Search Results (261)

Background/Objective: Pharmacological interventions often exert systemic effects beyond their primary targets, underscoring the need for a comprehensive evaluation of their metabolic impact. Etodolac is a nonsteroidal anti-inflammatory drug (NSAID) that alleviates pain, fever, and inflammation by inhibiting cyclooxygenase-2 (COX-2), thereby reducing prostaglandin synthesis. While its pharmacological effects are well known, the broader metabolic impact and potential mechanisms underlying improved clinical outcomes remain underexplored. Untargeted metabolomics, which profiles the metabolome without prior selection, is an emerging tool in clinical pharmacology for elucidating drug-induced metabolic changes. In this study, untargeted metabolomics was applied to investigate metabolic changes following a single oral dose of etodolac in healthy male volunteers. By analyzing serial blood samples over time, we identified endogenous metabolites whose concentrations were positively or inversely associated with the drug’s plasma levels. This approach provides a window into both therapeutic pathways and potential off-target effects, offering a promising strategy for early-stage drug evaluation and multi-target discovery using minimal human exposure. Methods: Thirty healthy participants received a 400 mg dose of Etodolac. Plasma samples were collected at five time points: pre-dose, before Cmax, at Cmax, after Cmax, and 36 h post-dose (n = 150). Samples underwent LC/MS-based untargeted metabolomics profiling and pharmacokinetic analysis. A total of 997 metabolites were significantly dysregulated between the pre-dose and Cmax time points, with 875 upregulated and 122 downregulated. Among these, 80 human endogenous metabolites were identified as being influenced by Etodolac. Results: A total of 17 metabolites exhibited time-dependent changes closely aligned with Etodolac’s pharmacokinetic profile, while 27 displayed inverse trends. Conclusions: Etodolac influences various metabolic pathways, including arachidonic acid metabolism, sphingolipid metabolism, and the biosynthesis of unsaturated fatty acids. These selective metabolic alterations complement its COX-2 inhibition and may contribute to its anti-inflammatory effects. This study provides new insights into Etodolac’s metabolic impact under healthy conditions and may inform future therapeutic strategies targeting inflammation. Full article

Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene. While hepatic manifestations are frequent, psychiatric symptoms occur in up to 30% of patients and may precede neurological signs. This study was the first to assess the relationship between oxidative stress, selected genetic polymorphisms, and psychiatric symptoms in WD. A total of 464 patients under the care of the Institute of Psychiatry and Neurology in Warsaw were studied. Genotyping for GPX1 (rs1050450), SOD2 (rs4880), and CAT (rs1001179) was performed, along with biochemical analyses of copper metabolism, oxidative DNA, lipid and protein damage, and systemic antioxidant capacity. Among the most important observations are the following: the homozygous GPX1 rs1050450 TT and SOD2 rs4880 CC genotypes were associated with the lowest prevalence of psychiatric symptoms. The CAT rs1001179 TT genotype was linked to a delayed onset of psychiatric symptoms by 6.0–8.5 years. Patients with or without psychiatric symptoms did not differ significantly in saliva 8-OHdG, total antioxidant capacity, serum glutathione (GSH), catalase, and MnSOD; however, patients reporting psychiatric symptoms had significantly higher prostaglandin F2α 8-epimer (8-iso-PGF2α) concentrations and tended to have lower serum glutathione peroxidase (Gpx) concentrations compared to those without such symptoms. Our data firstly provide consistent evidence that oxidative stress balance associated with copper overload in the CNS may be associated with CNS damage and the development of psychiatric symptoms of WD. In particular, our findings of increased oxidative lipid damage together with decreased Gpx activity indirectly suggest that damage to neuronal membrane lipids, which may be potentially related to abnormalities in GSH metabolism, may have an etiological role in CNS damage and related symptoms. Full article

