Search Results (142)

Neuroinflammation, triggered by lipoxygenase (LOX), contributes to Alzheimer’s disease (AD) progression. Overexpression of LOX-5 in patients with AD serum highlights its role. This study assessed the efficacy of the LOX-inhibitor-peptide YWCS in an AD rat model induced by Aβ_25–35 injection. Cognitive tests, magnetic resonance imaging (MRI) scans, and molecular analyses were conducted. YWCS treatment significantly improved cognitive function, as evidenced by improved performance in the open field, novel object recognition, elevated plus maze, and Morris water maze tests. MRI scans revealed hippocampal shrinkage in AD rats and no changes were observed from YWCS treatment. Molecular analysis revealed altered expression of LOX-5, LOX-12, Aβ, γ-secretase components, p-Tau¹⁸¹, Akt, p-Akt, and p53 in AD rats. Immunofluorescence staining confirmed increased expression of LOX, Aβ, and p-Tau¹⁸¹ in the hippocampus of AD rats, which was reduced by YWCS treatment. Serum LOX levels were elevated in AD rats and significantly decreased after YWCS treatment, aligning with previous findings in human AD patients and AD cell models. YWCS offered improvements in behavioral and inflammatory marker regulation and also prevented progression of the disease, as shown by MRI results. These results suggest that YWCS, by targeting LOX, has the potential to be a promising therapeutic agent for AD. Full article

Beetroot (Beta vulgaris L.) is a plant grown for its roots, which are used to obtain sugar, feed animals, and for human use. Beetroot skin, a by-product of food processing, is a significant source of bioactive compounds, including dietary fiber and antioxidants. The primary objective of this work was to utilize beetroot skin powder to produce value-added nougat. Analytical methods, like antioxidant activity tests, proximate analysis, and sensory assessments, are used to determine the impact of beetroot skin powder on the final product. The beetroot skin powder extract had a remarkable content of phytochemicals and antioxidant activity. The inhibitory effect of the extract was tested on enzymes linked to metabolic syndrome, oxidative stress, and inflammation. The beetroot skin powder extract inhibited α-glucosidase, α-amylase, lipase, and lipoxygenase enzymes. The characterization of value-added nougat illustrates the multifunctionality of beetroot peel powder within its composition, serving as a significant source of natural compounds with antioxidant, coloring, and flavoring properties. This enhances sensory attributes, including color, aroma, and texture, augmenting product diversity and consumer appeal. This is evidenced by the increase in the total content of betalains (3.77 ± 0.09 mg/g DW.) and polyphenols (69.48 ± 2.88 mg GAE/100 g DW.), which lead to high antioxidant activity (73.89 ± 3.65 mM Trolox/100 g DW.) for the nougat sample with 6% added beetroot powder. Thus, beetroot skin powder replaced chemically synthesized additives with antioxidants and natural pigments, improving life quality and implicitly capitalizing on beetroot processing by-products, supporting circular economy principles at the global level. Full article

Retinol and retinol-related compounds are essential for human health, particularly in cellular protection, skin health, and the management of medical conditions. Retinol—a vital form of vitamin A—is obtained through the diet as preformed vitamin A or provitamin A carotenoids, retinyl esters. These compounds are indispensable for vision, immune function, and skin health. While retinoic acid has important known biological roles, its presence is limited in the body as it is rapidly metabolized rather than stored, emphasizing the need for sufficient dietary intake. This paper is divided into chapters that highlight important aspects of retinol and retinoid-related compounds, such as their sufficient intake through food sources. The nutritional value of carotenoids is influenced by the balance between trans- and cis-isomers in food, with food processing affecting their bioactivity. Next, it is metabolism in the digestive tract. The bioavailability and efficacy of retinoids are further influenced by gut microbiota, which can modulate immune function and the expression of the genes involved in retinoid metabolism. A third important property greatly influencing their biological function is their structure, predisposing them to certain biological activities. Both retinoids and carotenoids exert key antioxidant functions by protecting cells from oxidative damage, quenching singlet oxygen, and stabilizing free radicals. However, the oxidation of carotenoids can result in various metabolites, such as epoxides and hydroxyketones, that further create a higher demand for antioxidant defenses. Additionally, carotenoids interact with lipoxygenases (LOXs), thus influencing oxidative stress, although this interaction may reduce their antioxidant efficacy. First- and second-generation retinoids regulate gene expression related to skin cell function and oncological diseases. Despite their therapeutic benefits, long-term use carries risks, such as teratogenicity. Ongoing research should aim to enhance the safety, precision, and effectiveness of retinoid therapies, expanding their therapeutic potential. Full article

