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Optimal omega-3 status, influenced by increased intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), is vital for physiological health. This study investigated the impact of ad libitum fish oil supplementation on the omega-3 status of female athletes in a professional rugby league team during a competitive season. Twenty-four (n = 24) athletes participated, and their omega-3 status was assessed using the Omega-3 Index (O3I) and arachidonic acid (AA) to EPA ratio through finger-prick blood samples taken at the start and end of the season. They were given access to a fish oil supplement (PILLAR Performance, Australia) with a recommended daily dose of four capsules per day (2,160 mg EPA and 1,440 mg docosahexaenoic acid). At the beginning of the season, the group mean O3I was 4.77% (95% confidence interval [CI: 4.50, 5.04]) and the AA to EPA ratio was 14.89 (95% CI [13.22, 16.55]). None of the athletes had an O3I exceeding 8%. By the season's end, the O3I was a significantly increased to 7.28% (95% CI [6.64, 7.93], p <.0001) and AA to EPA ratio significantly decreased to a mean of 6.67 (95% CI [5.02, 8.31], p <.0001), driven primarily by the significant increase in EPA of +1.14% (95% CI [0.77, 1.51], p <.0001). However, these changes were varied between the athletes and most likely due to compliance. This study has demonstrated that using the objective O3I feedback scale is possible with elite female rugby athletes, but individual strategies will be required to achieve daily intake targets of EPA + DHA. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BPD) is a debilitating mood disorder with an unclear etiology. A better understanding of the underlying pathophysiological mechanisms will help to identify novel targets for improved treatment options and prevention strategies. In this metabolome-wide Mendelian randomization study, we screened for metabolites that may have a causal role in BPD. We tested a total of 913 circulating metabolite exposures assessed in 14,296 Europeans using a mass spectrometry-based platform. For the BPD outcome, we used summary data from the largest and most recent genome-wide association study reported to date, including 41,917 BPD cases. We identified 33 metabolites associated with BPD (p adjusted < 5.48 × 10−5). Most of them were lipids, including arachidonic acid (β = −0.154, SE = 0.023, p = 3.30 × 10−11), a polyunsaturated omega-6 fatty acid, along with several complex lipids containing either an arachidonic or a linoleic fatty acid side chain. These associations did not extend to other closely related psychiatric disorders like schizophrenia or depression, although they may be involved in the regulation of lithium response. These lipid associations were driven by genetic variants within the FADS1/2/3 gene cluster, which is a robust BPD risk locus encoding a family of fatty acid desaturase enzymes that are responsible for catalyzing the conversion of linoleic acid into arachidonic acid. Statistical colocalization analyses indicated that 27 of the 33 metabolites shared the same genetic etiology with BPD at the FADS1/2/3 cluster, demonstrating that our findings are not confounded by linkage disequilibrium. Overall, our findings support the notion that arachidonic acid and other polyunsaturated fatty acids may represent potential targets for BPD. [ABSTRACT FROM AUTHOR]

• Pneumatic pressure on the native photosensitive membrane activates the light-dependent channels TRP and TRPL. • Tugging the membrane through superparamagnetic nanospheres opens TRP and TRPL. • Diacylglycerol, capable of opening TRP and TRPL, modifies the stiffness to an artificial lipid bilayer. • TRP and TRPL might participate as mechanosensitive channels in phototransduction. Drosophila phototransduction in light-sensitive microvilli involves a metabotropic signaling cascade. Photoisomerized rhodopsin couples to G-protein, activating phospholipase C, which cleaves phosphatidylinositol bisphosphate (PIP2) into inositol trisphosphate, diacylglycerol (DAG) and a proton. DAG is converted into phosphatidic acid by DAG-kinase and metabolized to L-linoleoyl glycerol (2-LG) by DAG-lipase. This complex enzyme cascade ultimately opens the light-dependent transient receptor potential channels, TRP and TRPL. PIP2, DAG, H+ and 2-LG are possible channel activators, either individually or combined, but their direct participation in channel-gating remains unresolved. Molecular interaction with the channels, modification of the channels' lipid moiety and mechanical force on the channels by changes in the membrane structure derived from light-dependent changes in lipid composition are possible gating agents. In this regard, mechanical activation was suggested, based on a rapid light-dependent contraction of the photoreceptors mediated by the phototransduction cascade. Here, we further examined this possibility by applying force to inside-out patches from the microvilli membrane by changing the pressure in the pipette or pulling the membrane with a magnet through superparamagnetic nanospheres. The channels were opened by mechanical force, while mutant lacking both channels was insensitive to mechanical stimulation. Atomic Force Microscopy showed that the stiffness of an artificial phospholipid bilayer was increased by arachidonic acid and diacylglycerol whereas elaidic acid was ineffective, mirroring their relative effects in channel activity previously observed electrophysiologically. Together, the results are consistent with the notion that light-induced changes in lipid composition alter the membrane structure, generating mechanical force on the channels leading to channel opening. [ABSTRACT FROM AUTHOR]

Background: Spontaneous preterm birth (sPTB) is a global disease that is a leading cause of death in neonates and children younger than 5 years of age. However, the etiology of sPTB remains poorly understood. Recent evidence has shown a strong association between metabolic disorders and sPTB. To determine the metabolic alterations in sPTB patients, we used various bioinformatics methods to analyze the abnormal changes in metabolic pathways in the preterm placenta via existing datasets. Methods: In this study, we integrated two datasets (GSE203507 and GSE174415) from the NCBI GEO database for the following analysis. We utilized the "Deseq2" R package and WGCNA for differentially expressed genes (DEGs) analysis; the identified DEGs were subsequently compared with metabolism-related genes. To identify the altered metabolism-related pathways and hub genes in sPTB patients, we performed multiple functional enrichment analysis and applied three machine learning algorithms, LASSO, SVM-RFE, and RF, with the hub genes that were verified by immunohistochemistry. Additionally, we conducted singlesample gene set enrichment analysis to assess immune infiltration in the placenta. Results: We identified 228 sPTB-related DEGs that were enriched in pathways such as arachidonic acid and glutathione metabolism. A total of 3 metabolismrelated hub genes, namely, ANPEP, CKMT1B, and PLA2G4A, were identified and validated in external datasets and experiments. A nomogram model was developed and evaluated with 3 hub genes; the model could reliably distinguish sPTB patients and term labor patients with an area under the curve (AUC) > 0.75 for both the training and validation sets. Immune infiltration analysis revealed immune dysregulation in sPTB patients. Conclusion: Three potential hub genes that influence the occurrence of sPTB through shadow participation in placental metabolism were identified; these results provide a new perspective for the development and targeting of treatments for sPTB. [ABSTRACT FROM AUTHOR]

Aim: Autism spectrum disorder (ASD) is associated with abnormal lipid metabolism, such as a high total ratio of omega‐6 to omega‐3 in polyunsaturated fatty acids (PUFAs). PUFAs are metabolized to epoxy fatty acids by cytochrome P450 (CYP); then, dihydroxy fatty acid is produced by soluble epoxide hydrolase. This study examined the association between PUFA metabolites in the cord blood and ASD symptoms and adaptive functioning in children. Methods: This prospective cohort study utilized cord blood to quantify PUFA metabolites of the CYP pathway. The Autism Diagnostic Observation Schedule (ADOS‐2) and Vineland Adaptive Behaviors Scales, Second Edition (VABS‐II) were used to assess subsequent ASD symptoms and adaptive functioning in children at 6 years. The analysis included 200 children and their mothers. Results: Arachidonic acid‐derived diols, 11,12‐diHETrE was found to impact ASD symptom severity on the ADOS‐2‐calibrated severity scores and impairment in the socialization domain as assessed by the VABS‐II (P = 0.0003; P = 0.004, respectively). High levels of 11,12‐diHETrE impact social affect in ASD symptoms (P = 0.002), while low levels of 8,9‐diHETrE impact repetitive/restrictive behavior (P = 0.003). Notably, there was specificity in the association between diHETrE and ASD symptoms, especially in girls. Conclusion: These findings suggest that the dynamics of diHETrE during the fetal period is important in the developmental trajectory of children after birth. Given that the role of diol metabolites in neurodevelopment in vivo is completely uncharacterized, the results of this study provide important insight into the role of diHETrE and ASD pathophysiology. [ABSTRACT FROM AUTHOR]

The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes. Our objectives were to evaluate the endometrial responsiveness of dairy heifers to an intrauterine infusion of recombinant bovine interferon-tau (rbIFN-τ) and to associate endometrial responses to rbIFN-τ with subsequent reproductive performance. In experiments 1 and 2, cyclic heifers were enrolled in a program for synchronization of the estrous cycle, and blood sampling and ultrasonography examinations were performed on d 0, 4, 7, 11, and 14 of the estrous cycle. In experiment 1, heifers were randomly assigned to receive an intrauterine infusion containing 2 µg of rbIFN-τ (rbIFN-τ = 19) or saline control (CTRL = 19) into the uterine horn ipsilateral to the corpus luteum (CL) on d 14 of the estrous cycle. Then, 6 hours after the infusion, the infused uterine horn was flushed for sampling of the uterine luminal fluid (ULF) for composition analysis, and the endometrium was biopsied for transcriptomics. In experiment 2, 100 heifers received an intrauterine infusion of rbIFN-τ, and the same procedures for uterine sample collection were performed as described in experiment 1. After the intrauterine test, heifers were enrolled in a breeding program and classified as highly fertile (HF; pregnant at first AI) or subfertile (SF; not pregnant at first AI). Statistical analyses were performed using regression models, which included the effects of treatment (experiment 1: CTRL vs. rbIFN-τ) or fertility group (experiment 2: HF vs. SF) and block of samples. Intrauterine infusion of rbIFN-τ increased the expression of classical interferon-stimulated genes in the endometrium (e.g., ISG15, MX1, OAS2, IRF9 , and USP18), and an antiviral response was predicted to be the main downstream effect of the transcriptome changes. In addition, rbIFN-τ increased the abundance of cholesterol, glycerol, and the overall concentration of oxylipins in the ULF. Analysis of endometrial transcriptome between HF and SF heifers revealed important differences in the expression of genes associated with cell signaling, metabolism, attachment, and migration, with a large representation of genes encoding extracellular matrix proteins. In general, differentially expressed genes were expected to be downregulated by IFN-τ but seemed to fail to be downregulated in SF heifers, resulting in higher expression in SF compared with HF heifers. Subfertile heifers had lower concentrations of glycerol and an altered profile of oxylipins in the ULF, with a lower abundance of oxylipins derived from arachidonic acid and dihomo-γ-linolenic acid, and a greater abundance of oxylipins derived from linoleic acid. Measurements of ovarian function did not differ between groups and, therefore, did not influence the observed results in uterine biology. Overall, the endometrial responsiveness to IFN-τ is variable among individuals and associated with subsequent fertility of heifers, indicating that communication between conceptus and endometrium is critical for the uterine receptivity and survival of pregnancy. [ABSTRACT FROM AUTHOR]