Background/Objectives: Localized provoked vulvodynia (LPV) is characterized by chronic vulvar pain upon light touch to the vestibule, a specialized ring of tissue immediately surrounding the vaginal opening. LPV affects about 14 million people in the US, yet the etiopathology of the disease is unknown. In LPV, the vestibule expresses elevated levels of the pro-nociceptive pro-inflammatory mediators prostaglandin E₂ (PGE2) and interleukin-6 (IL-6), which corresponds to lower pain thresholds. Previous studies have shown reduced amounts of arachidonic acid (AA)-derived pro-resolving lipid mediators in tissue biopsies from LPV patients that might impede the resolution of inflammation. AA is obtained from dietary linoleic acid, pointing to a defect in the metabolism of dietary polyunsaturated fatty acids in LPV. We aimed to further explore the involvement of AA metabolism in LPV, which appears dysregulated in the vestibule of LPV patients and culminates in chronic inflammation and chronic pain. Methods: Vestibular and vulvar tissue biopsies obtained from LPV and non-LPV patients were used to generate fibroblast strains and assessed for COX/LOX expression using qRT-PCR. Fibroblast strains were treated with inflammatory stimuli, and then COX-1 and COX-2 expression was assessed using Western blot analysis. Pro-inflammatory mediator production was assessed using enzyme-linked immunosorbent assays (ELISAs). ALOX5 and ALOX12 expression was assessed using qRT-PCR. Finally, lipidomic analysis was carried out to screen for 143 lipid metabolites following inflammatory challenge. Results: Tissue and fibroblasts from LPV patients exhibited altered expression of COX/LOX enzymes and production of AA-derived lipid mediators compared to non-LPV patients. Conclusions: Lipid profiles of tissue and vestibular fibroblasts from LPV patients differed from non-LPV patients, and this difference was attributed to differential COX/LOX expression and activity, which metabolizes AA derived from dietary linoleic acid. This dysregulation fosters chronic inflammation and reduced resolution capacity in LPV patients, causing chronic pain. While further work is needed, these findings suggest that dietary modifications could impact the LPV mechanism. Full article

Atherosclerosis is a chronic inflammatory disease and a major pathological basis of numerous cardiovascular conditions, with a high global mortality rate. Macrophages play a pivotal role in its pathogenesis through phenotypic switching and foam cell formation. Prostaglandin E2 receptor subtype 4 (EP4) highly expressed on the macrophage surface, is involved in various pathophysiological processes, such as inflammation and lipid metabolism. However, the role of macrophage EP4 in the progression of atherosclerosis remains unclear. To determine whether macrophage EP4 affects the progression of atherosclerosis by regulating foam cell formation and macrophage polarization. Myeloid-specific EP4 knockout mice with an ApoE-deficient background were fed a Western diet for 16 weeks. Our results showed that EP4 expression was significantly downregulated during atherosclerosis. EP4 deficiency was found to exacerbate atherosclerotic plaque formation and destabilizes plaques. In vitro studies further demonstrated that loss of EP4 in myeloid cells promoted foam cell formation and M1 macrophage polarization. Both transcriptomic and proteomic analysis showed that EP4 may regulate these processes by regulating CD36 expression in macrophage, which was further confirmed by Western blot and qPCR. In summary, deficiency of EP4 receptor in macrophages enhance foam cell formation and M1 polarization by upregulating CD36 expression, thereby accelerating the progression of atherosclerosis. Full article

The giant freshwater prawn (Macrobrachium rosenbergii, GFP) is a highly valuable crustacean species in global aquaculture. However, a social hierarchy exists among the distinct male morphotypes, specifically blue-clawed males (BC), orange-clawed males (OC), and small males (SMs). In this study, to identify the specific metabolites among BC, OC, and SM, hemolymph samples were collected for the untargeted liquid chromatography–mass spectrometry metabolomics (LC–MS). A total of 172, 546, and 578 significantly different metabolites (SDMs) were identified in OC vs. BC, SM vs. BC, and SM vs. OC, respectively. Notably, creatine and glutamate in BC males likely enhance their aggressive behavior through improved energy metabolism. In the SM group, the up-regulation of prostaglandin E3, testosterone, and arachidonic acid may lead to premature gonadal maturation and enhance immunity. Serotonin, Glu-Pro, and pentanoylcarnitine detected in OC males reflect their physiological need for rapid growth and adaptation to social behaviors. In the SM group, the up-regulation of prostaglandin E3, arachidonic acid, and testosterone may promote premature gonadal maturation and enhance immunodominance. These findings will enhance the understanding of the physiological basis of social hierarchy formation in male GFPs from a metabolomics perspective. Full article

