective inhibition of histone deacetylase (HDAC) class I enzymes, and was found to inhibit signal transducer and activator of transcription 3 (STAT3) expression.

The synthesis of indoles and their derivatives, more specifically bis(indolyl)methanes (BIMs), has been an area of great interest in organic chemistry, since these compounds exhibit a range of interesting biological and pharmacological properties. BIMs are naturally found in cruciferous vegetables and have been shown to be effective antifungal, antibacterial, anti-inflammatory, and even anticancer agents. Traditionally, the synthesis of BIMs has been achieved upon the acidic condensation of an aldehyde with indole, utilizing a variety of protic or Lewis acids. However, due to the increased environmental awareness of our society, the focus has shifted towards the development of greener synthetic technologies, like photocatalysis, organocatalysis, the use of nanocatalysts, microwave irradiation, ball milling, continuous flow, and many more. Thus, in this review, we summarize the medicinal properties of BIMs and the developed BIM synthetic protocols, utilizing the reaction between aldehydes with indoles, while focusing on the more environmentally friendly methods developed over the years.

Synthetic photochemistry is a research field, where organic transformations are promoted by the presence of photoactive species, under light irradiation. In particular, the sub-field of photoorganocatalysis, where organic molecules are used as photocatalysts, has been launched as a "green" and sustainable approach. Carbon allotrope nanostructures (CANs) and their derivatives exhibit unique photophysical and photochemical properties, which have been exploited for the preparation of efficient metal-free and sustainable photocatalytic systems. This review summarizes the progress on the field of photochemical carbocatalysis, presenting the achievements by fullerene-, carbon nanotube- and graphene-based nanomaterials. Additionally, future prospects for CAN-based nanomaterials as photochemical promoters for organic transformations are also mentioned. Owing to their extraordinary properties, carbon allotrope nanostructures are in the pole position of materials toward a sustainable planet. Fullerene-, carbon nanotube- and graphene-based nanomaterials have been employed efficiently as metal-free photocatalysts into organic transformations. In this review, the progress on the field of photochemical carbocatalysis and its perspectives are mentioned. image

The pervasive effects of plastic waste pollution affect both humanity and the environment, thus innovative and environmentally-friendly methods for recycling of plastics are crucially needed. The application of light to degrade or transform plastics into valuable products has gained significant attention. Numerous researchers have explored irradiation to achieve the photocatalytic breakdown of highly resilient plastic waste components into valuable monomers, which can be utilized for the synthesis of novel materials of synthetic or pharmacological interest. Many of these techniques have resulted in H2 evolution, while efforts were also made to reduce carbon emissions. In some cases, light was combined with additional energy sources, leading to development of photothermal or photoelectrochemical processes. With this tutorial review, our aim is to offer an overview of these novel photochemical upcycling protocols for the degradation of polymers, aspiring toward the introduction of novel processes in the near future. Recent developments in the photochemical upcycling and recycling of plastics.

Histone deacetylases (HDACs) are enzymes that play an essential role in the onset and progression of cancer. As a consequence, a variety of HDAC inhibitors (HDACis) have been developed as potent anticancer agents, several of which have been approved by the FDA for cancer treatment. However, recent accumulated research results have suggested that HDACs are also involved in several other pathophysiological conditions, such as fibrotic, inflammatory, neurodegenerative, and autoimmune diseases. Very recently, the HDAC inhibitor givinostat has been approved by the FDA for an indication beyond cancer: the treatment of Duchenne muscular dystrophy. In recent years, more and more HDACis have been developed as tools to understand the role that HDACs play in various disorders and as a novel therapeutic approach to fight various diseases other than cancer. In the present perspective article, we discuss the development and study of HDACis as anti-fibrotic and anti-inflammatory agents, covering the period from 2020–2024. We envision that the discovery of selective inhibitors targeting specific HDAC isozymes will allow the elucidation of the role of HDACs in various pathological processes and will lead to the development of promising treatments for such diseases.

The phenol moiety appears in a wide variety of natural products, exhibiting biological activity, and in numerous active pharmaceutical compounds. Boronic acids are potential precursors of the phenol scaffold, and a plethora of efforts has been focused in developing novel and green protocols, targeting their chemoselective transformation into phenols. Photochemistry is a rapidly expanding research field converting light energy into chemical potential. Photochemical aerobic processes possess additional advantages to photochemistry and may find applications in chemical industries. Herein, a low-catalyst-loading anthraquinone-catalyzed photochemical process is demonstrated, under CFL lamp irradiation, while exploiting 2-Me-THF as the reaction medium for the conversion of boronic acids into phenols. Furthermore, a broad substrate scope was employed.

Arylazo sulfones were used as Photoacid Generators (PAGs) for the visible-light photorelease of strong sulfonic acids to promote the ring opening of epoxides in benign media (DMC/water mixtures) or under neat conditions. Water, alcohols, azide and thiocyanate anions, as well as electron-rich aromatics were used in the role of the nucleophile. The resulting 1,2-disubstituted adducts were formed mostly in >99% yield in a high regioselective fashion.