(6S,9R)-vomifoliol (VO) is a natural norisoprenoid of the megastigmane type derived from Gaultheria procumbens, an aromatic, evergreen shrub whose leaves, fruits, and aerial parts are used in traditional phytotherapy to treat oxidative stress and inflammation-related disorders. The plant is known as a rich source of essential oil and polyphenols. However, the levels of other constituents of G. procumbens, including VO, have yet to be explored. There is also a knowledge gap in the pharmacological potential of VO in the context of inflammation. Therefore, the present study aimed to investigate the accumulation of VO in leaves, stems, and fruits of G. procumbens and to determine its antioxidant and anti-inflammatory effects in non-cellular in vitro and cell-based models of human immune cells ex vivo. The GC-FID-MS (gas chromatography coupled with flame ionisation detector and mass spectrometer) analysis revealed the leaves as the richest source of VO (0.36 mg/g dw of the plant material) compared to other G. procumbens organs. In non-cellular activity tests, VO showed comparable to positive control anti-inflammatory activity against lipoxygenase, with significantly weaker impact on hyaluronidase and cyclooxygenase-2, and no effect on cyclooxygenase-1 isozyme. VO at 5–75 μM revealed a significant and dose-dependent ability to reduce the reactive oxygen species (ROS) level, downregulate the release of pro-inflammatory cytokines [tumour necrosis factor-α (TNF-α), interleukin-8 (IL-8), IL-6, and IL-1β] and tissue-remodelling enzymes (elastase-2, metalloproteinase-9), and up-regulate the secretion of anti-inflammatory cytokine IL-10 in bacterial lipopolysaccharide (LPS)- and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-stimulated human neutrophils and peripheral blood mononuclear cells (PBMCs) ex vivo. Furthermore, a significant reduction in IL-6, lipoxygenase (LOX), nuclear factor κ-light-chain-enhancer of activated B cells 1 (NF-κB1), and NF-κB2 gene expression in LPS-stimulated peripheral blood lymphocytes was demonstrated by real-time PCR. The cellular safety of VO at 5–75 μM was confirmed by flow cytometry, with the viability of neutrophils and PBMCs after incubation with VO at 93.8–98.4%. The results encourage further studies of VO as a promising non-cytotoxic natural anti-inflammatory agent and support the use of leaves of G. procumbens in the adjuvant treatment of oxidative stress and inflammation-related diseases of affluence. Full article

Esterified ARA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2), which is further metabolized by COXs and lipoxygenases (LOXs) and cytochrome P450 (CYP) enzymes. PGs produce detrimental effects due to their proinflammatory properties. The generation of prostaglandin (PG)G₂ and PGH₂ is triggered by cyclooxygenase (COX) isozymes such as COX-1 and COX-2. Prostaglandin E2 (PGE2) is significantly elevated in ASD. Considerable data indicate that COX enzymes and their metabolites of ARA play important roles in the initiation and development of human neurodevelopmental diseases. The involvement of disrupted COX2/PGE2 signaling in ASD pathology in changing neuronal cell behavior and the expression of ASD-related genes and proteins is due to disrupted COX2/PGE2 signaling. Prostacyclin (PGI2) is synthesized from arachidonic acid by metabolic-pathway-dependent cyclooxygenase (COX) and synthesized in a primary step of ARA transformation (PGG2, PGH2), by degradation of the abovementioned prostaglandins. Full article

Background: In this study, two chalcone analogs were synthesized through in silico and experimental methods, and their potential to inhibit the lipoxygenase enzyme, which plays a role in the inflammation pathway, was assessed. Specifically, this study is a continuation of previous research in which chalcone derivatives were synthesized and characterized. Objectives/Methods: In the current work, we present the re-synthesis of two chalcones, with a focus on their docking studies, NMR analysis, and dynamic simulations. The structure of each chalcone was elucidated through a combination of Nuclear Magnetic Resonance (NMR) and Density Functional Theory (DFT). The substituent effect on the absorption spectrum of the two chalcone derivatives was studied. Results: A “LOX–chalcone” complex, predicted by docking studies, was further examined using molecular dynamics (MD) simulations to evaluate the stability of the complex. After fully characterizing the “LOX–chalcone” complexes in silico, the atomic details of each chalcone’s interaction with LOX-1 and 5-LOX were revealed through Saturation Transfer Difference (STD) NMR (Nuclear Magnetic Resonance). Finally, their selectivity profile was investigated against human 15-LOX-1 and general Lipoxidase activity. Conclusions: The in silico methods suggest that chalcones could be promising lead compounds for drug designs targeting the LOX enzyme. Full article