Androgens regulate broad physiologic and pathologic processes, including external genitalia development, prostate cancer progression, and anti-inflammatory effects in both cancer and asthma. In prostate cancer, several lines of evidence have implicated dietary and endogenous fatty acids in cell invasion, angiogenesis, and treatment resistance. However, the role of fatty acids in steroidogenesis and the mechanisms by which alterations in this pathway occur are not well understood. Here, we show that, of a panel of fatty acids tested, arachidonic acid and its specific metabolite 5-hydroxyeicosatetraenoic acid (5-HETE) regulate androgen metabolism. Arachidonic acid is metabolized to 5-HETE and reduces androgens by inducing aldo-keto reductase (AKR) family members AKR1C2 and AKR1C3 expression in human prostate, breast, and lung epithelial cells. Finally, we provide evidence that these effects require the expression of the antioxidant response sensor, nuclear factor erythroid 2-related factor 2 (Nrf2). Our findings identify an interconnection between conventional fatty acid metabolism and steroid metabolism that has broad relevance to androgen physiology and inflammatory regulation. [ABSTRACT FROM AUTHOR]

Introduction: Atopic dermatitis (AD) is a common clinical recurrent atopic disease in dermatology, most seen in children and adolescents. In recent years, AD has been found to be closely associated with microbial communities. Methods: To explore the synergistic effects between colonizing bacteria from different sites and AD, we comparatively analyzed the skin, oral, and gut microbiota of children with AD (50 individuals) and healthy children (50 individuals) by 16S rRNA gene sequencing. Twenty samples were also randomly selected from both groups for metabolic and macrogenomic sequencing. Results: The results of our sequencing study showed reduced microbiota diversity in the oral, skin, and gut of children with AD (P < 0.05). Metabolomics analysis showed that serotonergic synapse, arachidonic acid metabolism, and steroid biosynthesis were downregulated at all three loci in the oral, skin, and gut of children with AD (P < 0.05). Macrogenomic sequencing analysis showed that KEGG functional pathways of the three site flora were involved in oxidative phosphorylation, ubiquitin-mediated proteolysis, mRNA surveillance pathway, ribosome biogenesis in eukaryotes, proteasome, basal transcription factors, peroxisome, MAPK signaling pathway, mitophagy, fatty acid elongation, and so on (P < 0.05). Discussion: The combined microbial, metabolic, and macrogenetic analyses identified key bacteria, metabolites, and pathogenic pathways that may be associated with AD development. We provides a more comprehensive and in-depth understanding of the role of themicrobiota at different sites in AD patients, pointing to new directions for future diagnosis, treatment and prognosis. [ABSTRACT FROM AUTHOR]

Background: Antenatal steroid therapy for fetal lung maturation is routinely administered to women at risk of preterm delivery. There is strong evidence to demonstrate benefit from antenatal steroids in terms of survival and respiratory disease, notably in infants delivered at or below 32 weeks' gestation. However, dosing remains unoptimized and lung benefits are highly variable. Current treatment regimens generate high-concentration, pulsatile fetal steroid exposures now associated with increased risk of childhood neurodevelopmental diseases. We hypothesized that damage-associated changes in the fetal hippocampal transcriptome would be independent of preterm lung function. Methods: Date-mated ewes carrying a single fetus at 122 ± 2dGA (term = 150dGA) were randomized into 4 groups: (i) Saline Control Group, 4×2ml maternal saline intramuscular(IM) injections at 12hr intervals (n = 11); or (ii) Dex High Group, 2×12mg maternal IM dexamethasone phosphate injections at 12hr intervals followed by 2×2ml IM saline injections at 12hr intervals (n = 12; representing a clinical regimen used in Singapore); or (iii) Dex Low Group, 4×1.5mg maternal IM dexamethasone phosphate injections 12hr intervals (n = 12); or (iv) Beta-Acetate Group, 1×0.125mg/kg maternal IM betamethasone acetate injection followed by 3×2ml IM sterile normal saline injections 12hr intervals (n = 8). Lambs were surgically delivered 48hr after first maternal injection at 122–125dGA, ventilated for 30min to establish lung function, and euthanised for necropsy and tissue collection. Results: Preterm lambs from the Dex Low and Beta-Acetate Groups had statistically and biologically significant lung function improvements (measured by gas exchange, lung compliance). Compared to the Saline Control Group, hippocampal transcriptomic data identified 879 differentially significant expressed genes (at least 1.5-fold change and FDR < 5%) in the steroid-treated groups. Pulsatile dexamethasone-only exposed groups (Dex High and Dex Low) had three common positively enriched differentially expressed pathways related in part to neurodegeneration ("Prion Disease", "Alzheimer's Disease", "Arachidonic Acid metabolism"). Adverse changes were independent of respiratory function during ventilation. Conclusions: Our data suggests that exposure to antenatal steroid therapy is an independent cause of damage- associated transcriptomic changes in the brain of preterm, fetal sheep. These data highlight an urgent need for careful reconsideration and balancing of how antenatal steroids are used, both for patient selection and dosing regimens. [ABSTRACT FROM AUTHOR]

In the current study, systems biology approach was applied to get a deep insight regarding the regulatory mechanisms of Chromochloris zofingiensis under overall stress conditions. Meta-analysis was performed using p-values combination of differentially expressed genes. To identify the informative models related to stress conditions, two distinct weighted gene co-expression networks were constructed and preservation analyses were performed using medianRankand Zsummary algorithms. Moreover, functional enrichment analysis of non-preserved modules was performed to shed light on the biological performance of underlying genes in the non-preserved modules. In the next step, the gene regulatory networks between top hub genes of non-preserved modules and transcription factors were inferred using ensemble of trees algorithm. Results showed that the power of beta = 7 was the best soft-thresholding value to ensure a scale-free network, leading to the determination of 12 co-expression modules with an average size of 128 genes. Preservation analysis showed that the connectivity pattern of the six modules including the blue, black, yellow, pink, greenyellow, and turquoise changed during stress condition which defined as non-preserved modules. Examples of enriched pathways in non-preserved modules were Oxidative phosphorylation", "Vitamin B6 metabolism", and "Arachidonic acid metabolism". Constructed regulatory network between identified TFs and top hub genes of non-preserved module such as Cz06g10250, Cz03g12130 showed that some specific TFs such as C3H and SQUAMOSA promoter binding protein (SBP) specifically regulates the specific hubs. The current findings add substantially to our understanding of the stress responsive underlying mechanism of C. zofingiensis for future studies and metabolite production programs. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions 15‐oxo‐eicosatetraenoic acid (15‐oxo‐ETE), is a product of arachidonic acid (AA) metabolism in the 15‐lipoxygenase‐1 (15‐LOX‐1) pathway. 15‐oxo‐ETE was overproduced in the nasal polyps of patients with nonsteroidal anti‐inflammatory drug–exacerbated respiratory disease (N‐ERD). In this study we investigated the systemic biosynthesis of 15‐oxo‐ETE and leukotriene E4 (LTE4) and assessed their diagnostic value to identify patients with N‐ERD.The study included 64 patients with N‐ERD, 59 asthmatics who tolerated aspirin well (ATA), and 51 healthy controls. A thorough clinical characteristics of asthmatics included computed tomography of paranasal sinuses. Plasma and urinary 15‐oxo‐ETE levels, and urinary LTE4 excretion were measured using high‐performance liquid chromatography and tandem mass spectrometry. Repeatability and precision of the measurements were tested.Plasma 15‐oxo‐ETE levels were the highest in N‐ERD (p < .001). A receiver operator characteristic (ROC) revealed that 15‐oxo‐ETE had certain sensitivity (64.06% in plasma, or 88.24% in urine) for N‐ERD discrimination, while the specificity was rather limited. Modeling of variables allowed to construct the Aspirin Hypersensitivity Diagnostic Index (AHDI) based on urinary LTE4‐to‐15‐oxo‐ETE excretion corrected for sex and the Lund‐Mackay score of chronic rhinosinusitis. AHDI outperformed single measurements in discrimination of N‐ERD among asthmatics with an area under ROC curve of 0.889, sensitivity of 81.97%, specificity of 87.23%, and accuracy of 86.87%.We confirmed 15‐oxo‐ETE as a second to cysteinyl leukotrienes biomarker of N‐ERD. An index based on these eicosanoids corrected for sex and Lund‐Mackay score has a similar diagnostic value as gold standard oral aspirin challenge in the studied group of patients with asthma. [ABSTRACT FROM AUTHOR]

The enzymatic oxidation of polyunsaturated fatty acids, particularly arachidonic acid, produces important lipid mediators such as leukotrienes and prostaglandins, which are critical for triggering inflammatory cascades in the body. The enzyme lipoxygenase‐15 (LOX‐15) plays a crucial role in the oxygenation of unsaturated fatty acids. Targeting this enzyme for inhibition is essential for diminishing inflammation and averting numerous potentially fatal diseases. Therefore, the inhibitory activity of a series of isoniazid derivatives, selected from our in‐house library, was assessed against LOX‐15 by employing both in vitro and in silico methods. Among the 23 compounds evaluated, 15 showed activity in vitro. Notably, compound 7 was the most effective, demonstrating an IC50 value of 1.4±0.1 μM while the standard inhibitor, NDGA, showed an inhibition at 9.4±0.6 μM. These compounds were found to competitively inhibit LOX‐15, with Ki values ranging from 1.2–7.1 μM. Molecular docking was utilized to investigate the intermolecular interactions among the active compounds. The thermodynamic stability of the compound 7 and NDGA in complex with LOX‐15 was verified through 100 ns of molecular dynamics simulations. Post‐simulation analyses involved RMSD, RMSF, RoG, free energy landscape, principal component analysis, and dynamic cross‐correlation matrix. Compound 7 and NDGA had MM/GBSA binding energies of −54.14±2.55 kcal/mol and −35.24±3.23 kcal/mol, respectively. The study underscores the significant potential of isoniazid derivatives in LOX‐15 inhibition and their role in managing inflammatory diseases. [ABSTRACT FROM AUTHOR]

