Most studies on the biological effects of exogenous pollutants have focused on whole samples or cell populations, and lack spatial heterogeneity consideration due to technical limitations. Microcystin-LR (MC-LR) from cyanobacterial blooms threatens ecosystems and human health, while microcystin-LR disinfection by-products (MCLR-DBPs) in drinking water remain a concern for their toxin-like structure. This study introduces spatial multi-omics to investigate the disruptions caused by ingestion of MC-LR and MCLR-DBPs in zebrafish. The method integrates metabolomics, spatial metabolomics, and spatial transcriptomics to characterize the overall metabolic changes in whole zebrafish caused by MC-LR and MCLR-DBPs, then provides further insight into the variation of spatial distribution of metabolites and genes in MC-LR and MCLR-DBPs targeted organ. The results showed that MC-LR and MCLR-DBPs induced oxidative stress and metabolic imbalance, and disrupted the physiological homeostasis of zebrafish. Spatial multi-omics analysis further revealed that MC-LR and MCLR-DBPs exacerbate disruptions in energy and lipid metabolism, methylation processes, and immune pathways by modulating the expression of genes such as gatm, gnmt, cyp2p9, and tdo2b. In conclusion, this study developed a spatial multi-omics approach that not only enhances the understanding of the biological effects of MC-LR and MCLR-DBPs but also provides robust technical support for investigating other environmental pollutants.

Allergic asthma (AA) is a prevalent chronic respiratory disease characterized by airway hyperresponsiveness (AHR) and chronic inflammation, significantly impairing patients' quality of life.

This study investigates the therapeutic effects of Platycodin D (PLD) on AA and its underlying mechanisms via the EGFR/PI3K/Akt signaling pathway.

In vitro, BEAS-2B cells treated with IL-4 and IL-13 simulated asthma's inflammatory environment. Enzyme-linked immunosorbent assay (ELISA) assessed PLD's modulation of inflammatory factors, while Western blot (WB) analyzed its impact on airway remodeling proteins. Induced pluripotent stem cells (iPSC)-derived airway organoids (AOs) were used to evaluate PLD's effects on airway remodeling, observed through tissue staining and immunofluorescence. In vivo, an OVA-induced asthma mouse model was employed to assess PLD's therapeutic potential via lung function tests, serum biochemical analysis, and histopathology. Network pharmacology and transcriptomics predicted and validated PLD's target pathways.

In vivo experiments demonstrated that PLD significantly alleviated airway inflammation and remodeling in OVA-induced asthmatic mice. Specifically, treatment with 5 mg/kg PLD significantly reduced the number of inflammatory cells recovered from bronchoalveolar lavage fluid (BALF) compared to the model group (p < 0.05). Serum levels of IgE, IL-4, IL-5, IL-13, and IL-17A were markedly decreased following PLD treatment (p < 0.05). PLD also improved lung function by reducing airway resistance (RL) across all tested methacholine concentrations, with significant reductions at 5, 10, and 20 mg/mL doses (p < 0.05). Histological analysis revealed that PLD attenuated pathological changes in lung tissues, including goblet cell hyperplasia and collagen deposition. Western blot analysis confirmed that PLD significantly downregulated the expression of COL1A1 and α-SMA in lung tissues (p < 0.05), suggesting suppression of airway remodeling. In vitro, PLD inhibited the expression of IL-6, IL-8, COL1A1, and α-SMA in human bronchial epithelial (HBE) cells in a dose-dependent manner. Transcriptomic sequencing and RT-qPCR analysis further demonstrated that PLD downregulated key genes involved in the EGFR/PI3K/Akt pathway. Molecular docking showed high binding affinity between PLD and EGFR/PI3K proteins, supporting a potential mechanistic link.

PLD exerts therapeutic effects in allergic asthma by suppressing airway inflammation, improving lung function, and inhibiting airway remodeling. These effects are associated with the inhibition of the EGFR/PI3K/Akt signaling pathway. Our findings suggest that PLD may serve as a promising candidate for the treatment of allergic airway diseases.

Cadmium ion (Cd2+) is a non-essential metal that can increase cancer risk, including potentially renal cell carcinoma (RCC), though this link is not definitive. Cd2+ exposure impairs fatty acid metabolism in the kidneys, particularly affecting arachidonic acid (AA) levels, which are crucial for health. Previous studies have suggested that Cd2+-altered the AA metabolism associates with renal dysfunction. However, the role and mechanism of Cd2+-regulated AA source in promoting RCC progression are still unclear. This study aims to investigate how Cd2+ exposure affects AA levels in renal cancer cells and its role in promoting cell migration. Cd2+ exposure increases AA levels through cPLA2-mediated release. It also induces calcium ion (Ca2+) redistribution from the endoplasmic reticulum (ER) to mitochondria, activating the p38 MAPK/cPLA2 signaling pathway, and epithelial-mesenchymal transition (EMT) of Caki-1 cells. Cd2+-induced ER Ca2+ release, p38 MAPK/cPLA2 signaling activation, AA levels, and EMT of Caki-1 cells were effectively reversed by siRNA knockdown of IP3R. Both exogenous AA treatments and Cd2+-induced AA metabolite PGD2 promoted EMT and cell migration of Caki-1 cells. This study highlights Cd2+'s impact on fatty acid metabolism and organelle function in renal cancer cells, identifying potential therapeutic targets for RCC.

The severe pain linked to chemotherapy-induced peripheral neuropathy (CIPN) often becomes a critical factor limiting the effective dosage of life-saving chemotherapy treatments. This debilitating side effect not only hampers the effectiveness of cancer therapy but also poses challenges due to the adverse effects of current treatment options for managing CIPN-related pain complications. Soluble epoxide hydrolase (sEH) inhibitors, which elevate endogenous epoxy-fatty acid levels, have been shown to mitigate CIPN-related pain in different rodent models. In our quest to develop potent sEH inhibitors, we developed novel benzyl phenyl urea derivatives incorporating a pyridazinone ring alongside the urea group as a secondary pharmacophore. These compounds demonstrated remarkable potency in inhibiting sEH, with IC50 values ranging from 0.2 to 57 nM. Compound FP9 (IC50 = 0.2 nM), the most potent in this series, exhibited enhanced metabolic stability, translating into significantly improved oral bioavailability (F = 78 %). It consistently relieved pain perception in mice with paclitaxel-induced peripheral neuropathy, achieving a significant and sustained effect compared to gabapentin. In addition, docking studies and molecular dynamics simulations with FP9 provided valuable insights into the binding interactions between the inhibitor and the sEH binding site, offering direction for further optimization of new analogs. These findings align with recent research that highlights the beneficial effects of sEH inhibitors in reducing pain thresholds associated with CIPN.

Venous thromboembolism (VTE) is a significant global health burden, and metabolic alterations play a key role in its pathogenesis. However, previous studies have been constrained by several limitations, hindering clarification of the causal role of metabolites.