Background/Objectives: Cationic surfactants are potential antimicrobial candidates. Even so, they are the foremost irritative and incompatible group, which limits their usage. The incorporation of surfactants in biopolymer-based nanoparticles is a feasible strategy to improve their efficacy and reduce those drawbacks. Methods: Surfactants with one amino acid on the polar head (lauroyl arginine methyl ester—LAM and phenylalanine dodecyl amide—PNHC₁₂) and surfactants with two amino acids on the polar heads, arginine-phenylalanine (Lauroyl phenylalanine arginine methyl esther—C₁₂PAM and phenylalanine-arginine dodecyl amide—PANHC₁₂) were loaded to zein nanoparticles. Their antimicrobial and antibiofilm activities were evaluated. Also, the inhibitory activities of the surfactants and nanoparticles over skin-related enzymes were accessed in silico and in vitro, while their cytotoxicity was determined comparatively over immortal human keratinocytes (HaCaT) and human fibroblasts (3T3). Finally, the Vibrio fisheri luminescence reduction test was used to detect its ecotoxicity. Results: The nanoparticles were obtained successfully and exhibited good biocide activity against a wide range of pathogenic bacteria and yeasts. The surfactants were found active over the enzymes assayed: elastase > tyrosinase > collagenase > lipoxygenase, while the inhibitory activity was superior when nanoencapsulated over the enzymes tyrosinase and lipoxygenase. The surfactants and their corresponding nanoparticles presented acceptable cytotoxic levels, except for PNHC₁₂ in both forms, while their ecotoxicity was limited and acceptable. Conclusions: Accordingly, the nanoencapsulation of the arginine-phenylalanine surfactants loaded to zein nanoparticles was found to be a smart strategy to enhance the antimicrobial activity and improve their selectivity over representative skin and connective tissues cell lines. These biological properties render the arginine-phenylalanine surfactant nanoparticles as promising candidates for antimicrobial and tissue repairing applications in wound treatments. Full article

Diabetic retinopathy (DR) is a salient cause of blindness worldwide. There is still an immense need to understand the pathophysiology of DR to discover better diagnostic and therapeutic modalities. Human retinal endothelial cells (HRECs) were treated with 15-HETE or D-glucose, then miRNAs were isolated, and a microarray was performed. MirWALK 2 and Ingenuity Pathway Analysis (IPA) were used to analyze the microarray results. Exosomal miRNAs from 15-HETE-treated HRECs were isolated, microarrayed, and then imported into IPA for further analysis. The microarray results showed that 15-HETE downregulated 343 miRNAs and upregulated 297 miRNAs in HRECs. High glucose treatment induced a differential expression of HREC-miRNAs where 185 miRNAs were downregulated and 244 were upregulated. Comparing the impact of 15-HETE versus DG or diabetic mouse retina elaborated commonly changing miRNAs. Pathway and target analysis for miRNAs changed in 15-HETE-treated HRECs revealed multiple targets and pathways that may be involved in 15-HETE-induced retinal endothelial dysfunction. The HREC-exosomal miRNAs were differentially expressed after 15-HETE treatment, with 34 miRNAs downregulated and 45 miRNAs upregulated, impacting different cellular pathways. Here, we show that 15-HETE induces various changes in the cellular and exosomal miRNA profile of HRECs, highlighting the importance of targeting the 12/15 lipoxygenase pathway in DR. Full article

The human genome involves six functional arachidonic acid (AA) lipoxygenase (ALOX) genes, and the corresponding enzymes (ALOX15, ALOX15B, ALOX12, ALOX12B, ALOXE3, ALOX5) have been implicated in cell differentiations and in the pathogenesis of inflammatory, hyperproliferative, metabolic, and neurological disorders. Humans express two different AA 15-lipoxygenating ALOX isoforms, and these enzymes are called ALOX15 (15-LOX1) and ALOX15B (15-LOX2). Chromosomal localization, sequence alignments, and comparison of the enzyme properties suggest that pig and mouse ALOX15 orthologs (leukocyte-type 12-LOX) on the one hand and rabbit and human ALOX15 orthologs on the other (reticulocyte-type 15-LOX1) belong to the same enzyme family despite their different reaction specificities with AA as a substrate. In contrast, human ALOX12 (platelet-type 12-LOX), as well as pig and mouse ALOX15 (leukocyte-type 12-LOX), belong to different enzyme families, although they exhibit a similar reaction specificity with AA as a substrate. The complex multiplicity of mammalian ALOX isoforms and the controversial enzyme nomenclatures are highly confusing and prompted us to summarize the current knowledge on the biological functions, enzymatic properties, and allosteric regulation mechanisms of mammalian ALOX15, ALOX15B, and ALOX12 orthologs that belong to three different enzyme sub-families. Full article