AbstractPurposeMaterials and MethodsResultsConclusionsRadiation cystitis (RC) is a complex and common complication after radiotherapy for pelvic cancer. Icariside II (ICAII) is a flavonoid compound extracted from Epimedium, a traditional Chinese medicine, with various pharmacological activities. The aim of the present study was to investigate the cysto-protective effects of ICAII in RC rats and its possible mechanisms.A rat model of induced radiation cystitis using pelvic X-ray irradiation was used, and bladder function was assessed by bladder volume and bladder leakage point pressure (LPP) after ICAII treatment. HE and Masson stains were used to assess the histopathological changes in the bladder. IL-6, TNF-α, IL-10, IL-4 and IL-1β were measured by ELISA to assess the level of inflammation. The gene-level changes in ICAII-treated RC were observed by transcriptome sequencing, and then the potential targets of action and biological mechanisms were explored by PPI, GO and KEGG enrichment analysis of the differentially expressed genes. Finally, the predicted targets of action were experimentally validated using immunohistochemistry, RT–qPCR, molecular docking and CETSA.ICAII significantly increased bladder volume and the LPP, ameliorated pathological damage to bladder tissues, decreased the levels of IL-6, TNF-α, and IL-1β, and increased the levels of IL-10 and IL-4 in radiation-injured rats. A total of 90 differentially expressed genes were obtained by transcriptome sequencing, and PPI analysis identified H3F3C, ISG15, SPP1, and LCN2 as possible potential targets of action. GO and KEGG analyses revealed that these differentially expressed genes were mainly enriched in the pathways metabolism of xenobiotics by cytochrome P450, arachidonic acid metabolism, Staphylococcus aureus infection and chemical carcinogenesis - reactive oxygen species. Experimental validation showed that ICAII could significantly increase the expression of H3F3C and ISG15 and inhibit the expression of SPP1 and LCN2. ICAII binds well to H3F3C, ISG15, SPP1 and LCN2, with the best binding ability to H3F3C. Furthermore, ICAII inhibited the protein degradation of H3F3C in bladder epithelial cells.ICAII may alleviate the bladder inflammatory response and inhibit the fibrosis process of bladder tissues through the regulation of H3F3C, ISG15, SPP1, and LCN2 targets and has a protective effect on the bladder of radioinjured rats. In particular, H3F3C may be one of the most promising therapeutic targets. [ABSTRACT FROM AUTHOR]

Multifactorial lifestyle approaches could be more effective than a single factor for maintaining cognitive function. This study investigated the association of combining cognitively stimulating leisure activities (CSLAs), including puzzles, quizzes, and cognitive training games, with intake of long-chain polyunsaturated fatty acids (LCPUFAs), including docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (ARA), on cognitive function in the older Japanese individuals without dementia. Participants were community-dwelling Japanese individuals without a self-reported history of dementia (n = 906, aged 60-88 years) from datasets of a 2-year longitudinal study (baseline: 2006-2008 and follow-up: 2008-2010). CSLA engagement and LCPUFA intake were divided into high and low groups according to frequency (≥once/week and

ABSTRACT The gastropod Parvaplustrum wareni (Parvaplustridae) is an important faunal component in the ecosystem of deep‐sea hydrothermal vents of the Piip submarine volcano, Bering Sea. To highlight trophic relationships in this ecosystem, the fatty acid (FA) composition of the hydrothermal gastropod P. wareni has been studied. This is one of the few studies analyzing FA compositions of gastropods in a hydrothermal vent ecosystem. The major polyunsaturated FAs of this mollusk are represented by n‐3 and n‐6 FAs: arachidonic acid (20:4n‐6), eicosapentaenoic acid (20:5n‐3), docosatetraenoic acid (22:4n‐6), and docosapentaenoic acid (22:5n‐3). The low level of FA markers of phytoplankton suggests an insignificant role of organic matter created by photosynthesis in the nutrition of P. wareni. A high level of monounsaturated FAs (more than 70% of total FAs) dominated by palmitoleic (16:1n‐7) and cis‐vaccenic (18:1n‐7) FAs indicates the bacterial nutrition of the mollusk. In general, the analysis of the P. wareni FA composition has allowed a conclusion that the organic matter created by chemosynthesis provides a favorable basis for the P. wareni population to thrive in the hydrothermal vents of the Piip volcano. [ABSTRACT FROM AUTHOR]

Impedance aggregometry is an alternative to light transmission aggregometry that allows analysis of platelet function in whole blood samples. We hypothesized (1) impedance aggregometry would produce repeatable results, (2) inhibition of cyclooxygenase with aspirin would attenuate aggregation responses to collagen and abolish the aggregation response to arachidonic acid (AA), and (3) thromboxane receptor antagonism (terutroban) would attenuate the aggregation response to AA. Venous blood was obtained from 11 participants three times separated by at least 2 weeks. One sample followed 7‐day‐aspirin intervention (81 mg once daily; ASA), the others no intervention (control). Aggregation was induced using 1 μg/mL collagen ([col 1]), 5 μg/mL collagen ([col 5]), and 50 mM AA via impedance aggregometry to determine total aggregation (AUC) analyzed for intra‐test repeatability, inter‐test repeatability, intervention (ASA or control), and incubation (saline or terutroban). [col 1] showed high intra‐test (p ≤ 0.03 visit 1 and 2) and inter‐test repeatability (p < 0.01). [col 5] and AA showed intra‐ ([col 5] p < 0.01 visit 1 and 2; AA p < 0.001 visit 1 and 2) but not inter‐test repeatability ([col 5] p = 0.48; AA p = 0.06). ASA attenuated AUC responses to [col 1] (p < 0.01), [col 5] (p = 0.03), and AA (p < 0.01). Terutroban attenuated AUC in response to AA (p < 0.01). [col 1] shows sufficient repeatability for longitudinal investigations of platelet function. [col 5] and AA may be used to investigate mechanisms of platelet function and metabolism at a single time point. [ABSTRACT FROM AUTHOR]

Using stress elicitors in fruits and vegetables is considered a good strategy to increase the content of bioactive compounds in plant foods. However, bioactive compounds can affect the sensory characteristics of food products, and little is known about their shelf-life stability in fresh produce treated with elicitors. In the present work, carotenoids and polyphenols were quantified by spectrophotometric methods in red and green butterhead lettuce treated with elicitors that had previously been demonstrated to increase bioactive compounds: arachidonic acid (AA), methyl jasmonate (MJ), and Harpin protein (HP). The bioactive compounds were determined immediately and during three weeks after harvest. A descriptive sensory analysis was carried out, which included odor, taste, tactile, and visual attributes of control and elicitor-treated lettuce. Carotenoids showed greater shelf-life stability than polyphenols, and both were more stable in red than in green lettuce during the first two weeks of storage. The best elicitor was MJ, which increased phenolic compounds (red and green lettuce), anthocyanins, and carotenoids (red lettuce) through the storage period. Color intensity, crispness, wettability, and bitter taste were some of the primary sensory attributes in butterhead lettuce and were not affected by any treatment. Other organoleptic properties were also not affected by the elicitors. These results suggest that elicitation could improve the content of bioactive compounds, which is stable through the shelf-life of butterhead lettuce, without any adverse effect on the sensory properties. [ABSTRACT FROM AUTHOR]

Cold stress affects the seed germination and early growth of winter rapeseed, leading to yield losses. We employed transmission electron microscopy, physiological analyses, metabolome profiling, and transcriptome sequencing to understand the effect of cold stress (0 °C, LW) on the cotyledons of cold-tolerant (GX74) and -sensitive (XY15) rapeseeds. The mesophyll cells in cold-treated XY15 were severely damaged compared to slightly damaged cells in GX74. The fructose, glucose, malondialdehyde, and proline contents increased after cold stress in both genotypes; however, GX74 had significantly higher content than XY15. The pyruvic acid content increased after cold stress in GX74, but decreased in XY15. Metabolome analysis detected 590 compounds, of which 32 and 74 were differentially accumulated in GX74 (CK vs. cold stress) and XY15 (CK vs. cold stressed). Arachidonic acid and magnoflorine were the most up-accumulated metabolites in GX74 subjected to cold stress compared to CK. There were 461 and 1481 differentially expressed genes (DEGs) specific to XY15 and GX74 rapeseeds, respectively. Generally, the commonly expressed genes had higher expressions in GX74 compared to XY15 in CK and cold stress conditions. The expression changes in DEGs related to photosynthesis-antenna proteins, chlorophyll biosynthesis, and sugar biosynthesis-related pathways were consistent with the fructose and glucose levels in cotyledons. Compared to XY15, GX74 showed upregulation of a higher number of genes/transcripts related to arachidonic acid, pyruvic acid, arginine and proline biosynthesis, cell wall changes, reactive oxygen species scavenging, cold-responsive pathways, and phytohormone-related pathways. Taken together, our results provide a detailed overview of the cold stress responses in rapeseed cotyledons. [ABSTRACT FROM AUTHOR]