To comprehensively evaluate the causal roles of metabolites in the pathogenesis of VTE and determine whether metabolites mediate the relationships between modifiable risk factors and VTE.

Genetic associations involving 690 plasmas and 211 urinary metabolites were analyzed as exposures, while the outcomes for VTE were derived from a large-scale meta-analysis of genome-wide association studies. Metabolome-wide Mendelian randomization and colocalization analyses were performed to assess the causal role of metabolites in VTE. Metabolic pathway analysis was performed using MetOrigin, and druggability assessments were conducted to prioritize potential therapeutic targets. Additionally, a 2-step Mendelian randomization framework was employed to elucidate the mediating effects of metabolites on the relationships between modifiable risk factors and VTE.

After Bonferroni correction, 51 plasma metabolites and 18 urinary metabolites were significantly associated with VTE risk. Colocalization evidence supported causal relationships for 37 metabolites with VTE. Eleven metabolic pathways were identified for VTE-related metabolites, and 6 metabolites were prioritized as potential therapeutic targets. Twenty-four modifiable risk factors were associated with 28 VTE-related metabolites, 7 of which were linked to VTE risk. Mediation analyses further revealed significant mediating effect of 8 metabolites on how 6 modifiable factors influenced VTE.

This study identifies potential metabolite biomarkers associated with VTE risk and uncovered the metabolic mediators between modifiable risk factors and VTE, offering new insights for future prevention and treatment strategies.

A 30-day feeding trial was conducted to assess the effect of three fresh-live polychaetes as diets on growth and reproductive performance, biochemical indices and histology of different tissues in female Pacific white shrimp (Litopenaeus vannamei) broodstock. Two novel polychaete species, Marphysa maxidenticulata (MM group) and Perinereis nuntia (PN group), and a traditional species, Perinereis aibuhitensis (PA group), were used as a single diet and individual experimental groups, respectively. A total of 225 healthy female broodstock shrimp, initial weight of 59.70 ± 0.18 g, were randomly divided into three groups (three replicates of 25 shrimp each). The results showed that the MM group outperformed the PA and PN groups in growth indices, with the highest weight gain, specific growth rate, molting rate, protein efficiency ratio, gonadosomatic index, and lower feed conversion ratio compared to the PN group (P < 0.05). Regarding reproductive performance, the MM group had the highest daily number of sexually mature female broodstock shrimp, successful mating count, maturity rate, mating rate, spawning cycle, total number of fertilized eggs, individual fertilized egg yield, area of mature oocytes, total number of nauplii, naupliar yield/shrimp, hatching rate, and the lowest naupliar deformity rate than the other two groups (P < 0.05). Moreover, compared to the PA and PN groups, the MM group demonstrated superior activities of lipid metabolism-related enzymes and digestive enzymes, and antioxidant capacity in the hepatopancreas, intestine and serum, as well as reduced malondialdehyde levels. Meanwhile, the ovaries of the MM group showed a significant accumulation of triglycerides, estradiol, and vitellogenin compared to the other groups. Histology revealed more developed secretory cells in the hepatopancreas and larger mature oocytes in the MM group compared to the others. In conclusion, M. maxidenticulata can maximize growth, reproductive performance, the activities of lipid metabolism-related enzymes and digestive enzymes, antioxidant and immune ability of female broodstock shrimp. This study demonstrated that M. maxidenticulata could be used as a potential fresh-live diet for the female L. vannamei broodstock.

The causative agent of giardiasis in human and animals is the amitochondriate Giardia lamblia. We observed that exposing Giardia trophozoites to MTZ led to an increase in lipid peroxidation compared to the control group, which was expressed in terms of menadione production as it is the marker for lipo-peroxidation. Oxidative stress generated by reactive nitrogen species and peroxidation of membrane phospholipids are positively correlated with the enhanced PLA2 activity in several organisms to produce arachidonic acid (AA). Our data suggested Giardia produces a unique 56 kDa dimeric enzyme called Phospholipase B (gPLB) in contrast to higher eukaryotes which was responsible for the production of intracellular free AA. This free AA either reacylates to the cell membrane or deacylates to further produce prostaglandins. In normal un-induced controlled trophozoites the membrane reacylation process was dominant due the higher level of acyle CoA synthase (ACS) expression over the time. However, under the oxidative stressed condition the intracellular ACS expression was down regulated. This led to the increase in deacylation process. When AA deacylation becomes dominant over AA reacylation in cells, the free AA accumulates intracellularly. One of the lipid autacoids, derived from AA is prostaglandin2 (PGE2). Oxidative stress generated by reactive nitrogen species in trophozoites increased the PGE2 production via prostaglandin synthase over the time with respect to the controlled one.

Knee osteoarthritis (KOA) is a prevalent chronic knee joint disease, occurring mainly in the elderly and obese populations. In traditional Chinese medicine (TCM) theory, KOA is categorized as "knee bi" and "bi syndrome," primarily caused by external factors such as wind, cold, and dampness, as well as internal deficiencies. The treatment with Chinese herbal medicine focuses on dispelling wind, cold, and dampness, as well as promoting blood circulation and removing blood stasis. Huoluo Xiaoling Pellet (HXP), derived from Zhang Xichun's "The Records of Traditional Chinese and Western Medicine in Combination " during the Qing Dynasty, was known for its effects of activating blood circulation to remove stasis and alleviating pain by unblocking the collaterals, mainly used for treating conditions with stagnation of qi and blood. It has been included in the "Ancient Classic Prescriptions" by the National Administration of Traditional Chinese Medicine. However, the pharmacodynamic compounds, specific actions, and mechanisms of HXP on KOA have not yet been elucidated.

Through qualitative and quantitative analysis, combined with multi-omics technology and network pharmacology, the key bioactive compounds and related mechanisms of HXP in improving knee osteoarthritis were explored.

UHPLC-Q-Orbitrap-MS and HPLC were used to analyze the chemical composition of HXP, chemometric analyses was used for quality control. The therapeutic effect of HXP was evaluated by Anterior Cruciate Ligament Transaction (ACLT)-induced KOA mouse model, and proteomics and lipid metabolomics were combined with network pharmacology and molecular docking techniques to explore for the key bioactive compounds and mechanisms.

Identified 53 compounds in HXP, with Salvianolic acid B as a key quality marker and potential active compound for KOA. HXP reduced pain, protected chondrocytes, reduced oxidative stress, and improved bone parameters. The combined multi-omics analysis indicates that the protein targets of SHIP1, PTPRC, the cytochrome P450 enzyme family including Cyp1a2, Cyp2c29, Cyp2c50, Cyp2c544, as well as the JAK2/STAT3 pathway, play crucial roles in the improvement of KOA.

