Search Results (161)

This study investigated the effects and mechanisms of broccoli extract containing more than 99.0% β-NMN (BRC) on UVB-induced skin damage, including moisture loss, oxidative stress, inflammation, wrinkle formation, and melanin production, using in vitro and in vivo models. BRC treatment significantly alleviated UVB-induced skin dehydration, oxidative stress, and inflammatory responses, as well as inhibited wrinkle formation and melanin synthesis. Mechanistically, BRC enhanced skin hydration and barrier function by upregulating hyaluronic acid synthases and genes related to sphingolipid metabolism, while simultaneously suppressing NF-κB signaling and COX-2 expression, thereby re-ducing inflammation. Moreover, BRC promoted collagen synthesis by activating the TGF-βR1/Smad3/Collagen pathway and prevented extracellular matrix degradation by inhibiting JNK/c-Fos/c-Jun/MMPs signaling. In addition, BRC modulated the cAMP/PKA/CREB/MITF/TRPs pathway, leading to reduced melanin production. These findings suggest that BRC supplementation may effectively protect against UVB-induced skin damage, supporting its potential application as a functional ingredient for skin health. Full article

Sphingolipids are essential for cellular structure and signaling, and recent evidence implicates them in chronic inflammation. We hypothesized that altered sphingolipid metabolism contributes to the disease activity of systemic lupus erythematosus (SLE). Serum sphingolipids were quantified by liquid chromatography–tandem mass spectrometry in 38 female SLE patients (11 with lupus nephritis [LN], 27 without LN) and 30 age-matched healthy controls (HCs). Serum ceramide (Cer)16/sphingosine-1-phosphate (S1P) ratios were elevated in SLE compared to HCs (0.33 [0.26–0.38] vs. 0.25 [0.21–0.3], p = 0.019). Notably, Cer16/S1P levels were significantly higher in the LN group (0.33 [0.26–0.38]) than in non-LN SLE (0.27 [0.2–0.34], p = 0.027). ROC analysis showed good diagnostic potential for LN (AUC = 0.739). Cer16/S1P correlated positively with disease activity markers, including erythrocyte sedimentation rate (r = 0.519, p = 0.001), SLE Disease Activity Index 2000 (SLEDAI-2k) score (r = 0.547, p < 0.001), anti-double stranded DNA antibody levels (r = 0.359, p = 0.027), and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (r = 0.327, p = 0.045). The serum Cer16/S1P ratio may serve as a surrogate marker of disease activity in patients with LN. Full article

Objectives: Erhuang Quzhi Formula (EQF) has been used for the treatment of non-alcoholic fatty liver disease (NAFLD). However, its active components and mechanistic basis remain unclear. This study aims to systematically identify the therapeutic material basis of EQF and to elucidate its potential mechanisms of action against NAFLD through an integrated multi-omics strategy. Methods: An integrated strategy combining UPLC-Q-TOF-MS and network pharmacology was applied to characterize serum components of EQF and construct a compound–target network. Core targets were screened and validated by molecular docking. A NAFLD model was established in C57BL/6 mice through high-fat diet feeding. To evaluate the therapeutic effects, mice were treated with EQF and assessed by measurements of serum biochemical parameters, liver histopathology, and glucose tolerance. UPLC-Q-TOF-based lipidomic and metabolomic analyses of liver tissue were conducted to clarify EQF’s regulatory effects on global lipid profiles and endogenous metabolites. Key genes and proteins involved in relevant signaling pathways were verified by RT-qPCR and Western blot. Results: A total of thirty-one prototype compounds were identified in the EQF-containing serum. Network pharmacology analysis predicted that EQF may alleviate NAFLD by acting on core targets such as TNF, JUN, and STAT3. In vivo experiments demonstrated that EQF administration significantly improved liver function, attenuated dyslipidemia, and reduced inflammation in model mice. Furthermore, metabolomic and lipidomic analyses indicated that EQF effectively reversed abnormal glycerophospholipid and sphingolipid levels and restored their metabolic homeostasis. Conclusions: EQF exerts therapeutic effects in a NAFLD mouse model through multi-component, multi-target, and multi-pathway mechanisms, primarily associated with the regulation of lipid metabolism, improvement of liver function, and suppression of inflammatory responses. This study provides mechanistic insights and a pharmacodynamic basis for the future clinical investigation of EQF. Full article