The impact of steaming time on the lipid oxidation and flavor of sturgeon dorsal meat were investigated. The study characterized the degree of lipid oxidation using peroxide value, acid value, malondialdehyde, and conjugated dienes. The effects of changes in fatty acid on volatile compounds and nutritional quality were examined and lipid profile was identified in a non-targeted metabolomics approach. Finally, an oxidation model was established to explore the specific effects of phospholipids on flavor formation. Results showed that the steaming sturgeon dorsal meat for 16 minutes resulted in moderate levels of lipid oxidation, which was conducive to the formation of characteristic flavors and high nutritional value due to the presence of abundant unsaturated fatty acids. The main unsaturated fatty acids found in association with phospholipids were linoleic acid (C18:2), docosahexaenoic acid (C22:6), oleic acid (C18:1), and arachidonic acid (C20:4), while the phospholipids were the primary precursors of volatile flavor compounds. Simulation of steaming conditions showed that the oxidation of phospholipids produced a large amount of pyrazine and furan compounds, providing roasted aromas for sturgeon dorsal meat steamed. In conclusion, moderate levels of lipid oxidation were beneficial for enhancing the flavor and nutritional quality of steamed sturgeon dorsal meat, and phospholipid oxidation had a significant impact on the formation of flavor. This study provides a theoretical basis for improving the flavor of sturgeon meat. [ABSTRACT FROM AUTHOR]

Background and objective: Hemorrhagic stroke, characterized by acute bleeding due to cerebrovascular lesions, is associated with plasma lipids and endothelial damage. The causal relationship between genetic plasma lipid levels and hemorrhagic stroke remains unclear. This study employs a two-sample Mendelian randomization (MR) analysis to explore the causal relationship between plasma lipid profiles with different fatty acid chains and the risk of intracerebral and subarachnoid hemorrhage, the two main subtypes of hemorrhagic stroke. Methods: The datasets for exposure and outcome summary statistics were obtained from publicly available sources such as the GWAS Catalog, IEU OpenGWAS project, and FinnGen. The two-sample MR analysis was employed to initially assess the causal relationship between 179 plasma lipid species and the risk of intracerebral and subarachnoid hemorrhage in the Finnish population, leading to the identification of candidate lipids. The same methods were applied to reanalyze data from European populations and conduct a meta-analysis of the candidate lipids. The Inverse Variance Weighting (IVW) method served as the primary analysis for causal inference, with additional methods used for complementary analyses. Sensitivity analysis was conducted to clarify causal relationships and reduce biases. Results: Two analyses using Mendelian randomization were performed, followed by meta-analyses of the results. A causal relationship was established between 11 specific lipid species and the occurrence of intracerebral hemorrhage within the European population. Additionally, 5 distinct lipid species were associated with subarachnoid hemorrhage. Predominantly, lipids with linoleic acid and arachidonic acid side chains were identified. Notably, lipids containing arachidonic acid chains (C20:4) such as PC 18:1;0_20:4;0 consistently showed a decreased risk of both intracerebral hemorrhage [p < 0.001; OR(95% CI) = 0.892(0.835-0.954)] and subarachnoid hemorrhage [p = 0.002; OR(95% CI) = 0.794(0.689-0.916)]. Conversely, lipids with linoleic acid chains (C18:2) were associated with an increased risk of intracerebral hemorrhage. Conclusion: This study identifies a potential causal relationship between lipids with different fatty acid side chains and the risk of intracerebral and subarachnoid hemorrhagic stroke, improving the understanding of the mechanisms behind the onset and progression of hemorrhagic stroke. [ABSTRACT FROM AUTHOR]

Abstract Cytochrome P450 (CYP) 2J2 is responsible for the epoxidation of arachidonic acid, producing epoxyeicosatrienoic acids (EETs) that are known to enhance tumorigenesis. CYP2J2 is prominently expressed in the heart and also found in the lungs. Furthermore, the expression level of CYP2J2 in tumour tissues is higher than that in adjacent normal tissues. Non-small cell lung carcinoma is a common cancer, and tyrosine kinase inhibitors (TKIs) are powerful tools for its treatment. This study aimed to elucidate the inhibitory effects of 17 TKIs on CYP2J2 activity using LC-MS/MS.Seventeen TKIs exhibited different inhibitory effects on CYP2J2-catalysed astemizole O-demethylation in recombinant CYP2J2. Pralsetinib and selpercatinib showed strong competitive inhibition, with inhibition constant values of 0.48 and 1.1 µM, respectively. They also inhibited other CYP2J2 activities, including arachidonic acid epoxidation, hydroxyebastine carboxylation, and rivaroxaban hydroxylation.In conclusion, we showed that pralsetinib and selpercatinib strongly inhibit CYP2J2 activity. Inhibition of 14,15-EET production by these TKIs may be a novel mechanism for suppressing tumour growth and proliferation. Additionally, when these TKIs are co-administered with a CYP2J2 substrate, we may consider the possibility of drug–drug interactions via CYP2J2 inhibition.Cytochrome P450 (CYP) 2J2 is responsible for the epoxidation of arachidonic acid, producing epoxyeicosatrienoic acids (EETs) that are known to enhance tumorigenesis. CYP2J2 is prominently expressed in the heart and also found in the lungs. Furthermore, the expression level of CYP2J2 in tumour tissues is higher than that in adjacent normal tissues. Non-small cell lung carcinoma is a common cancer, and tyrosine kinase inhibitors (TKIs) are powerful tools for its treatment. This study aimed to elucidate the inhibitory effects of 17 TKIs on CYP2J2 activity using LC-MS/MS.Seventeen TKIs exhibited different inhibitory effects on CYP2J2-catalysed astemizole O-demethylation in recombinant CYP2J2. Pralsetinib and selpercatinib showed strong competitive inhibition, with inhibition constant values of 0.48 and 1.1 µM, respectively. They also inhibited other CYP2J2 activities, including arachidonic acid epoxidation, hydroxyebastine carboxylation, and rivaroxaban hydroxylation.In conclusion, we showed that pralsetinib and selpercatinib strongly inhibit CYP2J2 activity. Inhibition of 14,15-EET production by these TKIs may be a novel mechanism for suppressing tumour growth and proliferation. Additionally, when these TKIs are co-administered with a CYP2J2 substrate, we may consider the possibility of drug–drug interactions via CYP2J2 inhibition. [ABSTRACT FROM AUTHOR]

BACKGROUND: Low plasma levels of eicosapentaenoic acid (EPA) are associated with cardiovascular events. This trial aimed to assess the clinical benefits of icosapent ethyl in patients with coronary artery disease, a low EPA/arachidonic acid (AA) ratio, and statin treatment. METHODS: In this prospective, multicenter, randomized, open-label, blinded end-point study, patients with stable coronary artery disease and a low EPA/AA ratio (<0.4) were randomized to EPA (1800 of icosapent ethyl administered daily) or control group. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina pectoris, and coronary revascularization. The secondary composite end points of coronary events included sudden cardiac death, fatal and nonfatal myocardial infarction, unstable angina requiring emergency hospitalization and coronary revascularization, or coronary revascularization. RESULTS: Overall, 3884 patients were enrolled at 95 sites in Japan. Among them, 2506 patients had a low EPA/AA ratio, and 1249 and 1257 patients were randomized to the EPA and control group, respectively. The median EPA/AA ratio was 0.243 (interquartile range, 0.180-0.314) and 0.235 (interquartile range, 0.163-0.310) in the EPA and control group, respectively. Over a median period of 5 years, the primary end point occurred in 112 of 1225 patients (9.1%) and 155 of 1235 patients (12.6%) in the EPA and control group, respectively (hazard ratio, 0.79 [95% CI, 0.62-1.00]; P=0.055). Meanwhile, the secondary composite end point of coronary events in the EPA group was significantly lower (81/1225 [6.6%] versus 120/1235 [9.7%] patients; hazard ratio, 0.73 [95% CI, 0.55-0.97]). Adverse events did not differ between the groups, but the rate of new-onset atrial fibrillation was significantly higher in the EPA group (3.1% versus 1.6%; P=0.017). CONCLUSIONS: Icosapent ethyl treatment resulted in a numerically lower risk of cardiovascular events that did not reach statistical significance in patients with chronic coronary artery disease, a low EPA/AA ratio, and statin treatment. [ABSTRACT FROM AUTHOR]

Objective: This research aims to explore how Puerariae Lobatae Radix regulates sebaceous gland secretion using network pharmacology, and validate its effects on important targets through animal studies. Methods: This study utilized UPLC-EQ-MS to analyze Puerariae Lobatae Radix extract and identify potential bioactive compounds. Predicted targets of these compounds were obtained from the Swiss Target Prediction database, while targets associated with sebaceous gland secretion were obtained from the GeneCards database. Common targets between the databases were identified and a protein-protein interaction (PPI) network was established using the STRING platform. The PPI network was further analyzed using Cytoscape software. Pathway enrichment analysis was performed using Reactome, and molecular docking experiments targeted pivotal pathway proteins. Animal experiments were then conducted to validate the regulatory effects of the primary active compounds of Puerariae Lobatae Radix on key pathway proteins. Results: This research identified 17 active compounds in Puerariae Lobatae Radix and 163 potential targets associated with the regulation of sebum secretion. Pathway enrichment analysis indicates that these targets may modulate lipid metabolism pathways through involvement in peroxisome proliferator-activated receptor α, SREB, steroid metabolism, and arachidonic acid metabolism pathways. Molecular docking analysis demonstrates that puerarin and daidzein show favorable binding interactions with key targets in these pathways. Animal experiments demonstrated that the administration of Puerariae Lobatae Radix resulted in a significant reduction in the area of sebaceous gland patches compared to the control group. Histological analysis revealed notable alterations in the structure of sebaceous glands, including reductions in size, thickness, and density. Furthermore, the expression levels of TG, DHT, and IL-6 were significantly decreased in the Puerariae Lobatae Radix group (p < 0.05), and immunoblotting indicated a significant decrease in the expression of PPARG and ACC1 (p < 0.05). Conclusion: This study demonstrates that Puerariae Lobatae Radix can regulate skin lipid metabolism by targeting multiple pathways. The primary mechanism involves inhibiting sebaceous gland growth and reducing TG secretion by modulating the expression of PPARG and ACC1. Puerarin and Daidzein are identified as key bioactive compounds responsible for this regulatory effect. These findings highlight the therapeutic potential of Puerariae Lobatae Radix in addressing sebaceous gland-related conditions. [ABSTRACT FROM AUTHOR]