Our results demonstrated that HXP was an effective drug to improve the development of KOA. Among them, Salvianolic acid B, the most abundant compound in HXP and the best computer simulation result, may be the key monomer compound of HXP for KOA treatment. The results of the visualisation analysis further contributed to our understanding of HXP treatment of KOA in terms of changes in SHIP1, PTPRC proteins and cytochrome P450 enzyme family. This is associated with the SHIP1/PI3K/AKT and JAK2/STAT3 pathways, as well as arachidonic acid metabolism and immune regulation.

Background: Although prostate cancer (PCa) is the most diagnosed cancer in men worldwide, there is geographical variance in both incidence and morbidity, with higher levels in developed "Western Diet" countries. In particular the high levels of the omega-6 polyunsaturated fatty acid, arachidonic acid (AA), in Western diets has been shown to promote aggressive PCa in vitro. However the exact mechanism through which AA induces the aggressive phenotype has not been fully characterised. Methods: In this study Fourier transform infrared (FTIR) imaging coupled with fluorescence microscopy (FM), is used to follow AA metabolism in PCa cell lines. This is achieved using partially deuterated AA, with a distinctive C-D stretch seen at 2251 cm-1 providing molecular specificity, coupled with Nile Red Fluorescence imaging. Results: We show that, invasive cell lines PC-3, LNCaP C4-2B and DU145 readily uptake and metabolise AA, producing prostaglandins via the COX-2 pathway. Inhibition of the COX-2 pathway with either NS938 or the omega-3 polyunsaturated fatty acid Docosahexaenoic acid (DHA), reduces the invasive stimulus of AA and blocks its uptake. Conclusion: This demonstrates that FTIR imaging can be utilised to follow metabolomics processes within a PCa model and provide an insight to the molecular pathways underlying the cancer metabolome. Additionally, these works provide key insights into the rapid uptake of AA within certain invasive cell lines of prostate cancer, suggesting that AA exposure initiates early cellular responses prior to the uptake and processing of lipids within the cells.

Microbiota-metabolome interactions play a crucial role in host physiological regulation and metabolic homeostasis. The aim of this study was to investigate that sex induces alterations in rumen microbial community composition and metabolite profiles in lambs and the influence on body weight. This study aimed to demonstrate that sex- induced alterations in rumen microbial community and metabolite profiles and blood indices and their linkage to growth performance in lambs.

This study examined (growth indices, serum indices, rumen fermentation parameters, rumen fluid microbiota community and metabolome profiles) in 180 Hu lambs (90 males, and 90 females) with the same age and diet. At six months, male lambs showed significantly greater body weight, serum indices (glutamic pyruvic transaminase, glutamic oxalacetic transaminase, growth hormone, glucagon-like peptide 1, and ghrelin), and molar percentage of propionic acid, isobutyric acid, butyric acid, isovaleric acid and valeric acid compared to female. However, male had lower VFA molar concentrations (acetic acid, propionic acid, butyric acid, and TVFAs), acetic acid/propionic acid, and VFA molar percentage (acetic acid) than female. Significant sex-related differences were observed in rumen microbiota and metabolic enrichment between genders. Moreover, compared with the females lambs, the relative abundance of Succiniclasticum, uncultured_rumen_bacterium, NK4 A214_group, Veillonellaceae_UCG_001 and Butyrivibrio in the male lambs has been significantly increased, while the relative abundance of Prevotella has been significantly decreased (P < 0.05). Notably, there were significant rumen microbiota-metabolite interactions, especially Firmicutes and Bacteroidota as dominant phyla in the sheep rumen with significant differences in correlation with rumen metabolic modules. Additionally, there are pronounced correlations among the microbiota, particularly within the Firmicutes phylum. Furthermore, the up-regulated metabolites in the rumen fluid of male lambs were predominantly enriched in the amino acid metabolite pathway, and these metabolites exhibited a significant positive correlation with body weight. However, the metabolites that were up-regulated in ewe lambs were predominantly enriched in the lipid metabolic pathway, and these metabolites exhibited a significant negative correlation with body weight. Moreover, lamb rumen microbial markers (Lachnospiraceae_UCG_008, Saccharofermentans, unclassified_Clostridia, Christensenellaceae_R_7_group, Anaerovorax, Mogibacterium, and unclassified_Erysipelotrichaceae) and metabolic markers (C75, 4-Coumarate, Flibanserin,3-Amino-5-mercapto-1,2,4-triazole, 1,3-Propane sultone, Fingolimod phosphate ester, S-,) were significantly positively correlated with body weight, but lamb rumen microbial markers (Anaeroplasma, unclassified_Acholeplasmataceae, uncultured_rumen_bacterum_4c28 d_15) and metabolic markers (Mozenavir, Reduced riboflavin, PG(18:2(9Z,12Z)/0:0), Cowanin) were significantly negatively correlated body weight.

This study shows that sex-induced alterations in rumen microbial communities and metabolite profiles, adapting to the growth and development of lambs. The findings may help develop targeted strategies to optimize sheep rumen microbiota and improve productivity.

Oxylipins are bioactive lipids involved in inflammation. This study evaluated how a 2-week anti-inflammatory diet (ITIS, omega-3/omega-6 ratio of 1:1.5) affects plasma oxylipin profiles in patients with active Rheumatoid Arthritis (RA).

In an open-label pilot trial, 20 RA patients (≥3 tender and ≥3 swollen joints) followed the ITIS diet. Targeted lipidomics by mass spectrometry was used to quantify oxylipins. Patients were classified as responders or non-responders based on ≥50 % pain reduction (Pain-50). Dietary intake was assessed through diet scores, and statistical analyses were performed using RStudio.

Participants were predominantly female (90 %) with an average age of 57.1. At baseline, responders consumed more walnuts (p = 0.08), almond milk (p = 0.06), avocado (p = 0.04), and quinoa (p = 0.05), and fewer burgers (p = 0.02). No differences in diet adherence were observed between groups. Baseline oxylipin levels did not differ significantly. However, after the intervention, six oxylipins-5-HETE, 11,12-diHETrE, 14,15-diHETrE, 19,20-DiHDPA, 9-oxo-ODE, and 14,15-EET-differed significantly between responders and non-responders. Notably, oxylipins derived from both arachidonic acid (omega-6) and eicosapentaenoic acid (omega-3) decreased significantly after the diet (p = 0.0006 and p = 0.01, respectively).

The anti-inflammatory diet modified circulating levels of both pro- and anti-inflammatory oxylipins. These changes varied by pain response, suggesting that diet can influence inflammatory pathways in RA. Further studies are warranted to clarify the mechanisms linking dietary changes, oxylipin modulation, and clinical outcomes.

NCT04999683.