Gulf War Illness (GWI) is a chronic multi-symptom condition affecting veterans of the 1990–1991 Gulf War, with ocular discomfort increasingly recognized among its manifestations. This pilot study evaluated whether lipid alterations in tears and plasma could serve as potential biomarkers of GWI. Participants included Gulf War-era veterans seen in the Miami Veterans Affairs Hospital eye clinic from 2018–2022. Cases met GWI criteria, while controls were non-deployed, age- and gender-matched veterans without GWI. Participants completed systemic and ocular symptom questionnaires, and lipidomic profiling of tears and plasma quantified sphingolipids and eicosanoids. Compared to controls (n = 21), GWI cases (n = 19) reported greater ocular symptom burden, while ocular signs were similar between groups. Lipidomic analyses revealed increased tear eicosanoids ((±)14(15)-EET and (±)8(9)-EET), elevated plasma sphingomyelins (SM C16:0 DH, SM C20:0, SM C22:0), and reduced plasma monohexosylceramide (MHC C16:0) and sphingomyelin (SM C14:0) in cases. Logistic regression and random forest models identified plasma SM C16:0 DH and SM C20:0 as top predictors distinguishing GWI cases from controls, with an area under the receiver operating characteristic curve (AUC) of 0.89. These findings suggest lipid dysregulation in ocular and systemic compartments and support further investigation of tears as a minimally invasive source for biomarker discovery. Full article

Lipid debris generated after ischemic stroke overwhelms myeloid cells, leading to foam cell-like dysfunction and chronic neuroinflammation. 2-hydroxypropyl-β-cyclodextrin (HPβCD), a cholesterol-mobilizing agent, has been shown to improve recovery and reduce chronic inflammation after stroke by enhancing lipid processing and cholesterol efflux in infarcts. To identify plasma biomarkers of HPβCD activity and gain mechanistic insight into lipid pathway modulation, aged (21-month-old) male mice underwent the distal middle cerebral artery occlusion + hypoxia (DH) model of stroke and received 2 g/kg HPβCD twice daily beginning 1 d after stroke. Plasma metabolomic and lipidomic profiling was performed 4 d after stroke using untargeted (Global Discovery) and targeted (Complex Lipid, Oxysterols, and Lipid Mediators of Inflammation) panels. Acute neuroprotection was assessed by magnetic resonance imaging (MRI) quantification of infarct, ventricle, and hippocampus volumes 2 d after stroke and by plasma neurofilament light (NfL) levels 4 d after stroke. HPβCD treatment did not provide acute neuroprotection; however, HPβCD did induce distinct plasma metabolomic and lipidomic signatures, including decreases in sphingolipids, cholesterol, long-chain fatty acids, 4β-hydroxycholesterol, 7-dehydrocholesterol, and 8-dehydrocholesterol and increases in 27-hydroxycholesterol and 7α-hydroxy-3-oxo-4-cholestenoic acid (7-HOCA), consistent with enhanced cholesterol efflux and metabolism. Pro-inflammatory oxylipins were also suppressed by HPβCD treatment. These results support the role of HPβCD in promoting lipid debris clearance and suppressing inflammatory lipid pathways after stroke and, together with prior studies demonstrating improved long-term recovery, highlight HPβCD as a biomarker-supported therapeutic candidate for stroke recovery. Full article

Type 2 diabetes mellitus (T2DM) is a chronic disease that has become a serious health problem worldwide. Moreover, increased systemic and cerebrovascular inflammation is one of the major pathophysiological features of T2DM, and a growing body of evidence emphasizes T2DM with memory and executive function decline. Bioactive sphingolipids regulate a cell’s survival, inflammatory response, as well as glucose and insulin signaling/metabolism. Moreover, current research on the role of sphingosine kinases (SPHKs) and sphingosine-1-phosphate receptors (S1PRs) in T2DM is not fully understood, and the results obtained often differ. The aim of the present study was to evaluate the effect of metformin (anti-diabetic agent, MET) on the brain’s sphingosine-1-phosphate-related signaling and ultrastructure in diabetic mice. Our results revealed elevated mRNA levels of genes encoding sphingosine kinase 2 (SPHK2) and sphingosine-1-phosphate receptor 3 (S1PR3), which was accompanied by downregulation of sphingosine-1-phosphate receptor 1 (S1PR1) in the hippocampus of diabetic mice. Simultaneously, upregulation of genes encoding pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) was observed. Administration of MET significantly reversed changes in mRNA levels in the hippocampus and reduced Sphk2, Il6, and Tnf, with concomitant upregulation of S1pr1 gene expression. Ultrastructural analysis of diabetic mice hippocampus revealed morphological alterations in neurons, neuropil, and capillaries that were manifested as mitochondria swelling, blurred synaptic structure, and thickened basal membrane of capillaries. The use of MET partially reversed those changes. Our research emphasizes the important role of insulin sensitivity modulation by metformin in the regulation of SPHKs and S1PRs and inflammatory gene expression in a murine model of T2DM. Full article