Objective: Tangbi capsule (TBC) is a traditional Chinese medicine prescription, which has the potential to improve the vascular insufficiency of lower extremities and limb numbness in diabetes. However, the potential mechanism remains unknown. This study aims to investigate the pharmacological effects and mechanism of TBC on rats with diabetic lower extremities arterial disease (LEAD). Methods: The mechanism of TBC on diabetic LEAD was investigated through metabolomics and transcriptomics analysis, and the main components of TBC were determined by mass spectrometry. The efficacy and mechanism of TBC on diabetic LEAD rats were investigated through in vitro experiments, histopathology, blood flow monitoring, western blot, and real-time polymerase chain reaction. Results: Mass spectrometry analysis identified 31 active chemical components in TBC including (2R)-2,3-Dihydroxypropanoic acid, catechin, citric acid, miquelianin, carminic acid, salicylic acid, formononetin, etc. In vitro analysis showed that TBC could reduce endothelial cell apoptosis and promote angiogenesis. Histopathological analysis showed that TBC led to an obvious improvement in diabetic LEAD as it improved fibrous tissue proliferation and reduced arterial wall thickening. In addition, TBC could significantly increase the expression levels of HIF-1α, eNOS, and VEGFA proteins and genes while reducing that of calpain-1 and TGF-β, suggesting that TBC can repair vascular injury. Compared with the model group, there were 47 differentially expressed genes in the whole blood of TBC groups, with 25 genes upregulated and 22 downregulated. Eighty-seven altered metabolites were identified from the serum samples. Combining the changes in differentially expressed genes and metabolites, we found that TBC could regulate arginine biosynthesis, phenylalanine metabolism, pyrimidine metabolism, arachidonic acid metabolism, pyrimidine metabolism, arachidonic acid metabolism, nucleotide metabolism, vitamin B6 metabolism and other metabolic pathways related to angiogenesis, immune-inflammatory response, and cell growth to improve diabetic LEAD. Conclusion: TBC improved vascular endothelial injury, apoptosis, lipid accumulation, liver and kidney function, and restored blood flow in the lower extremities of diabetic LEAD rats. The mechanism of TBC in the treatment of diabetic LEAD may be related to the modulation of inflammatory immunity, lipid metabolism, and amino acid metabolism. This study presented preliminary evidence to guide the use of TBC as a therapy option for diabetic LEAD. [ABSTRACT FROM AUTHOR]

Microsomal glutathione transferase 3 (MGST3) regulates eicosanoid and glutathione metabolism. These processes are associated with oxidative stress and apoptosis, suggesting that MGST3 might play a role in the pathophysiology of Alzheimer’s disease. Here, we report that knockdown (KD) of MGST3 in cell lines reduced the protein level of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and the resulting amyloidogenesis. Interestingly, MGST3 KD did not alter intracellular reactive oxygen species level but selectively reduced the expression of apoptosis indicators which could be associated with the receptor of cysteinyl leukotrienes, the downstream metabolites of MGST3 in arachidonic acid pathway. We then showed that the effect of MGST3 on BACE1 was independent of cysteinyl leukotrienes but involved a translational mechanism. Further RNA-seq analysis identified that regulator of G-protein signaling 4 (RGS4) was a target gene of MGST3. Silencing of RGS4 inhibited BACE1 translation and prevented MGST3 KD–mediated reduction of BACE1. The potential mechanism was related to AKT activity, as the protein level of phosphorylated AKT was significantly reduced by silencing of MGST3 and RGS4, and the AKT inhibitor abolished the effect of MGST3/RGS4 on phosphorylated AKT and BACE1. Together, MGST3 regulated amyloidogenesis by controlling BACE1 protein expression, which was mediated by RGS4 and downstream AKT signaling pathway. [ABSTRACT FROM AUTHOR]

The effects of feeding frequency on Hippocampus reidi broodstock were examined using oocyte fatty acid profile, reproduction, and larval resistance to starvation as evaluation criteria. Twelve breeding pairs (approx. 27 g; 18 cm per individual) were fed to satiation with defrosted enriched caridean shrimp Palaemon sp. in one (F1), two (F2), three (F3), or four (F4) meals per day. Three broodstock pairs were subjected to each feeding regime and treatments were continued for 101 days. Fish of both sexes fed once a day had lower weight gain and specific growth rates than broodstock from the other treatments (p < 0.05). Newly born larvae produced by the pairs in F3 and F4 treatments presented similar weight and length (mean 2.06 ± 0.11 mg; 7.9 ± 0.06 mm, respectively) and were larger than those produced by pairs that received one or two daily feedings (mean 1.62 ± 0.17 mg; 6.7 ± 0.05 mm) (p < 0.05). Mean number of larvae per parturition in F3 and F4 (928.5) was almost two times the mean number of larvae in F1 and F2. The total mortality of the starved larvae was observed after 72 h in the couples of treatments F1 and F2, while in treatments F3 and F4 it occurred after 96 h. The highest concentrations of polyunsaturated fatty acids, arachidonic acid (AA), and docosahexaenoic acid (DHA) were observed in the oocytes produced by fish subjected to the F4 treatment. It is recommended that when broodstock H. reidi are given defrosted enriched shrimp to apparent satiation, they should be fed three to four times per day to promote egg production and to give good quality larvae. [ABSTRACT FROM AUTHOR]

Purpose: The impact of dietary nutrients on body growth performance and the composition of gut microbes and metabolites is well-established. In this study, we aimed to determine whether dietary protein can regulate the physiological indexes and changes the intestinal tissue morphology in rats, and if dietary protein was a crucial regulatory factor for the composition, function, and metabolic pathways of the gut microbiota. Method: A total of thirty male Sprague Dawley (SD) rats (inbred strain, weighted 110 ± 10 g) were randomly assigned to receive diets containing animal-based protein (whey protein, WP), plant-based protein (soybean protein, SP), or a blended protein (soybean-whey proteins, S-WP) for a duration of 8 weeks. To investigate the effects of various protein supplement sources on gut microbiota and metabolites, we performed a high throughput 16S rDNA sequencing association study and fecal metabolomics profiling on the SD rats. Additionally, we performed analyses of growth indexes, serum biochemical indexes, and intestinal morphology. Results: The rats in S-WP and WP group exhibited a significantly higher body weight and digestibility of dietary protein compared to the SP group (P < 0.05). The serum total protein content of rats in the WP and S-WP groups was significantly higher (P < 0.05) than that in SP group, and the SP group exhibited significantly lower (P < 0.05) serum blood glucose levels compared to the other two groups. The morphological data showed the rats in the S-WP group exhibited significantly longer villus height and shallower crypt depth (P < 0.05) than the SP group. The gut microbial diversity of the SP and S-WP groups exhibited a higher level than that of the WP group, and the microbiomes of the WP and S-WP groups are more similar compared to those of the SP group. The Arachidonic acid metabolism pathway is the most significant KEGG pathway when comparing the WP group and the SP group, as well as when comparing the SP group and the S-WP group. Conclusion: The type of dietary proteins exerted a significant impact on the physiological indices of SD rats. Intake of S-WP diet can enhance energy provision, improve the body's digestion and absorption of nutrients, as well as promote intestinal tissue morphology. In addition, dietary protein plays a crucial role in modulating fecal metabolites by regulating the composition of the gut microbiota. Metabolomics analysis revealed that the changes in the levels of arachidonic acid metabolites and secondary bile acid metabolite induced by Clostridium_sensu_stricto_1 and [Eubacterium]_coprostanoligenes_group maybe the primarily causes of intestinal morphological differences. [ABSTRACT FROM AUTHOR]

Background: The primary cause of cancer‐related fatalities globally is lung cancer. Although the chemotherapy drug cisplatin (DDP) has brought certain benefits to patients, the rapid development of drug resistance has greatly hindered treatment success. Methods: We used the lung squamous cell carcinoma (LUSC) mRNA data set to explore the differentially expressed gene (RND1) in LUSC and detected RND1 expression in LUSC cells and DDP‐resistant cells by qRT‐PCR. Meanwhile, we performed abnormal expression treatment on RND1 and conducted CCK8, colony formation, and flow cytometry to evaluate the impact of RND1 expression on cell proliferation, apoptosis, and DDP resistance. In addition, we analyzed metabolism pathways involving RND1 using GSEA. We also used online tools such as hTFtarget and JASPAR to screen for the upstream transcription factor FOXA2 of RND1 and verified their relationship through CHIP and dual luciferase experiments. Finally, we validated the role of FOXA2‐RND1 in DDP resistance in LUSC through the above experiments. Results: RND1 was downregulated in LUSC, and overexpression of RND1 repressed proliferation and DDP resistance of LUSC cells and facilitated cell apoptosis. RND1 modulated the arachidonic acid (AA) metabolism pathway, and FOXA2 positively manipulated RND1 expression. By activating FOXA2, stabilizing RND1, and regulating AA levels, the sensitivity of LUSC cells to DDP could be enhanced. Conclusion: Our study suggested that FOXA2 positively modulated the RND1‐AA pathway, which repressed the resistance of LUSC cells to DDP. [ABSTRACT FROM AUTHOR]

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 OliveNetTM 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. [ABSTRACT FROM AUTHOR]

Rugulopteryx okamurae is an invasive non-indigenous species (NIS) of marine alga present in the benthic communities of the Strait of Gibraltar, where it has colonized most of the coast triggering ecological, economic and social consequences. The purple sea urchin Paracentrotus lividus is a generalist herbivore with potential to provide resistance to this NIS. Two experiments were carried out to determine if (i) P. lividus consumes R. okamurae under laboratory conditions, (ii) to assess its grazing preferences when this NIS is offered together with the native Ulva sp. and (iii) to find biochemical tissue markers related to R. okamurae ingestion. In the first experiment, sea urchins fed with R. okamurae, Ulva sp. or both diets were evaluated in groups for two months. Ingestion, food preference, growth and survival were assessed. In the second one, the same specimens from the R. okamurae and mixed diets were used to analyse their individual preferences, ingestion rates, growth and fatty acid profiles during another two months. Ingestion rates showed that sea urchins accepted the NIS R. okamurae as food under laboratory conditions, increasing its intake after a long exposure period. The electivity values for R. okamurae also increased when P. lividus was exposed to this alga for a long time. Regarding the fatty acids profile of tissues, the results showed that intestinal arachidonic acid (ARA, 20:4n-6) clearly differentiates sea urchins fed with R. okamurae from those fed with the mixed diet. ARA also appeared to be related to the feeding preferences, highlighting this fatty acid as a reliable marker of R. okamurae ingestion. Further research is needed in order to determine P. lividus feeding behaviour and its role as a biocontrol species in the areas invaded by R. okamurae. Sea urchin Paracentrotus lividus can feed on the alien macroalga Rugulopteryx okamurae. Ingestion rates and electivity increase after long exposure periods. Intestinal arachidonic fatty acid can be used as dietary biomarker. [ABSTRACT FROM AUTHOR]