Epstein-Barr virus (EBV) is a gamma herpesvirus that infects up to 95% of the human population by adulthood, typically remaining latent in the host memory B cell pool. In immunocompromised individuals, EBV can drive the transformation and rapid proliferation of infected B cells, ultimately resulting in neoplasia. The same transformation process can be induced in vitro, with EBV-infected peripheral blood B cells forming immortalized lymphoblastoid cell lines (LCLs) within weeks. In this study, we found that the fatty acid desaturases stearoyl-CoA desaturase 1 (SCD1) and fatty acid desaturase 2 (FADS2) are upregulated by EBV and crucial for EBV-induced B cell proliferation. We show that pharmacological and genetic inhibition of both SCD1 and FADS2 results in a significantly greater reduction in proliferation and cell cycle arrest, compared to perturbing either enzyme individually. Additionally, we found that inhibiting either SCD1 or FADS2 alone hypersensitizes LCLs to palmitate-induced apoptosis. Further free fatty acid profiling and metabolic analysis of dual SCD1/FADS2-inhibited LCLs revealed an increase in free unsaturated fatty acids, a reduction of oxidative phosphorylation, and a reduction of glycolysis, thereby linking the activity of SCD1 and FADS2 to overall growth-promoting metabolism. Lastly, we show that SCD1 and FADS2 are important in the growth of clinically derived EBV+ immunoblastic lymphoma cells. Collectively, these data demonstrate a previously uncharacterized role of lipid desaturation in EBV+ transformed B cell proliferation, revealing a metabolic pathway that can be targeted in future anti-lymphoma therapies.

Myocardial ischemia/reperfusion (I/R) injury is a substantial challenge to the management of ischemic heart disease, the leading cause of mortality worldwide. Arachidonic acid (AA) is a prominent polyunsaturated fatty acid in the human body and plays an important role in various physiological and pathological conditions. AA metabolic enzymes determine AA levels; however, currently there is no comprehensive analysis of AA enzymes in cardiac I/R injury.

The profiling of AA metabolic enzymes was analyzed with the RNA sequencing transcriptome data from the mouse heart tissues with I/R injury. Cultured neonatal and adult rat ventricular myocytes, human embryonic stem cell-derived cardiomyocytes, and in vivo mouse I/R models were used to confirm the role of L-PGDS (lipocalin-type prostaglandin D2 synthase)/15d-PGJ2 in I/R injury. A biotin-tagged 15d-PGJ2 analog combined with liquid chromatography-tandem mass spectrometry was used to identify the downstream signaling of L-PGDS/15d-PGJ2.

Based on the transcriptome data and experimental validations, L-PGDS, together with its downstream metabolite 15d-PGJ2, was downregulated in cardiac tissue with I/R injury. Functionally, L-PGDS overexpression mitigates myocardial I/R injury, whereas knockdown exacerbates the damage. Supplementation of 15d-PGJ2 alleviated I/R injury. Mechanistically, 15d-PGJ2 covalently bound to the Ca2+/CaMKII (calmodulin protein kinase II) and induced lipoxidation of its cysteine 495 (CaMKII-δ9) to dampen the formation of CaMKII oligomers and alleviate its overactivation, consequently ameliorating cardiomyocyte death and cardiac injury.

Our study uncovered L-PGDS/15d-PGJ2/CaMKII signaling as a new mechanism underlying I/R-induced cardiomyocyte death. This provides new mechanistic insights and therapeutic targets for myocardial I/R injury and subsequent heart failure. We also showed that lipoxidation is a new post-translational modification type for CaMKII, deepening our understanding of the regulation of its activity.

Type I and type II pyrethroids are widely used and frequently detected in agricultural environments. The neurotoxic effects and underlying mechanisms of pyrethroids in native animal populations, including lizards as common farmland inhabitants, remain unclear. This study exposed male lizards (Eremias argus) to type I bifenthrin (BF) and type II fluvalinate (FA) pyrethroids for 28 days, resulting in abnormal behaviors. Targeted analyses indicated that neurotransmitters, including dopamine, GABA, acetylcholine, and choline in lizard plasma, were significantly decreased with alterations in the cholinergic synapse, dopaminergic synapse, and cAMP signaling pathway in the brain after BF and FA treatment. Nervous system-related genes such as CACNA1A, CACNA1B, and CACNA1C were significantly down-regulated and highly correlated with arachidonic acid metabolism pathway-related metabolites in lizard gut. A notable decrease in metabolites within the arachidonic acid metabolism pathway and alterations in the gut microbiome were indicative for anti-inflammatory responses and neurotoxic effects. Interestingly, increased type I BF bioaccumulation in lizard intestines induced a higher abundance of Akkermansia, which resulted in reduced inflammation in the gut and lower neurotoxic effects compared to the low-dose BF exposure group. This study reveals contrasting dose-responses between pyrethroid types and suggests gut-brain axis-regulated neurotoxicity in lizards.

Saussurea graminea Dunn (SG), a traditional Chinese medicinal herb known as "Za Chi" in Tibet of China, is frequently utilized in the treatment of inflammatory diseases such as hepatitis. However, the active ingredients and mechanism of its therapeutic effect on Sepsis - associated liver injury (SALI) remain unclear.

To elucidate the effect of SG in combating SALI, uncover its mechanism of action, and explore possible active compounds.

We established a SALI model by intraperitoneal injection of lipopolysaccharide to assess the efficacy of SG. Transcriptomics and metabolomics were employed to reveal its possible mechanism of action. Subsequently, Western blot, flow cytometry, confocal microscopy, quantitative PCR, HPLC-MS, and molecular docking were utilized to verify its mechanism and active ingredients.

SG effectively counteracts SALI by inhibiting the cytokine storm. Transcriptomics indicates that SG regulates SALI through mitochondrial/TNF and metabolic pathways. Metabolomics demonstrates that arachidonic acid metabolism is involved in the process of SG treating SALI. HPLC-MS identified the main components of SG as chlorogenic acid, syringin, scopoletin, rutin, isochlorogenic acid, and narcissin, and these six compounds were confirmed as potential active components in the RAW264.7 inflammation model.

SG and its active ingredients play a role in alleviating SALI by reducing the cytokine storm through mtDNA/TNF/arachidonic acid metabolism.

Parkinson's disease (PD) is the second most common neurodegenerative disease, with a rapidly increasing prevalence worldwide. Biomarkers monitoring state and progression are urgently needed, and metabolomics from easily accessible biofluids holds the potential to elucidate pathophysiological underpinnings in PD. Several studies suggested metabolomic differences between patients and controls, but findings are controversial, and independent replication is scarce. We thus applied state-of-the-art, large-scale metabolomics in patients with idiopathic and monogenic PD and controls from two independent samples, analyzed by a strict meta-analysis approach. Thereby, we (i) debunked that l-Dopa medication and not disease status causes the most substantial metabolomic differences and (ii) identified polyamine metabolism alterations, partly, but not entirely associated with l-Dopa treatment. Furthermore, we found explorative but robust evidence for alterations in endocannabinoid metabolites; detected lipid metabolism alterations, highlighting potential crosslinks with alpha-synuclein pathology; and provided evidence for a metabolomic signature for the role of oxidative damage in patients with PRKN- and PINK1-linked PD.