Background. Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than 30% of the world population. Progression to its inflammatory state, MASH, is associated with increasing liver fibrosis, leading to end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC). SW033291, an inhibitor of 15-PGDH (the PGE2 degradation enzyme), has been shown to increase in vivo regeneration of liver parenchyma, ameliorating oxidative stress and inflammation. We hypothesized that SW033291 abrogates MASH progression by inducing a paucity of the initial apoptotic switch and restoring physiological collagen’s microenvironment. Methods. The expression levels of the cell metabolic proteins FOXO1, mTOR, and SIRT7 were determined in a diet-induced MASH-mouse model at 16, 20, and 24 weeks. Non-targeted metabolomics in mouse plasma were measured by LC-MS/MS. Liver morphology and apoptotic activity were quantified by the NAS score and TUNEL assay, respectively. Statistical analyses between groups (NMC, HFD, and SW033291) were determined by ANOVA, t-test/Tukey’s post hoc test using GraphPad Prism. Metabolomics data were analyzed using R-lab. Results. The treated group showed significant decreases in total body fat, cellular oxidative stress, and inflammation and an increase in total lean mass with improved insulin resistance and favorable modulation of metabolic protein expressions (p < 0.05). SW033291 significantly decreased GS:SG, citric acid, and corticosterone, NAS scores (9.4 ± 0.2 vs. 6.2 ± 0.1, p < 0.05), liver fibrosis scores (1.3 ± 0.5 vs. 0.25 ± 0.1, p < 0.05), and apoptotic activity (43.9 ± 4.6 vs. 0.38 ± 0.1%, p < 0.05) compared with controls at 24W. Conclusions. The inhibition of 15-PGDH appears to normalize the metabolic and morphological disturbances during MASH progression with a paucity of the initial apoptotic switch, restoring normal collagen architecture. SW033291 warrants further investigation for its translation. Full article

Meloxicam (MLX), a member of the non-steroidal anti-inflammatory drugs (NSAIDs), is a preferential inhibitor of cyclooxygenase-2 (COX-2) responsible for the synthesis of pro-inflammatory prostaglandins. MLX, due to its inhibition of the COX-2 enzyme, which is overexpressed in many cancers, including melanoma, leading to rapid growth, angiogenesis, and metastasis, represents a potentially important compound with anticancer activity. This study aimed to investigate the potential anticancer activity of meloxicam against amelanotic C32 and melanotic COLO 829 melanoma cell lines. The objective was achieved by assessing cell metabolic activity using the WST-1 assay and analyzing mitochondrial potential, levels of reduced thiols, annexin, and caspases 3/7, 8, and 9 by imaging cytometry, as well as assessing reactive oxygen species (ROS) levels using the H₂DCFDA probe. The amelanotic melanoma C32 was more sensitive to MLX exposure, thus exhibiting antiproliferative effects, a disruption of redox homeostasis, a reduction in mitochondrial potential, and an induction of apoptosis. The results provide robust molecular evidence supporting the pharmacological effects of MLX, highlighting its potential as a valuable agent for in vivo melanoma treatment. Full article