This study aims to comprehensively examine the chemical composition, physicochemical characterization, as well as antioxidant and antiplatelet activities of Pistacia lentiscus fruit oil (PLFO). Our results showed that the prominent class of fatty acids was represented by monounsaturated fatty acids (42.73%), followed by saturated fatty acids (33.99%) and polyunsaturated fatty acids (23.13%). The different ratios of fatty acids were determined (PUFA/MUFA = 0.54, PUFA/SAFA = 0.68 and MUFA/SAFA = 1.25). The obtained results related to saturated and polysaturated fatty acids ratios were in line with the recommendations of the World Health Organization (WHO). The principal fatty acid (FA) consisted in oleic acid (41.32%), followed by linoleic acid (23.08%). A comparison was made with Moroccan and Algerian PLFO showing that Tunisian PLFO is the richest in linoleic acid. The main tentatively identified triacylglycerols, which are in monounsaturated and polyunsaturated forms, were SLL+PLO (19.73%), OOL+LnPP (13.12%) and POO (10.57%). The primary sterol identified in PLFO was β‐sitosterol (80.19%). However, tocopherols were quantified at a content of 1249.16 mg g–1 of oil. The effect on platelet aggregation was evaluated on human platelet‐rich plasma treated with various PLFO concentrations, dissolved in ethanol (named POE) and then induced by ADP, collagen, and arachidonic acid (AA). The outcome revealed that 8 µL mL–1 of POE strongly inhibited ADP‐induced platelet aggregation in humans. Additionally, the expression of CD63 and P‐selectin as markers of platelet secretion, and αΙΙβ3 integrin activation were assessed by flow cytometry. It has been found that PLFO significantly reduced platelet activation as well as alpha and dense granule secretion. Moreover, the cytotoxicity assay on normal HEK‐293 cells, the hemolysis test and the platelet viability confirmed that PLFO is a safe substance. These findings are valuable for assessing the nutritional composition of PLFO within a preventive and/or therapeutic framework in a clinical context. Practical applications: PLFO is mainly used to alleviate problems related to poor blood circulation, especially for women but it is also employed to treat problems such as heavy legs and varicose veins. Furthermore, PLFO would prevent certain diseases such as phlebitis, and alleviates various disorders, including cardiovascular problems. [ABSTRACT FROM AUTHOR]

Monascus red pigments (MRP) may have benefits against NAFLD with an unclear mechanism. This study aimed to explore the protective effect of MRP supplementation against NAFLD through regulation of gut microbiota and metabolites. The C57BL/6 mice animals were randomly allocated into the normal diet (NC), HFHS diet‐induced NAFLD model, and MRP intervention group fed with HFHS diet. Serum lipid profiles and liver function parameters were measured. Liver and colon histopathology analysis was conducted to determine the injury in the liver and colon. 16S rRNA gene sequencing was employed to analyze gut microbial composition from fecal samples. Untargeted metabonomics was performed to analyze changes in metabolites in serum and fecal samples. MRP supplementation significantly improved the HFHS‐induced alterations in body weight, lipid profiles, and liver function (p <.01). MRP supplementation decreased the abundance of Akkermansia, Candidatus saccharimonas, Dubosiella, and Oscillibacter, while increasing Lactobacillus, Lachnospiraceae NK4A136 group, and Rikenella in mice fed the HFHS diet. Furthermore, MRP supplementation improved the serum and fecal metabolic profiles induced by the HFHS diet, primarily involving the arachidonic acid metabolism, unsaturated fatty acid biosynthesis, and adipocyte lipolysis pathways. Liver function and lipid profiles were closely associated with the abundance of Lactobacillus, Streptococcus, Oscillibacter, Akkemansia, and Desulfovibrio (p <.01). These findings revealed that MRP supplementation may help restore gut microbiota composition and balance its metabolites, thereby improving NAFLD. This study presents a novel outlook on the potential benefits of MRP supplementation in ameliorating NAFLD and supports the application of MRP as a new functional food. [ABSTRACT FROM AUTHOR]

This study investigated the impact of various Ge132 (Bis‐carboxyethyl germanium sesquioxide) concentrations on frozen bovine semen. Ejaculates from three bulls were pooled and divided into six groups, each one with different Ge132 concentrations (0, 500, and 1000 μg/mL) and each group was incubated in different conditions (33°C for 30 min (D: D0, D500, and D1000), and the other was immediately cooled to 4°C (R: R0‐control; R500 and R1000)). Thawed semen was evaluated for sperm characteristics by CASA and flow cytometer. Results showed better motility in the immediate cooling group without Ge132 compared with high Ge132 concentrations. Values for total motility dropped after 5 and 60 min in groups with high Ge132 levels and some control groups. Linearity increased with 1000 μg/mL Ge132, while straightness differed between moments in multiple groups. Membrane integrity was higher in a control group and certain Ge132 groups. Lower O2− generation occurred without Ge132. After oxidative stress induction, lipid peroxidation intensity increased with arachidonic acid, but D1000 had lower peroxidation than R0. Overall, Ge132 appears to have provided protection against PLM when subjected to oxidative stress, since even at high concentrations it maintained sperm metabolism. [ABSTRACT FROM AUTHOR]

To examine associations between serum oxylipins, which regulate tissue repair and pain signalling, and knee pain/radiographic osteoarthritis (OA) at baseline and knee pain at 3 year follow-up. Baseline, and 3 year follow-up, knee pain phenotypes were assessed from 154 participants in the Knee Pain in the Community (KPIC) cohort study. Serum and radiographic Kellgren and Lawrence (KL) and Nottingham line drawing atlas OA scores were collected at baseline. Oxylipin levels were quantified using liquid chromatography coupled with mass spectrometry. Associations were measured by linear regression and receiver operating characteristics (ROC). Serum levels of 8,9-epoxyeicosatrienoic acid (EET) (β(95% confidence intervals (CI)) = 1.809 (−0.71 to 2.91)), 14,15-dihydroxyeicosatrienoic acid (DHET) (β(95%CI) = 0.827 (0.34–1.31)), and 12-hydroxyeicosatetraenoic acid (HETE) (β(95%CI) = 4.090 (1.92–6.26)) and anandamide (β(95%CI) = 3.060 (1.35–4.77)) were cross-sectionally associated with current self-reported knee pain scores (numerical rating scale (NRS) item 3, average pain). Serum levels of 9- (β(95%CI) = 0.467 (0.18–0.75)) and 15-HETE (β(95%CI) = 0.759 (0.29–1.22)), 14-hydroxydocosahexaenoic acid (β(95%CI) = 0.483(0.24–0.73)), and the ratio of 8,9-EET:DHET (β(95%CI) = 0.510(0.19–0.82)) were cross-sectionally associated with KL scores. Baseline serum concentrations of 8,9-EET (β(95%CI) = 2.166 (0.89–3.44)), 5,6-DHET (β(95%CI) = 152.179 (69.39–234.97)), and 5-HETE (β(95%CI) = 1.724 (0.677–2.77) showed positive longitudinal associations with follow-up knee pain scores (NRS item 3, average pain). Combined serum 8,9-EET and 5-HETE concentration showed the strongest longitudinal association (β(95%CI) = 1.156 (0.54–1.77) with pain scores at 3 years, and ROC curves distinguished between participants with no pain and high pain scores at follow-up (area under curve (95%CI) = 0.71 (0.61–0.82)). Serum levels of a combination of hydroxylated metabolites of arachidonic acid may have prognostic utility for knee pain, providing a potential novel approach to identify people who are more likely to have debilitating pain in the future. [ABSTRACT FROM AUTHOR]

Sea buckthorn (Hippophae rhamnoides L.) is a tree or shrub with small, orange berries. Sea buckthorn seeds have shown many properties beneficial to human health, including antioxidant, anti-hypertensive, anti-hyperlipidemic, and retinoprotective activities. Seeds, as a component of food, are often exposed to high temperatures, which can increase or decrease their biological activity. In our previous study, we showed that both raw and roasted sea buckthorn seeds had significant antioxidant activity, which was measured in human plasma in vitro. In this paper, we evaluated the effect of extracts from raw and roasted sea buckthorn seeds on several parameters of hemostasis in vitro, including thrombus formation in full blood (measured by the Total Thrombus formation Analysis System—T-TAS), blood platelet activation (based on the exposition of P-selectin, the active form of GPIIb/IIIa on their surface and platelet-derived microparticles formation), aggregation (measured with impedance aggregometry), adhesion to fibrinogen and collagen, arachidonic acid metabolism in washed platelets stimulated by thrombin, and COX-1 activity. We also measured the levels of free 8-isoprostane in plasma and the total non-enzymatic antioxidant status of plasma. The extract from roasted seeds (50 µg/mL) significantly prolonged the time of occlusion measured by T-TAS—the AUC10 (area under the curve) value was decreased by approximately 18%. Both extracts decreased the exposition of the active form of GPIIb/IIIa on the surface of platelets activated with 10 μM ADP (by 38.4–62.2%) and 20 μM ADP (by 39.7–51.3%). Moreover, the extract from raw seeds decreased the exposition of P-selectin on the surface of platelets stimulated with 20 μM ADP (by 31.2–34.9%). The adhesion of thrombin-stimulated platelets to fibrinogen and collagen was inhibited only by the extract from roasted sea buckthorn seeds (by 20–30%). Moreover, the extract from raw seeds inhibited the level of TBARS (thiobarbituric acid-reactive substances, an indicator of enzymatic peroxidation of arachidonic acid) in washed platelets stimulated with thrombin; the activity of COX-1 was inhibited by both extracts, although the effect of the extract from raw seeds was stronger. These results indicate that sea buckthorn seeds have anti-platelet activity that is not decreased by thermal processing, but more research is needed to determine which exact chemical compounds and mechanisms are responsible for this phenomenon. [ABSTRACT FROM AUTHOR]