Pygeum africanum bark has been shown to inhibit the production of pro-inflammatory prostaglandins in the prostate and reduces the production of leukotrienes and other 5-lipoxygenase (5-LO) metabolites. It has been suggested that inflammation plays an important role in the pathophysiology of benign prostatic hyperplasia (BPH). Data from clinical trials have shown that P. africanum improves the symptoms and objective measures of BPH. This in vitro study aimed to assess the anti-inflammatory potential of a proprietary Pygeum bark standardized extract (Prunera^®) on cytokine release from lipopolysaccharide-stimulated human peripheral blood mononuclear cells (PBMCs). PBMCs were obtained from four donors, and a bead-based assay (ProcartaPlex™ panel) was used for the detection and quantitation of cytokines. Pygeum africanum bark standardized extract (PABE) induced a statistically significant decrease (p < 0.05) of IL-6 in three donors. Other effects were as follows: IL-2 was lowered in all donors in the absence of a clear dose–response relationship; IL-4, IL-5, IL-9, and IL-13 levels were decreased in most donors; IL-22 levels seemed to be suppressed only for donor 4 at lower and medium concentrations; and IL-27 and TNF-α levels decreased at all PABE concentrations in all donors. The anti-inflammatory effect of PABE, particularly the reduction in IL-6 as a marker of inflammation, supports the potential use of this natural compound in the management of BPH and other conditions in which pro-inflammatory cytokines are involved in their underlying pathophysiological mechanisms. Full article

Fabiana punensis S. C. Arroyo is a subshrub or shrub that is indigenous to the arid and semiarid region of northern Argentina and is known to possess several medicinal properties. The objective of this study was to optimize the extraction conditions so as to maximize the yield of bioactive total phenolic compound (TPC) and flavonoids (F) of F. punensis’ aerial parts by using non-conventional extraction methods, namely ultrasound-assisted extraction, UAE, and microwave-assisted extraction, MAE, and to compare the biological activities and toxicity of optimized extracts vs. conventional extracts, i.e., those gained by maceration. Response Surface Methodology (RSM) was used to apply factorial designs to optimize the parameters of extraction: solid-to-liquid ratio, extraction time, ultrasound amplitude, and microwave power. The experimental values for TPC and F and antioxidant activity under the optimal extraction conditions were not significantly different from the predicted values, demonstrating the accuracy of the mathematical models. Similar HPLC-DAD patterns were found between conventional and UAE- and MAE-optimized extracts. The main constituents of the extracts correspond to phenolic compounds (flavonoids and phenolic acids) and apigenin was identified. All extracts showed high scavenger capacity on ABTS^•+, O₂^•− and H₂O₂, enabling the inhibition of the pro-inflammatory enzymes xanthine oxidase (XO) and lipoxygenase (LOX). They also showed an antimutagenic effect in Salmonella Typhimurium assay and cytotoxic/anti-proliferative activity on human melanoma cells (SKMEL-28). Toxicological evaluation indicates its safety. The results of this work are important in the development of efficient and sustainable methods for obtaining bioactive compounds from F. punensis for the prevention of chronic degenerative diseases associated with oxidative stress, inflammation, and DNA damage. Full article

In a landmark study, oleocanthal (OLC), a major phenolic in extra virgin olive oil (EVOO), was found to possess anti-inflammatory activity similar to ibuprofen, involving inhibition of cyclooxygenase (COX) enzymes. EVOO is a rich source of bioactive compounds including fatty acids and phenolics; however, the biological activities of only a small subset of compounds associated with Olea europaea have been explored. Here, the OliveNet^TM library (consisting of over 600 compounds) was utilized to investigate olive-derived compounds as potential modulators of the arachidonic acid pathway. Our first aim was to perform enzymatic assays to evaluate the inhibitory activity of a selection of phenolic compounds and fatty acids against COX isoforms (COX-1 and COX-2) and 15-lipoxygenase (15-LOX). Olive compounds were found to inhibit COX isoforms, with minimal activity against 15-LOX. Subsequent molecular docking indicated that the olive compounds possess strong binding affinities for the active site of COX isoforms, and molecular dynamics (MD) simulations confirmed the stability of binding. Moreover, olive compounds were predicted to have favorable pharmacokinetic properties, including a readiness to cross biological membranes as highlighted by steered MD simulations and umbrella sampling. Importantly, olive compounds including OLC were identified as non-inhibitors of the human ether-à-go-go-related gene (hERG) channel based on patch clamp assays. Overall, this study extends our understanding of the bioactivity of Olea-europaea-derived compounds, many of which are now known to be, at least in part, accountable for the beneficial health effects of the Mediterranean diet. Full article