Microplastics, particularly polymethyl methacrylate (PMMA), have emerged as significant environmental pollutants, with growing concerns about their impact on various biological processes. However, the effects of chronic PMMA exposure on hepatic lipid metabolism remain insufficiently studied. This research aimed to examine the consequences of chronic exposure to PMMA particles of different sizes (100 nm and 2 μm) on hepatic lipid metabolism in mice. Female C57BL/6J mice were administered PMMA particles in drinking water over an 8-week period, and the effects on intestinal and liver morphology and function were evaluated. Histopathological analyses, gut microbiota profiling, and serum and liver assays were conducted to assess oxidative stress, lipid metabolism-related biomarkers, and liver metabolomics. The results revealed that PMMA particles accumulated in both the liver and colon, causing liver injury characterized by elevated ALT and AST levels. The exposure also induced oxidative stress by inhibiting the NRF2/HO-1 signaling pathway. Furthermore, PMMA exposure resulted in significant alterations to the gut microbiota and hepatic metabolism. These changes were linked to increased microbial diversity, which impacted cholesterol metabolism through the gut-liver axis. Additionally, the activation of the PI3K/AKT/PPARγ signaling pathway disrupted hepatic lipid metabolism, leading to increased cholesterol synthesis and hepatic lipid accumulation. This study underscores the potential of PMMA to disrupt both hepatic lipid metabolism and gut microbiota composition, suggesting a novel mechanism by which PMMA exposure could contribute to metabolic disorders and liver disease.

Alopecia areata (AA) is a common autoimmune disorder marked by non-scarring hair loss, which imposes significant psychosocial stress on patients. To investigate key metabolites and ions involved in AA's pathogenesis, we utilized gas chromatography-mass spectrometry (GC-MS) for non-targeted metabolomics and inductively coupled plasma mass spectrometry (ICP-MS) for ionomics.

A total of 36 six-week-old Kunming mice were divided into control (n = 12), an AA model (n = 12), and tofacitinib-treated groups (n = 12). A mouse model of AA was established by sodium sulfide (Na2S) induction in both the model and treatment groups, while the treatment group (n = 12) received tofacitinib treatment at a dose of 1 mg/kg. GC-MS was used to determine the metabolic profiling in serum samples, and ICP-MS was applied to assess ionomic changes in the serum samples. Potential metabolites and ions were identified using orthogonal partial least squares-discriminant analysis (OPLS-DA). Subsequently, MetaboAnalyst 5.0 and the Kyoto Encyclopedia of Genes and Genomes database (KEGG) were used to map the metabolic pathways. Spearman correlation analysis was conducted to identify relationships and potential regulatory interactions between differential metabolites and individual ions.

Metabolomics analysis revealed that D-lactic acid, glycolic acid, linoleic acid, petroselinic acid, and stearic acid are key differential metabolites between the control, AA model, and tofacitinib groups. Pathway analysis highlighted that the biosynthesis of unsaturated fatty acids and linoleic acid metabolism are pivotal pathways implicated in the onset and progression of AA. Furthermore, ionomics analysis identified magnesium, aluminum, titanium, and nickel as differential ions among the three groups. The integrated metabolomics and ionomics analysis indicated that linoleic acid, a key differential metabolite according to the KEGG database, shows a positive correlation with phosphorus, vanadium, magnesium, and zinc. Among these, Mg2+ (Mg2+) play a crucial role in modulating CD8+ T cell infiltration, thereby influencing the disease progression in AA.

Tofacitinib inhibits CD8+ T cell infiltration in hair follicles affected by sodium sulfide-induced AA by modulating the linoleic acid metabolism-Mg2+ pathway. Our findings offer new insights and potential avenues for the clinical diagnosis and treatment of AA, suggesting that targeting metabolic and ionic pathways could enhance therapeutic outcomes.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that is prevalent worldwide with complex etiology. Skin barrier defects and abnormal immune activation are crucial in the occurrence and development of AD. In the classic model of the skin barrier, lipids are essential for the formation and maintenance of this barrier as a "mortar" component. However, abnormally activated immune responses promote the lipid barrier deficiency through the secretion of various types of immune mediators directly or indirectly. In this review, we first introduce the skin lipid barrier (SLB) under both normal and abnormal conditions, highlighting the contributions of lipids derived from keratinocytes and sebaceous glands (SGs). Subsequently, the relationships between the immune mediators of Th1, Th2, Th17, Th22, and other types (adipokines, prostaglandins, leukotrienes) and SLB are elaborated in turn. Finally, the therapies for restoring SLB to treat AD are summarized, with a focus on the restoration effect of dupilumab on SLB. We hope that this review will offer a comprehensive perspective for understanding the pathogenesis of lipid metabolism disorders and SLB deficiency caused by immune mediators in AD. It also aims to provide guidance for further research on targeting inflammatory mediators to restore SLB.

The complex interplay between protein palmitoylation, mitochondrial dynamics, and inflammatory responses plays a pivotal role in respiratory diseases. One significant feature of post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS) is the occurrence of a storm of inflammatory cytokines related to the NOD-like receptor protein 3 (NLRP3). However, the specific mechanisms via which palmitoylation affects mitochondrial function and its impact on the NLRP3 inflammasome under pathological respiratory conditions remain to be elucidated.

This study aimed to investigate how protein palmitoylation influences inflammatory responses and mitochondrial dynamics in respiratory diseases, such as those induced by the SARS-CoV-2 spike S protein in PACS, thereby providing a therapeutic target for inflammatory lung injury.

In vivo experiments were conducted using AdV5-pADM-CMV-COVID-19-S (AdV5-S) nasal drip-treated C57BL/6 mice to assess NLRP3 inflammasome activation and inflammatory response. In vitro experiments were performed using pCMV-S-transfected human lung epithelial BEAS-2B cells to analyze the effects of DHHC5-mediated palmitoylation of cyclooxygenase-2 (COX-2) at cysteine 555 (COX-2Cys555) on mitochondrial metabolism and NLRP3 inflammasome activation.

Palmitoylation of COX-2Cys555 enhanced its interaction with hexokinase 2 (HK2) to regulate mitochondrial metabolic reprogramming, leading to NLRP3 inflammasome activation and pyroptosis. Pharmacological and genetic suppression of palmitoylation diminished the mitochondrial localization of palmitoylated COX-2 and its interaction with HK2, thereby reducing mitochondrial metabolic reprogramming. Furthermore, genetic intervention targeting DHHC5 (shDhhc5) alleviated NLRP3 activation and pyroptosis, mitigating the chronic inflammatory damage associated with PACS.

This study highlights the regulatory role of COX-2Cys555 palmitoylation in mitochondrial metabolism and lung inflammatory injury, and suggests potential therapeutic targets to combat respiratory pathogenesis linked to palmitoylated COX-2.