Lipids are emerging as important potential targets for the early diagnosis and prognosis of several inflammatory diseases. Studying the lipid profiles is important for understanding cellular events such as low-grade inflammation, a condition common to many human diseases, including cancer, neurodegenerative diseases, diabetes, and obesity. This work aimed to explore lipid signatures in an inflammation cellular model using an advanced bioanalytical approach complemented by Machine Learning techniques. Analyses based on the high-resolution mass spectrometry of extracted lipids in TNF-α inflamed cells (R3/1 NF-κB reporter cells) versus lipids in control cells resulted in 469 quantified lipids, of which 20% were phosphatidylcholines (PCs) and phosphatidylethanolamines (PEs), 10% were sphingomyelins (SMs), 6% were phosphatidylinositols (PIs), 7% were ceramides (Cer), 6% were phosphatidylglycerols (PGs), and 5% were phosphatidylserines (PSs). TNF-α induced a significant alteration compared to the control, with a fold change higher than 1.5; of the 88 lipids, 71 were upregulated and 17 were downregulated, impacting various pathways as revealed by network analyses. To validate the inflammation model, the TNF-α induced cells were treated with polyphenols from thinned young apples (TAPs), which are known to have anti-inflammatory properties. The dysregulation of ceramides (Cer(d18:1/23:0), Cer(d18:1/23:0), and Cer(d18:1/22:0)) observed in TNF-α inflamed cells was completely reverted after TAP treatment. Network analyses showed the alteration of arachidonic acid and TNF signaling, which were modulated by polyphenols from thinned young apples. The results highlighted the potentiality of the inflammatory model and the bioanalytical approach to describe lipid profiles in complex biological matrices and different states. In addition, the quantified lipids were interpreted by an Artificial Intelligence approach to identify relevant signatures and clusters of lipids that can impact cellular states. Lastly, this study underlines both the potential applications of lipidomics combined with Machine Learning and how to build and validate Machine Learning models to predict inflammation based on lipid-related pattern signatures. [ABSTRACT FROM AUTHOR]

Currently, the clinical cure rate for primary liver cancer remains low. Effective screening and early diagnosis of hepatocellular carcinoma (HCC) remain clinical challenges. Exosomes are intimately associated with tumor development and their contents have the potential to serve as highly sensitive tumor-specific markers. A comprehensive untargeted metabolomics study was conducted using exosome samples extracted from the serum of 48 subjects (36 HCC patients and 12 healthy controls) via a commercial kit. An ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) strategy was used to identify the metabolic compounds. A total of 18 differential metabolites were identified using the non-targeted metabolomics approach of UPLC-QTOF-MS/MS. Pathway analysis revealed significant alterations in the arachidonic acid metabolism, linoleic acid metabolism, and unsaturated fatty acid metabolism pathways. ROC analysis indicated that three metabolites with AUC values exceeding 0.900 were selected as potential biomarkers: caprylic acid and linoleic acid were upregulated in the HCC group, whereas pentadecanoic acid was downregulated. Linoleic acid, caprylic acid, and pentadecanoic acid are potential biomarkers for diagnosing HCC. The significant alterations in these three metabolic pathways offer new insights into the mechanisms underlying HCC formation and progression. [ABSTRACT FROM AUTHOR]

Aberrant increase of arachidonic acid (ARA) has long been implicated in the pathology of Alzheimer's disease (AD), while the underlying causal mechanism remains unclear. In this study, we revealed a link between ARA mobilization and microglial dysfunction in Aß pathology. Lipidomic analysis of primary microglia from AppNL-GF mice showed a marked increase in free ARA and lysophospholipids (LPLs) along with a decrease in ARA-containing phospholipids, suggesting increased ARA release from phospholipids (PLs). To manipulate ARA-containing PLs in microglia, we genetically deleted lysophosphatidylcholine acyltransferase 3 (Lpcat3), the main enzyme catalyzing the incorporation of ARA into PLs. Loss of microglial Lpcat3 reduced the levels of ARA-containing PLs, free ARA and LPLs, leading to a compensatory increase in monounsaturated fatty acid (MUFA)-containing PLs in both male and female AppNL-GF mice. Notably, the reduction of ARA in microglia significantly ameliorated oxidative stress and inflammatory responses while enhancing the phagocytosis of Aß plaques and promoting the compaction of Aß deposits. Mechanistically, scRNA seq suggested that LPCAT3 deficiency facilitates phagocytosis by facilitating de novo lipid synthesis while protecting microglia from oxidative damage. Collectively, our study reveals a novel mechanistic link between ARA mobilization and microglial dysfunction in AD. Lowering brain ARA levels through pharmacological or dietary interventions may be a potential therapeutic strategy to slow down AD progression. [ABSTRACT FROM AUTHOR]

Extremely preterm infants are at risk of developing retinopathy of prematurity (ROP), characterized by neovascularization and neuroinflammation leading to blindness. Polyunsaturated fatty acid (PUFA) supplementation is recommended in preterm infants to lower the risk of ROP, however, with no significant improvement in visual acuity. Reasonably, this could be as a result of the non‐consideration of PUFA metabolizing enzymes. We hypothesize that abnormal metabolism of the arachidonic acid (AA) pathway may contribute to severe stages of ROP. The present study investigated the AA‐metabolizing enzymes in ROP pathogenesis by a targeted gene expression analysis of blood (severe ROP = 70, No/Mild = 56), placenta (preterm placenta = 6, full term placenta = 3), and human primary retinal cell cultures and further confirmed at the protein level by performing IHC in sections of ROP retina. The lipid metabolites were identified by LC–MS in the vitreous humor (VH; severe ROP = 15, control = 15). Prostaglandins D2 (p = 0.02), leukotrienes B5 (p = 0.0001), 11,12‐epoxyeicosatrienoic acid (p = 0.01), and lipid‐metabolizing enzymes of the AA pathway such as CYP1B1, CYP2C8, COX2, and ALOX15 were significantly upregulated while EPHX2 was significantly (0.04) downregulated in ROP cases. Genes involved in hypoxic stress, angiogenesis, and apoptosis showed increased expression in ROP. An increase in the metabolic intermediates generated from the AA metabolism pathway further confirmed the role of these enzymes in ROP, while metabolites for EPHX2 activity were low in abundance. Inflammatory lipid intermediates were higher compared to anti‐inflammatory lipids in VH and showed an association with enzyme activity. Both the placenta of preterm infants who developed ROP and hypoxic retinal cultures showed a reduced expression of EPHX2. These findings suggested a strong involvement of EPHX2 in regulating retinal neovascularization and inflammation. The study results underscore the role of arachidonic acid metabolism in the development of ROP and as a potential target for preventing vision loss among preterm‐born infants. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Effects of paternal arachidonic acid supplementation on offspring behavior and hypothalamus inflammation markers in the mouse" published in the journal PLoS ONE. The correction states that there are errors in Figures 2 to 6, including incorrect labels and axes. The authors have provided the correct versions of the figures and tables. The article explores the effects of paternal arachidonic acid supplementation on offspring behavior and inflammation markers in the hypothalamus. [Extracted from the article]

Background and aims: Recent studies suggest that empagliflozin reduces total and cardiovascular mortality in both diabetic and nondiabetic subjects. Although the exact mechanism is unclear, it is understood to positively affect myocardial energetics, including the metabolism of ketone bodies, lipids, and fatty acids. In this study, we compared empagliflozin effects on lipid metabolism in the heart and liver in a prediabetic rat model with severe dyslipidemia. Materials and methods: Wistar rats served as the control group, while hereditary hypertriglyceridemic (HHTg) rats were used as a nonobese, prediabetic model. Rats were treated with or without empagliflozin at a dose of 10 mg/kg body weight (BW) for 8 weeks. Results: In HHTg rats, empagliflozin decreased body weight and adiposity, improved glucose tolerance, and decreased serum triacylglycerols (TAGs) (p < 0.001). Empagliflozin decreased the activity and gene expression of the lipogenic enzyme SCD-1 (p < 0.001) in the myocardium, which may have led to a decrease in the ectopic accumulation of TAGs and lipotoxic diacylglycerols and lysophosphatidylcholines (p < 0.001). Changes in the myocardial phosphatidylcholine/phosphatidylethanolamine ratio (p < 0.01) and in the fatty acid profile of myocardial phospholipids may have contributed to the antifibrotic effects of empagliflozin. The anti-inflammatory effects of empagliflozin were evidenced by an increased IL-10/TNFa ratio (p < 0.001), a marked decrease in arachidonic acid metabolites (20-HETE, p < 0.001), and an increase in PUFA metabolites (14,15-EETs, p < 0.001) in the myocardium. However, empagliflozin did not significantly affect either the concentration or utilization of ketone bodies. In the liver, empagliflozin decreased lipogenesis and the accumulation of TAGs and lipotoxic intermediates. Its effect on arachidonic acid metabolites and alterations in n-3 PUFA metabolism was less pronounced than in the myocardium. Conclusion: Our findings suggest that empagliflozin treatment in the heart and liver reduced the accumulation of neutral lipids and lipotoxic intermediates and altered the metabolism of n-3 PUFA. In the heart, empagliflozin altered arachidonic acid metabolism, which is likely associated with the anti-inflammatory and antifibrotic effects of the drug. We assume that these alterations in lipid metabolism contribute to the cardioprotective effects of empagliflozin in prediabetic states with severe dyslipidemia. [ABSTRACT FROM AUTHOR]

Articular chondrocytes are the primary cells responsible for maintaining the integrity and functionality of articular cartilage, which is essential for smooth joint movement. A key aspect of their role involves mechanosensitive ion channels, which allow chondrocytes to detect and respond to mechanical forces encountered during joint activity; nonetheless, the variety of mechanosensitive ion channels involved in this process has not been fully resolved so far. Because some members of the two-pore domain potassium (K2P) channel family have been described as mechanosensors in other cell types, in this study, we investigate whether articular chondrocytes express such channels. RT-PCR analysis reveals the presence of TREK-1 and TREK-2 channels in these cells. Subsequent protein expression assessments, including Western blotting and immunohistochemistry, confirm the presence of TREK-1 in articular cartilage samples. Furthermore, whole-cell patch clamp assays demonstrate that freshly isolated chondrocytes exhibit currents attributable to TREK-1 channels, as evidenced by activation by arachidonic acid (AA) and ml335 and further inhibition by spadin. Additionally, exposure to hypo-osmolar shock activates currents, which can be attributed to the presence of TREK-1 channels, as indicated by their inhibition with spadin. Therefore, these findings highlight the expression of TREK channels in rat articular chondrocytes and suggest their potential involvement in regulating the integrity of cartilage extracellular matrix. [ABSTRACT FROM AUTHOR]