Identifying the specific factors secreted during early pregnancy is an effective method for pregnancy detection in cattle, helping to reduce empty pregnancies in the industry. To systematically investigate metabolic variations between early pregnancy and the estrous cycle and their relationship with pregnancy progression, this study utilized four-dimensional data-independent acquisition (4D-DIA) proteomics and liquid chromatography–tandem mass spectrometry (LC-MS/MS) metabolomics to analyze serum samples collected from Chinese native yellow cattle at day 0 and day 21 post-mating, combining bioinformatics analysis with experimental validation. The platelet activation signaling pathway and angiogenesis-related proteins were significantly upregulated. Among them, fibrinogen alpha/beta/gamma chains (FG) exhibited notable differences, with their branched-chain protein FGB showing highly significant upregulation (p = 0.003, Log₂FC = 2.167) and tending to increase gradually during early pregnancy, suggesting that FGB could be one of the important indicators of early pregnancy in Chinese native yellow cattle. Among the differential metabolites, 11-Deoxy prostaglandin F1α (p < 0.001, Log₂FC = 1.563), Thromboxane B1 (p = 0.002, Log₂FC = 3.335), and Homo-Gamma-Linolenic Acid (C20:3) (p = 0.018, Log₂FC = 1.781) were also increased, indicating their involvement in the regulation of the platelet activation signaling pathway. The platelet activation signaling pathway plays a crucial role in maternal immune tolerance and placental vascularization, which are essential for embryo implantation and placental development. These findings indicate that FGB has the potential to be a valuable biomarker for early cattle pregnancy detection, thereby improving pregnancy diagnosis accuracy, reducing economic losses caused by undetected empty pregnancies and enhancing reproductive efficiency in the cattle industry. Undoubtedly, our research outcomes must be validated with future studies, and a larger sample size as well as the evaluation of the potential endocrine effects induced by the synchronized estrus treatment must be considered. Full article

Medicinal plants from the genus Saururus are commonly used to treat inflammatory pathologies. They contain numerous bioactive compounds, notably the polycyclic lignan sauchinone from the species Saururus chinensis. An in-depth analysis of benzoxanthenone lignans related to sauchinone, and the analogous products carpanone and polemannones, has been carried out. The review reports the product’s isolation, biosynthetic pathway, and chemical strategies to synthesize benzoxanthenones via liquid- and solid-phase syntheses. The metabolic and pharmacokinetic properties of sauchinone are discussed. At the pharmacological level, sauchinone is a potent blocker of the production of pro-inflammatory mediators, such as nitric oxide and prostaglandin E2, and an efficient antioxidant agent. The properties of sauchinone can be exploited to combat multiple pathologies, such as liver injuries, renal dysfunction, osteoarthritis, inflammatory bowel disease, ulcerative colitis, and cancers. The capacity of the natural product to inhibit tumor cell proliferation and to reduce migration/invasion of cancer cells and the development of metastases is underlined, together with the regulation of the epithelial-mesenchymal transition and immune checkpoints. Altogether, the review offers a complete survey of the chemical and biochemical properties of sauchinone-type benzoxanthenones. Full article

Addressing the escalating global burdens of inflammatory bowel disease and antimicrobial resistance demanded innovative food-based approaches to fortify gut health and suppress pathogens. We introduced a novel edible probiotic, Enterococcus faecalis HY0110, isolated from marine Thunnus thynnus. Through comprehensive in vitro, in vivo, and metabolomic analyses, we demonstrated its superior antibacterial effects compared to Lactobacillus rhamnosus GG, along with significantly enhanced antioxidant and free-radical scavenging capacities. Notably, elevated acetic acid production strongly correlated with its antimicrobial efficacy (R ≥ 0.999). HY0110 also exerted antiproliferative effects on HT-29 colorectal cancer cells by attenuating β-catenin and BCL-2 expression while upregulating pro-apoptotic markers P62 and c-PARP. In a DSS-induced colitis model, HY0110 alleviated inflammation, restored gut microbial homeostasis, and enhanced deterministic processes in community assembly dynamics. Furthermore, fermenting Periplaneta americana powder with HY0110 triggered extensive metabolic remodeling, notably a 668.73-fold rise in astragaloside A, plus increases in L-Leucyl-L-Alanine, S-lactoylglutathione, and 16,16-dimethyl prostaglandin A1. These shifts diminished harmful components and amplified essential amino acids and peptides to bolster immune modulation, redox balance, and anti-inflammatory responses. This work established a transformative paradigm for utilizing marine probiotics and novel entomological substrates in functional foods, presenting strategic pathways for precision nutrition and inflammatory disease management. Full article