This study investigates the therapeutic mechanisms of Qiliqiangxin (QLQX) capsules in treating Heart Failure with Preserved Ejection Fraction (HFpEF). The study aims to understand how QLQX impacts cardiac function and underlying molecular pathways.

HFpEF was induced in a rat model through unilateral nephrectomy, DOCA pellet implantation, and a high-salt diet. Cardiac function was assessed via M-mode imaging and Doppler flow measurements, focusing on key parameters like ejection fraction and diastolic function. A network pharmacology approach identified active QLQX components and potential targets, followed by comprehensive multi-omics analyses-including transcriptomics, proteomics, and metabolomics-to uncover the molecular mechanisms modulated by QLQX. Quantitative RT-PCR was employed to measure mRNA levels of key cardiac markers, providing further insights into QLQX's impact on cardiac remodeling.

QLQX treatment significantly improved cardiac function, with notable enhancements in ejection fraction and left ventricular diastolic function. Network pharmacology revealed 530 potential targets of QLQX, with 38 overlapping HFpEF targets. Key pathways identified include cGMP-PKG, adrenergic signaling, and calcium signaling. Transcriptomic analysis showed significant gene expression changes related to inflammation, energy metabolism, and myocardial remodeling, which were reversed by QLQX. Proteomic analysis identified 401 differentially expressed proteins, enriched in pathways such as cGMP-PKG and NF-κB signaling. Metabolomic profiling highlighted the role of lipid metabolism and adrenergic signaling in HFpEF, which were normalized by QLQX. In vivo validation confirmed the involvement of the cGMP-PKG pathway, with increased serum NO and cGMP levels, improved endothelial function, and reduced pro-fibrotic markers following QLQX treatment.

QLQX exerts multifaceted therapeutic effects on HFpEF by modulating gene expression, protein function, and metabolic pathways, particularly through the cGMP-PKG signaling pathway. These findings support QLQX as a promising therapeutic intervention for HFpEF, offering improvements in cardiac function and reversing pathological changes at multiple molecular levels.

Acute intra-abdominal infection (IAI) is a prevalent and life-threatening condition in general surgery, with significant implications for patient mortality. However, the timely identification of IAI is often hindered by the limitations of current medical laboratory sciences and imaging diagnostics.

To address this critical issue, we employed metabolomics to identify early biomarkers for IAI. In this study, we enrolled a cohort of 30 IAI patients and 20 healthy volunteers. Following preliminary experimental processing, all serum and urinary samples were subjected to ultrahigh performance liquid chromatography-triple time-of-flight mass spectrometry analysis. Initial metabolite profiling was conducted using total ion current chromatography and principal component analysis. Differential metabolites were subsequently identified through Student's t-test, partial least squares discriminant analysis, and support vector machine. Hierarchical clustering analysis was then applied to assess the discriminatory power of the selected metabolites. Based on receiver operating characteristic curve analysis, we identified the most promising biomarkers, which were further subjected to enrichment analysis. Additionally, we stratified patients according to the severity and etiology of IAI to explore potential differences among these subgroups.

Our findings revealed five serum and two urinary metabolites as potential biomarkers for IAI. The serum biomarkers were associated with the Fatty Acid Biosynthesis pathway, while the urinary biomarkers were linked to the Catecholamine Biosynthesis pathway. Notably, no significant differences were observed among the three types of IAI or the seven etiologies studied.

For individuals at risk of IAI, regular screening of these biomarkers could facilitate the early and convenient identification of the condition, thereby improving patient outcomes.

Apolipoproteins are the defining functional component of lipoproteins and play critical roles in lipid transport and metabolism. High-density lipoprotein (HDL) and its primary functional constituent, apolipoprotein A-I, are of particular importance because of anti-inflammatory and antioxidant properties. Apolipoprotein mimetic peptides are short-chain amino acids designed to mimic the functions and alpha-helical structure of endogenous apolipoproteins and have demonstrated efficacy in ameliorating animal models of cardiovascular disease (CVD) and cancer. The mechanisms underlying the mimetics are yet to be fully elucidated, but a comprehensive review of the literature suggests that the peptides attack pathways shared in the pathophysiology of both diseases. This review also discusses the many pre-clinical studies on the mimetic peptides, highlighting possible mechanisms at work in each. Proposed mechanisms of protection against CVD and cancer include binding and removal of pro-inflammatory oxidized lipids, reduction in reactive oxygen species, and modulation of immune cell populations. Additionally, nanoparticles (NP) formulations incorporating apolipoprotein mimetic peptides or recombinant apolipoproteins have exhibited anti-atherogenic and anti-cancer activity. To date, clinical trials to assess the effect of reconstituted HDL NPs on CVD outcomes have not shown significant improvement. The large body of successful animal studies on apolipoproteins and apolipoprotein mimetic peptides presents a disconnect between pre-clinical and clinical efficacy, highlighting the need for a more complete understanding of the underlying pathways and mechanisms.

Neuropsychiatric disorders such as bipolar disorder, migraine, major depressive disorder, epilepsy, attention-deficit/hyperactivity disorder, autism spectrum disorder and schizophrenia, are a huge burden on global health, impacting millions of individuals worldwide and posing significant barriers to effective treatment. Despite advancements in medication and psychotherapy, many patients continue to suffer from severe symptoms and receive little alleviation. All of these conditions are quite frequent, yet they affect people in a way that is exceedingly detrimental. The increasing evidence suggests the connection between these disorders and inflammation. Therefore, the use of anti-inflammatory agents, namely cyclooxygenase-2 (COX-2) inhibitors, offers a new approach to prevent and treat neuropsychiatric disorders. This review discusses about the COX pathway and the role of COX-2 in the neuroinflammation. Furthermore, this review highlights the COX-2 inhibitors as a promising therapeutic agent in these neuropsychiatric disorders, however, further studies are required to assess appropriate illness stage-related indication.

This study aims to explore the anti-pharyngitis mechanisms of Achyranthes longifolia (Makino) Makino. extract (ALE) and the anti-inflammatory mechanisms of its major bioactive component, chikusetsusaponin IVa (CIVa). To this end, the present study established an ammonia-induced acute pharyngitis rat model to assess the therapeutic efficacy of ALE and a lipopolysaccharide (LPS)-induced RAW264.7 cells model to evaluate the anti-inflammatory and antioxidant properties of CIVa. Pharyngeal severity was evaluated using appearance index and HE staining, while ELISA was employed to quantify inflammatory cytokines TNF-α, PGE2, and IL-6. Additionally, the levels of SOD, CAT, and MDA were measured to assess antioxidant status. Western blot was conducted to analyze the expression of proteins associated with the Nrf2/NF-κB pathways. The findings indicate that ALE provides protection in the ammonia-induced acute pharyngitis rat model, as evidenced by reduced pharyngeal redness, swelling, and improved histopathological changes. CIVa, the primary constituent of ALE, demonstrates anti-inflammatory effects in LPS-induced RAW 264.7 cells by inhibiting NO production and reducing the levels of inflammatory cytokines in a dose-dependent manner. The underlying mechanism appears to involve the inhibition of the NF-κB pathway, activation of the Nrf2 pathway, modulation of oxidative stress, and reduction of pro-inflammatory cytokine release. These results position ALE and CIVa as promising alternative therapeutic agents for the management of acute pharyngitis and potentially other inflammatory disorders.