Apples are rich in phytochemicals useful for human health. However, environmental factors can greatly affect the accumulation of these compounds. To face this problem, the callus culture technique was used to obtain large quantities of phytochemicals. Specifically, two callus cultures were obtained from ripe Annurca apple pulp (Malus pumila cv Miller) and cultivated under different light conditions: darkness and an 18-h photoperiod. The hydro-alcoholic extracts from the calli underwent analysis using GC-MS, GC-FID, and HPLC-DAD-ESI-MSⁿ to determine the qualitative and quantitative content of phenolic and triterpenic acids. The study revealed the predominant presence of triterpenic compounds in both calli. Furthermore, we investigated their radical scavenging and antioxidant activities through DPPH, ABTS, ORAC assays, and lipoxygenase inhibition activity. Genoprotection was evaluated via nicking assay, and the anti-inflammatory effect was investigated via Griess assay on LPS-injured murine macrophages. All the analyses performed were compared with peel and pulp hydroalcoholic extracts. The results showed that both calli primarily show anti-inflammatory activity and moderate antioxidant effect and can protect DNA against oxidative stimuli. This data encouraged further research aimed at utilizing callus as a bioreactor to produce secondary metabolites for use in preventive and therapeutic applications to combat acute or chronic age-associated diseases. Full article

Research over the last 25 years related to structural elucidations and biological investigations of the specialized pro-resolving mediators has spurred great interest in targeting these endogenous products in total synthesis. These lipid mediators govern the resolution of inflammation as potent and stereoselective agonists toward individual G-protein-coupled receptors, resulting in potent anti-inflammatory activities demonstrated in many human disease models. Specialized pro-resolving mediators are oxygenated polyunsaturated products formed in stereoselective and distinct biosynthetic pathways initiated by various lipoxygenase and cyclooxygenase enzymes. In this review, the reported stereoselective total synthesis and biological activities of the specialized pro-resolving mediators biosynthesized from the polyunsaturated fatty acid n-3 docosapentaenoic acid are presented. Full article

Here, we demonstrate that human neutrophil interaction with the bacterium Salmonella typhimurium fuels leukotriene B4 synthesis induced by the chemoattractant fMLP. In this work, we found that extracellular ATP (eATP), the amount of which increases sharply during tissue damage, can effectively regulate fMLP-induced leukotriene B4 synthesis. The vector of influence strongly depends on the particular stage of sequential stimulation of neutrophils by bacteria and on the stage at which fMLP purinergic signaling occurs. Activation of 5-lipoxygenase (5-LOX), key enzyme of leukotriene biosynthesis, depends on an increase in the cytosolic concentration of Ca²⁺. We demonstrate that eATP treatment prior to fMLP, by markedly reducing the amplitude of the fMLP-induced Ca²⁺ transient jump, inhibits leukotriene synthesis. At the same time, when added with or shortly after fMLP, eATP effectively potentiates arachidonic acid metabolism, including by Ca²⁺ fluxes stimulation. Flufenamic acid, glibenclamide, and calmodulin antagonist R24571, all of which block calcium signaling in different ways, all suppressed 5-LOX product synthesis in our experimental model, indicating the dominance of calcium-mediated mechanisms in eATP regulatory potential. Investigation into the adhesive properties of neutrophils revealed the formation of cell clusters when adding fMLP to neutrophils exposed to the bacterium Salmonella typhimurium. eATP added simultaneously with fMLP supported neutrophil polarization and clustering. A cell-derived chemoattractant such as leukotriene B4 plays a crucial role in the recruitment of additional neutrophils to the foci of tissue damage or pathogen invasion, and eATP, through the dynamics of changes in [Ca²⁺]_i, plays an important decisive role in fMLP-induced leukotrienes synthesis during neutrophil interactions with the bacterium Salmonella typhimurium. Full article