Background/Objectives: Eggshell quality is a critical factor influencing consumer preference and the economic benefits of poultry enterprises, and the uterus is the key site for eggshell synthesis. Yaoshan chicken (YS), an indigenous chicken breed in China, is renowned for its flavorful meat and high-quality eggs. However, its egg production is lower compared to specialized strains. Therefore, the GYR crossbreed was developed by three-line hybridization for YS chicken, which can produce green-shelled eggs with better eggshell thickness and strength than YS chicken (p < 0.01). To explore the molecular mechanisms underlying the differences in eggshell quality between GYR and YS chickens, we conducted an integrated transcriptomic and metabolomic analysis. Methods: Twelve uterus samples (six from GYR and six from YS chickens) were collected during the period of eggshell calcification at 260 days of age. RNA sequencing (RNA-seq) and liquid chromatography–mass spectrometry (LC-MS/MS) were performed to identify differentially expressed genes (DEGs) and differential metabolites (DMs), respectively. Results: A total of 877 DEGs were identified in the GYR group, including 196 upregulated and 681 downregulated genes (|log₂ (fold change)| > 1, p-value < 0.05). Additionally, 79 DMs were detected, comprising 50 upregulated and 29 downregulated metabolites (|log₂ (fold change)| > 1, VIP > 1). Notably, the key DEGs (SLCO1B3, SLCO1B1, PTGR1, LGR6, MELTF, CRISP2, GVINP1, and OVSTL), important DMs (prostaglandin-related DMs and biliverdin) and signaling pathways (calcium signaling, neuroactive ligand–receptor interaction, arachidonic acid metabolism, bile secretion, and primary bile acid biosynthesis) were major regulators of the eggshell quality. Furthermore, an integrated transcriptomic and metabolomic analysis revealed two significant gene–metabolite pairs associated with eggshell quality: PTGDS–prostaglandin E2 and PTGS1–prostaglandin E2. Conclusions: This study provides a theoretical foundation for the improved eggshell quality of Yaoshan chicken. Full article

Egg production is a complex biological process closely linked to ovarian development and metabolic adaptation in laying hens. As the core reproductive organ, the ovary undergoes significant changes during different egg-laying stages. This study employed untargeted metabolomics to analyze metabolites in serum and ovarian tissues of hens at 20W and 30W. The results revealed that metabolic reprogramming in ovarian tissues was more pronounced than in serum. Shared metabolites between serum and ovarian tissues demonstrated coordinated interactions between systemic and local metabolic networks. The synthesis of prostaglandin E1 during lipid metabolism was identified as a key driver of ovulation and hormone production. Extracellular matrix remodeling and polyamine metabolism, particularly spermidine/spermine, enhanced cell adhesion and antioxidant capacity during ovarian development. These findings provide new insights into follicular development, ovulation regulation, and steroid hormone biosynthesis, while suggesting potential metabolic targets to improve poultry reproductive efficiency. Full article

Atherosclerosis (AS) is emerging as a major global public health problem. Researchers are developing and implementing various anti-AS strategies. This study aimed to investigate gut microbiota and metabolite changes associated with elevated serum low-density lipoprotein cholesterol (LDL-c). Mice were divided into two equal groups: Group C (mice with gut microbiota from healthy subjects) and Group B (mice with gut microbiota from AS). At the end of the 8-week study, blood samples were collected for blood lipid analysis; rectal feces were collected for microbial 16S rRNA sequencing analysis and metabolomics analysis. Our results showed that the B group significantly increased serum lipid levels of LDL-c. However, no statistically significant differences were observed in the richness and diversity of the gut microbiota, but we observed an increase in the ratio of Firmicutes to Bacteroidetes and an increase in the abundance of Parabacteroides Goldstein. In addition, untargeted metabolomic analysis of fecal samples revealed 128 metabolites that were differentially expressed between groups C and B. Notably, group B was found to have significantly increased levels of metabolites involved in lipid metabolism pathways, such as estrogen glucuronide, ginsenoside f1, Pe (16:1e/14,15-epete), and prostaglandin E1. Those data highlight the importance of understanding AS from the gut microbiota perspective and establish a foundation for future research on AS. Full article