The well-paced trigger of inflammation resolution following an inflammatory response is crucial for tissue homeostasis and cancer. In gastrointestinal tumors the Formyl peptide receptor 1 (FPR1) stimulates an inflammation resolution response able to restrain cancer angiogenesis and growth. A preceding inflammatory signal is necessary for the induction of the pro-resolving response. However, if FPR1-induced inflammation resolution and tumor suppressor function require an early pro-inflammatory trigger and how this is achieved remains unknown. A ROS-dependent signaling is activated in response to FPR1 activation. In colorectal carcinoma (CRC) cells, we carefully analyzed this signal showing that FPR1 activation by the fMLF peptide induces biphasic ROS production: a first wave, early, mitochondrial (mROS), followed by a second, late, NADPH oxidase (NOX1)-dependent. mROS cause SHP2 phosphatase inactivation restraining its ability to dephosphorylate and inactivate SRC. SRC, in turn, allows the activation of RAS and Rac1 GTPases. RAS activates MAPK signaling, while Rac1 supports NOX1 activation, that causes the second wave of ROS, reinforcing this signaling cycle. Importantly, for the first time, we demonstrate that mROS production precedes and is necessary for pro-inflammatory mediators' release, while NOX1-dependent ROS are only required for pro-resolving mediators' synthesis. Pharmacological and genetic approaches and functional assays show that this signaling cascade is essential for the pro-resolving and anti-angiogenic properties of FPR1 in CRC. In conclusion, we show that FPR1 elicits pro-resolving effects in CRC activating two waves of ROS production characterized by different strength and kinetics, that parallel and are necessary for pro-inflammatory or pro-resolving mediators' production.

Intestinal barrier damage is frequently caused by antibiotic therapy, potentially leading to bacterial translocation and toxin leakage, which triggers inflammation and increases the risk of various diseases. In this study, Tamarind seed polysaccharides (TSP) with different molecular weights were administered to mice during the recovery phase from clindamycin-induced intestinal barrier damage. The results indicated that TSP restored the shortened colon length, reduced the enlarged cecum index, and decreased the elevated level of inflammatory infiltration. Biochemical testing revealed that TSP decreased the levels of intestinal permeability biomarkers and inflammatory factors that were elevated by clindamycin treatment. Transcriptomics and non-targeted metabolomics analyses respectively uncovered changes in colon gene expression and fecal metabolites. The joint analysis of these omics data identified critical pathways, including arachidonic acid metabolism, retinol metabolism, and steroid hormone biosynthesis. These findings suggest that TSP could be a promising dietary supplement for protecting the intestinal barrier and alleviating inflammation.

In order to evaluate anti-inflammatory role of eucalyptol (100, 200, and 400 mg/kg orally), inflammation was induced in rats using 0.1 ml of histamine and 0.1 ml of formaldehyde. Furthermore, in vivo gastroprotective potential of eucalyptol (100, 200 and 400 mg/kg) was determined via the intraperitoneal injection of 25 mg/kg indomethacin as an ulcerative agent and omeprazole (30 mg/kg) orally as a standard. Estimation of biochemical (PGE2, ICAM-1, COX-I, COX-II, eNOS and 5-LOX) and oxidative stress (SOD, CAT, GSH, and MDA) markers were carried out in gastric tissues using ELISA. The morphological and histopathological features of the gastric tissues were studied. In vitro, eucalyptol stabilized red blood cell membranes and inhibited protein denaturation, with the maximum effect observed at a concentration of 6400 μg/mL. Eucalyptol significantly reduced rat paw edema in histamine- and formaldehyde-induced inflammation models. It increased gastric PGE2, COX-I and eNOS levels, and decreased COX-II, 5-LOX and ICAM-1. Eucalyptol reduced ulcer indices and improved histopathological changes. Eucalyptol also increased antioxidants levels with decreased MDA levels in isolated rat stomach tissues. Therefore, eucalyptol shows gastroprotective effects against histamine- and formaldehyde induced inflammation and indomethacin-induced gastric ulcers through the modulation of the COX/LOX, ICAM-1, eNOS pathways and oxidative stress biomarkers.

Sepsis-related acute liver injury involves complex immune dysfunctions. Epoxyeicosatrienoic acids (EETs), bioactive molecules derived from arachidonic acid (AA) via cytochrome P450 (CYP450) and rapidly hydrolyzed by soluble epoxide hydrolase (sEH), possess anti-inflammatory properties. Nevertheless, the impact of the sEH inhibitor TPPU on sepsis-related acute liver injury remains uncertain.

This study utilized comprehensive single-cell analysis to investigate the immunoregulatory mechanism of TPPU in alleviating sepsis-related acute liver injury.

Hepatic bulk RNA sequencing and proteomics analyses were employed to investigate the mechanisms underlying sepsis-related acute liver injury induced by cecal ligation and puncture in mice. Cytometry by time-of-flight and single-cell RNA sequencing were conducted to thoroughly examine the immunoregulatory role of TPPU at single-cell resolution.

Downregulation of AA metabolism and the CYP450 pathway was observed during sepsis-related acute liver injury, and TPPU treatment reduced inflammatory cytokine production and mitigated sepsis-related hepatic inflammatory injury. Comprehensive single-cell analysis revealed that TPPU promotes the expansion of anti-inflammatory CD206+CD73+ M2-like macrophages and PDL1-CD39-CCR2+ neutrophils, reprogramming liver neutrophils to an anti-inflammatory CAMP+NGP+CD177+ phenotype. Additionally, TPPU inhibits the CCL6-CCR1 signaling mediated by M2-like macrophages and CAMP+NGP+CD177+ neutrophils, altering intercellular communication within the septic liver immune microenvironment.

This study demonstrated TPPU's protective efficacy against sepsis-related acute liver injury, underscoring its vital role in modulating liver macrophages and neutrophils and enhancing prospects for personalized immunomodulatory therapy.