Laurus nobilis L. is commonly used in folk medicine in the form of infusion or decoction to treat gastrointestinal diseases and flatulence as a carminative, antiseptic, and anti-inflammatory agent. In this study, the essential oil (EO) composition of wild-grown L. nobilis L. leaves collected from seven different altitudinal locations in the Molise region and adjacent regions (Abruzzo and Campania) was investigated. EOs from the leaves were obtained by hydrodistillation and analyzed by GC-FID and GC/MS, and 78 compounds were identified. The major oil components were 1,8-cineol (43.52–31.31%), methyl-eugenol (14.96–4.07%), α-terpinyl acetate (13.00–8.51%), linalool (11.72–1.08%), sabinene (10.57–4.85%), α-pinene (7.41–3.61%), eugenol (4.12–1.97%), and terpinen-4-ol (2.33–1.25%). Chemometric techniques have been applied to compare the chemical composition. To shed light on the nutraceutical properties of the main hydrophobic secondary metabolites (≥1.0%) of laurel EOs, we assessed the in vitro antioxidant activities based on 2,2-diphenyl-1-picrylhydrazyl (DPPH•) radical scavenging activity and the reducing antioxidant power by using a ferric reducing power (FRAP) assay. Furthermore, we highlighted the anti-inflammatory effects of seven EOs able to interfere with the enzyme soluble epoxide hydrolase (sEH), a key enzyme in the arachidonic acid cascade, in concentrations ranging from 16.5 ± 4.3 to 8062.3 ± 580.9 mg/mL. Thanks to in silico studies, we investigated and rationalized the observed anti-inflammatory properties, ascribing the inhibitory activity toward the disclosed target to the most abundant volatile phytochemicals (≥1.0%) of seven EOs. [ABSTRACT FROM AUTHOR]

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Trained immunity is the long-term functional reprogramming of innate immune cells, which results in altered responses toward a secondary challenge. Despite indoxyl sulfate (IS) being a potent stimulus associated with chronic kidney disease (CKD)-related inflammation, its impact on trained immunity has not been explored. Here, we demonstrate that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production. Mechanistically, the aryl hydrocarbon receptor (AhR) contributes to IS-trained immunity by enhancing the expression of arachidonic acid (AA) metabolism-related genes such as arachidonate 5-lipoxygenase (ALOX5) and ALOX5 activating protein (ALOX5AP). Inhibition of AhR during IS training suppresses the induction of IS-trained immunity. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and after 6 days training, they exhibit enhanced TNF-α and IL-6 production to lipopolysaccharide (LPS). Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-α and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-α after in vivo and ex vivo LPS stimulation compared to that of control mice. These results provide insight into the role of IS in the induction of trained immunity, which is critical during inflammatory immune responses in CKD patients. [ABSTRACT FROM AUTHOR]

Introduction: Idiopathic epilepsy (IE) and meningoencephalomyelitis of unknown origin (MUO) are common causes of brain diseases leading to seizures in dogs. In this study, the concentrations of 196 lipid metabolites and nitrogen oxide (NO) production in the cerebrospinal fluid (CSF) and plasma of dogs with MUO or IE were measured using a LC-MS/MS and a NOx analyzer, respectively. Methods: Nine clinically healthy dogs and 11 and 12 dogs with IE and MUO, respectively, were included in the study. Results: Lipid analysis revealed variations in the levels of four and six lipid metabolites in CSF and plasma, respectively, between the groups. The levels of 6-keto-prostaglandin (PG) F1a (PGF1a), 20-carboxy arachidonic acid (20-carboxy-AA), 9-hydroxyoctadecadienoic acid, and lyso-platelet-activating factor were high in the CSF of dogs with MUO. In addition, the plasma levels of 11,12-dihydroxyeicosatrienoic acid, 20-carboxy-AA, and oleoylethanolamide were high in dogs with IE, and those of PGF1a were high in dogs with MUO. NO production levels were high in CSF but not in plasma in dogs with MUO or IE. Discussion: It remains unknown whether these changes represent the cause or effect of diseases of the central nervous system; however, lipid metabolites and NO production in CSF and plasma may be used as diagnostic biomarkers and could be exploited for treating idiopathic or inflammatory epilepsy in dogs. [ABSTRACT FROM AUTHOR]

Summary: The red alga Gracilaria vermiculophylla is a prostaglandin (PG)‐producing macroalga. The alga is rich in polyunsaturated fatty acids with 20 carbon atoms, mainly arachidonic acid (AA), which is a precursor of PGs. The purpose of the present study was to analyze the ability of the red alga to produce PGs using acetone powder as the crude enzyme prepared from the alga. The acetone powder (250 mg) was incubated with different amounts of exogenous AA (0.1–4 mg). For the determination of PG contents, 5 μL of a sample solution (5 mL in water) consisting of acetone powder and AA was injected into the HPLC column. For PG analysis, an HPLC system connected with a mass spectrometer was used. Results of the study showed that the released PGs from incubation of acetone powder and AA consisted of PGE2, 15‐keto‐PGE2, 15‐hydroperoxy‐PGE2, PGA2, and PGF2α. The capability of the crude enzyme prepared from the red alga to produce PGs was affected by available oxygen and AA concentrations. The crude enzyme (250 mg) was capable of producing 164 and 141 μg of PGE2 and 15‐keto‐PGE2, respectively, from incubation with 250 μg of AA. This in vitro method could be a simple way to provide PGs in the laboratory. [ABSTRACT FROM AUTHOR]

Acute respiratory tract infections, including influenza A (FluA), respiratory syncytial virus (RSV) infection, and COVID-19, can aggravate to levels requiring hospitalization, increasing morbidity and mortality. Identifying biomarkers for an accurate diagnosis and prognosis of these infections is a clinical need. We performed a cross-sectional study aimed to investigate the changes in circulating levels of arachidonic acid, interleukin 6 (IL-6), and C-reactive protein (CRP) in patients with FluA, RSV, or COVID-19, and to analyze the potential of these parameters as diagnosis or prognosis biomarkers. We analyzed serum samples from 172 FluA, 80 RSV, and 217 COVID-19 patients, and 104 healthy volunteers. Individuals with lung viral diseases showed reduced arachidonic acid concentrations compared to healthy people, with these differences being most pronounced in the order COVID-19 > RSV > FluA. Conversely, IL-6 and CRP levels were elevated across diseases, with IL-6 emerging as the most promising diagnostic biomarker, with areas under the curve (AUC) of the receiver operating characteristics plot higher than 0.85 and surpassing arachidonic acid and CRP. Moreover, IL-6 displayed notable efficacy in distinguishing between FluA patients who survived and those who did not (AUC = 0.80). These findings may provide useful tools for diagnosing and monitoring the severity of acute viral respiratory tract infections, ultimately improving patient outcomes. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is preceded by cellular hypertrophy (CeH) which alters expression of cytochrome P450 enzymes (CYPs) and arachidonic acid (AA) metabolism. Inflammation is involved in CeH pathophysiology, but mechanisms remain elusive. This study investigates the impacts of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and lipopolysaccharides (LPS) on the development of CeH and the role of CYP1B1. AC16 cells were treated with TNF-α, IL-6, and LPS in the presence and absence of CYP1B1-siRNA or resveratrol. mRNA and protein expression levels of CYP1B1 and hypertrophic markers were determined using PCR and Western blot analysis, respectively. CYP1B1 enzyme activity was determined, and AA metabolites were analyzed using liquid chromatography–tandem mass spectrometry. Our results show that TNF-α, IL-6, and LPS induce expression of hypertrophic markers, induce CYP1B1 expression, and enantioselectively modulate CYP1B1-mediated AA metabolism in favor of mid-chain HETEs. CYP1B1-siRNA or resveratrol ameliorated these effects. In conclusion, our results demonstrate the crucial role of CYP1B1 in TNF-α, IL-6, and LPS-induced CeH. [ABSTRACT FROM AUTHOR]

Background: Despite the potential radiotoxicity in differentiated thyroid cancer (DTC) patients with high-dose 131I therapy, the alterations and regulatory mechanisms dependent on intestinal microecology remain poorly understood. We aimed to identify the characteristics of the gut microbiota and metabolites in DTC patients suffering from high-dose 131I therapy and explore the radioprotective mechanisms underlying arachidonic acid (ARA) treatment. Methods: A total of 102 patients with DTC were recruited, with fecal samples collected before and after 131I therapy for microbiome and untargeted and targeted metabolomic analyses. Mice were exposed to total body irradiation with ARA replenishment and antibiotic pretreatment and were subjected to metagenomic, metabolomic, and proteomic analyses. Results: 131I therapy significantly changed the structure of gut microbiota and metabolite composition in patients with DTC. Lachnospiraceae were the most dominant bacteria after 131I treatment, and metabolites with decreased levels and pathways related to ARA and linoleic acid were observed. In an irradiation mouse model, ARA supplementation not only improved quality of life and recovered hematopoietic and gastrointestinal systems but also ameliorated oxidative stress and inflammation and preserved enteric microecology composition. Additionally, antibiotic intervention eliminated the radioprotective effects of ARA. Proteomic analysis and ursolic acid pretreatment showed that ARA therapy greatly influenced intestinal lipid metabolism in mice subjected to irradiation by upregulating the expression of hydroxy-3-methylglutaryl-coenzyme A synthase 1. Conclusion: These findings highlight that ARA, as a key metabolite, substantially contributes to radioprotection. Our study provides novel insights into the pivotal role that the microbiota-metabolite axis plays in radionuclide protection and offers effective biological targets for treating radiation-induced adverse effects. [ABSTRACT FROM AUTHOR]