Background: High-altitude hypoxia is known to adversely affect bone health, leading to accelerated bone loss and metabolic alterations. Recent studies suggest that factors such as bicarbonate and gut microbiota may play key roles in bone health. Mineral water, rich in bicarbonate, may influence bone health and the gut–bone axis under such conditions. Methods: Mice were exposed to hypoxia and treated with different concentrations of drinking water. Bone-related parameters were assessed using dual-energy X-ray absorptiometry (DXA) and Micro-CT. Bone health was assessed using the measurement of serum biomarkers. Additionally, Untargeted Metabolomics was employed to analyze differential metabolites between groups, while gut microbiota composition was analyzed using 16S rRNA sequencing. Results: BMW consumption increased bone mineral density (BMD) and helped alleviate the damage to the microstructure of bones caused by hypoxia and delayed the progression of osteoporosis. Additionally, BMW was shown to enhance probiotics such as Akkermansia and Dubosiella and regulate the longevity-regulating pathway as well as the PI3K/AKT/mTOR (PAM) signaling pathway. This study also discovered changes in metabolic products due to BMW intervention, predominantly in pathways such as the amino acid, prostaglandin, and purine metabolisms, with correlation analysis further exploring the relationships between gut microbiota and these differential metabolites. Conclusions: Long-term exposure to high-altitude hypoxic conditions affects the structure of gut microbiota and bone metabolism in mice. The consumption of BMW improves the structure of gut microbiota and regulates the metabolic pathways to maintain bone health under high-altitude hypoxia. Full article

Background/Objectives: To analyze the genotype that predicts the phenotypic characteristics of a cohort of patients with glaucoma and ocular hypertension (OHT) and explore their influence on the response to ocular hypotensive treatment. Methods: This was a prospective study that included 193 eyes of 109 patients with glaucoma or OHT under monotherapy with beta-blockers, prostaglandin, or prostamide analogues (BBs, PGAs, PDs). Eight single-nucleotide polymorphisms were genotyped using real-time PCR assays: prostaglandin-F2α receptor (PTGFR) (rs3766355, rs3753380); beta-2-adrenergic receptor (ADRB2) (rs1042714); and cytochrome P450 2D6 (CYP2D6) (*2 rs16947; *35 rs769258; *4 rs3892097; *9 rs5030656, and *41 rs28371725). The main variables studied were baseline (bIOP), treated (tIOP), and rate of variation in intraocular pressure (vIOP), and mean deviation of the visual field (MD). The metabolizer phenotype and the CYP2D6 copy number variation were also evaluated. Results: In total, 112 eyes were treated with PGAs (58.0%), 59 with BBs (30.6%), and 22 with PDs (11.4%). For PTGFR (rs3753380), statistically significant differences were observed in vIOP in the PGA group (p = 0.032). Differences were also observed for ADRB2 (rs1042714) in MD (p < 0.001) and vIOP (p = 0.017). For CYP2D6, ultrarapid metabolizers exhibited higher tIOP (p = 0.010) and lower vIOP (p = 0.046) compared to the intermediate and poor metabolizers of the BB group. Additionally, systemic treatment metabolized by CYP2D6 showed a significant influence on vIOP (p = 0.019) in this group. Conclusions: These preliminary findings suggest the future potential of pharmacogenetic-based treatments in glaucoma to achieve personalized treatment for each patient, and thus optimal clinical management. Full article