The increasing prevalence of depression profoundly affects female ovarian health. Although Cuscutae Semen (CS) is acknowledged for treating reproductive disorders, its pharmacological mechanisms in depression-induced ovarian dysfunction remain insufficiently explored. This study investigated CS's effects in a chronic unpredictable mild stress (CUMS) mouse model of depression. Mice were divided into control, CUMS model, CS treatment and estradiol treatment group. Behavioral and biochemical analyses assessed depressive-like behaviors and hormone levels. Untargeted metabolomics utilizing ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was applied to identify differential metabolites of CS in the treatment of depression-induced ovarian dysfunction. These findings were confirmed through real-time quantitative polymerase chain reaction assays. Based on the outcomes from behavioral and biochemical assays, CS effectively ameliorated the chronic unpredictable mild stress-induced reproductive ailment in mice. Ten differential metabolites were identified, highlighting the impact of CUMS and CS's ameliorative effects. Pathways linked to arachidonic acid metabolism, glycerophospholipid metabolism, linoleic acid metabolism, and steroid hormone biosynthesis were involved. Seven target genes further validated the metabolomic analysis. This study provides strong evidence of CS's therapeutic potential in alleviating depression-induced ovarian dysfunction, shedding light on its pharmacological mechanisms and supporting its use as a functional medical food.

15-Lipoxygenase-2 (15-Lox-2) is one of the key enzymes in arachidonic acid (AA) metabolic pathway, which belongs to the unsaturated fatty acid metabolic pathway. This pathway is involved in the foam cell transformation of macrophages during the progression of atherosclerosis (AS). The role of salidroside (SAL) in cardiovascular diseases has been extensively studied, but its impact on macrophage foam cell formation has not yet been clearly clarified. We aimed to determine the effects of 15-Lox-2 deficiency on macrophage (Ana-1 cell) foam cell formation, and those of SAL on 15-Lox-2-deficient macrophages. 15-Lox-2-deficient macrophages were generated using short hairpin RNA. Results indicated that 15-Lox-2 expression in the aorta of atherosclerotic patients is lower than that of the normal group. Additionally, 15-Lox-2 deficiency dramatically promoted macrophage uptake of oxidized low-density lipoprotein (ox-LDL) and increased the Cyclin D1 level while dramatically decreasing caspase3 expression. Furthermore, inflammation, complement, and TNF-α signaling pathways, along with IL1α, IL1β, IL18, and Cx3cl1, were activated in 15-Lox-2-deficient macrophages. These changes were alleviated by SAL through inhibiting AA effects, and the effects of AA on macrophages could be inhibited by SAL. Consistently, phospholipase A2-inhibitor arachidonyl trifluoromethyl ketone (AACOCF3) restored these changes. In summary, SAL reversed the effects of 15-Lox-2 deficiency on macrophages by inhibiting excessive AA and may be a promising therapeutic potential in treating atherosclerosis resulting from 15-Lox-2 deficiency.

Bioactive lipid mediators (LMs) derived from polyunsaturated fatty acids (PUFAs) are key molecules in both the initiation and resolution of inflammatory responses. Previous findings suggest that a dysregulated LM balance, especially within the arachidonic acid (AA) pathway, may contribute to an impaired resolution response and subsequent chronic neuroinflammation in multiple sclerosis (MS). However, to date, the local biosynthesis and signaling of LMs within the brain of people with MS (PwMS) remains unexplored. In this study, we, therefore, mapped the distribution of AA and its key downstream LM prostaglandin E2 (PGE2) in white matter MS brain tissue and of non-neurological controls (NNCs) for the first time using mass spectrometry imaging. We found that AA levels are lower in MS cases compared to NNCs and reduced in MS lesions compared to peri-lesional tissue. Furthermore, the PGE2/AA ratio, indicating the PGE2 synthesis from the AA substrate, was increased in lesion areas compared to fully myelinated regions in MS. In line with that, the expression of prostaglandin synthesizing enzymes as measured by RT-qPCR was partially increased in MS tissue compared to NNCs. In addition, the expression of prostaglandin E2 receptor 4 (EP4) decreased, while prostaglandin E2 receptor 2 (EP2) showed increased expression levels in MS lesions compared to NNCs and localized specifically to microglia. We also found that PGE2 addition to pro-inflammatory human-induced pluripotent stem cell (iPSC)-derived microglia resulted in enhanced cytokine signaling pathways, but also the upregulation of its synthase PTGES and homeostatic/resolving signaling, the latter of which might mainly occur through EP2 signaling. Collectively, our results provide detailed information about the region-specific levels of AA and PGE2 in MS lesions and we propose enhanced PGE2-EP2 signaling in inflamed microglia in MS.

Tumor metabolism plays a pivotal role in shaping immune responses within the tumor microenvironment influencing tumor progression, immune evasion, and the efficacy of cancer therapies. Radiotherapy has been shown to impact both tumor metabolism and immune modulation, often inducing immune activation through damage-associated molecular patterns and the STING pathway. In this study, we analyse the particular characteristics of the tumour metabolic microenvironment and its effect on the immune microenvironment. We also review the changes in the metabolic and immune microenvironment that are induced by radiotherapy, with a focus on metabolic sensitisation to the effects of radiotherapy. Our aim is to contribute to the development of research ideas in the field of radiotherapy metabolic-immunological studies.

This study explored the impact of Bacteroides uniformis (B. uniformis) on fatty liver hemorrhagic syndrome (FLHS) induced by a high-energy and low-protein (HELP) diet in laying hens, mainly focusing on hepatic lipid metabolism, gut microbiota, and arachidonic acid (AA) metabolism. A total of 120 Dawu Golden Phoenix laying hens (210-day-old) were randomly divided into four groups. The control group (CON) was fed a standard diet and received a daily gavage of PBS, while the other groups were fed with a HELP diet to induce FLHS and received a daily gavage of PBS (MOD), 1 × 109 CFU/ml B. uniformis (BUL), and 1 × 1011 CFU/ml B. uniformis (BUH) for 70 days. All hens were administered 1 ml daily by gavage. Each group had 6 replications with 5 hens per replication. The results showed that B. uniformis increased the egg production rate and feed conversion ratio and decreased body weight, liver index, and abdominal fat rate (p < 0.05). B. uniformis treatment reduced liver lipid accumulation by reducing the levels of Triglyceride (TG), Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), alanine transaminases (ALT), and aspartate transaminases (AST) in serum and significantly elevated high-density lipoprotein cholesterol (HDL-C) (p < 0.05). The results indicated that B. uniformis altered the gut microbiota. Specifically, the abundance of Bacteroides was higher, and the relative abundances of Treponema, Helicobacter, and Spirochaetota were lower than those of the MOD group (p < 0.05). Moreover, targeted metabolomic analysis showed that supplementation of B. uniformis significantly elevated 6-keto-PGF1α and AA levels, along with significantly reduced levels of thromboxane B2 (TXB2), leukotriene D4 (LTD4), 8-isoprostaglandin F2α (8-iso-PGF2α), 12S-hydroxyeicosatetraenoic acid (12S-HETE), 15S-hydroxyeicosatetraenoic acid (15S-HETE), 9-S-hydroxy-octadecadienoic acid (9S-HODE), and 13-S-hydroxy-octadecadienoic acid (13S-HODE) (p < 0.05). In conclusion, the oral intake of B. uniformis can improve liver function, gut microbiota, and AA metabolism, thereby helping to ameliorate FLHS in Dawu Golden Phoenix laying hens.

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