Microcystin-LR (MC-LR) is a hepatotoxin produced by toxic cyanobacteria such as Microcystis aeruginosa and it poses significant risks to aquatic organisms and human health. However, research on the long-term effects of environmental MC-LR exposure on lipid metabolism in fish is relatively scarce. This research investigates the effects and underlying mechanisms of chronic (one month) low-dose (3.5 μg/kg) MC-LR exposure in common carp (Cyprinus carpio) by using biochemical assays, histopathology, molecular analyses, and lipidomics. In this study, MC-LR exposure significantly altered serum enzyme activities and lipid profiles, induced hepatic inflammation and lipid accumulation, and disrupted hepatopancreatic structure. Meanwhile, key regulators of lipogenesis, fatty acid β-oxidation, and cholesterol metabolism were dysregulated, indicating enhanced lipid synthesis and impaired catabolism. Elevated oxidative stress and pro-inflammatory cytokines likely contributed to lipid metabolic disturbances, exacerbating the hepatotoxicity of MC-LR. Lipidomics profiling revealed significant disruptions in glycerophospholipids, glycerolipids, and sphingolipids, highlighting impaired lipid homeostasis. This study provides novel insights into the hepatic lipid metabolic disorders induced by MC-LR in fish. Full article

Multiple sclerosis (MS) is a chronic, immune-mediated neurodegenerative disorder marked by inflammation, demyelination, and neuronal loss within the central nervous system. Despite advances in diagnostics, current tools remain insufficiently sensitive and specific. Metabolomics has emerged as a promising approach to explore MS pathophysiology and discover novel biomarkers. This PRISMA-guided systematic review included 29 original studies using validated metabolomic techniques in adult patients with MS. Biological samples analyzed included serum, cerebrospinal fluid, and feces. Consistent metabolic alterations were identified across several pathways. The kynurenine pathway demonstrated a shift toward neurotoxic metabolites, alongside reductions in microbial-derived indoles, indicating inflammation and gut dysbiosis. Energy metabolism was impaired, with changes in glycolysis, tricarboxylic acid (TCA) cycle, and mitochondrial function. Lipid metabolism showed widespread dysregulation involving phospholipids, sphingolipids, endocannabinoids, and polyunsaturated fatty acids, some modulated by treatments such as ocrelizumab and interferon-β. Nitrogen metabolism was also affected, including amino acids, peptides, and nucleotides. Non-classical and xenobiotic metabolites, such as myo-inositol, further reflected host–microbiome–environment interactions. Several studies demonstrated the potential of metabolomics-based machine learning to distinguish MS subtypes. These findings highlight the value of metabolomics for biomarker discovery and support its integration into personalized therapeutic strategies in MS. Full article

Background/Objectives: Ulcerative colitis (UC) incidence has risen alarmingly worldwide, posing significant clinical challenges due to limitations of therapeutic efficacy and side effects of current drugs. While Polygonatum kingianum polysaccharides (PKPs) exhibit anti-inflammatory and antioxidant properties, their anti-colitis potential remains unexplored. This study aimed to validate the protective effects of PKPs against dextran sulfate sodium (DSS)-induced colitis and elucidate its mechanisms. Methods: Acute UC was induced in C57BL/6J mice by 3% DSS. PKPs (125 mg/kg) were administered via gavage for 10 days. Integrated approaches included histopathology, tight junction protein (ZO-1/Occludin/Claudin-1) immunohistochemistry, inflammatory/oxidative markers (ELISA), Nrf2 pathway proteins (Western blot), 16S rRNA gut microbiota sequencing, fecal untargeted metabolomics (UHPLC-MS), short-chain fatty acids (SCFAs) analysis and combined analysis. Results: PKPs significantly alleviated colitis phenotypes: reduced weight loss, lowered disease activity index (DAI), and attenuated colon shortening. They restored intestinal barrier integrity by upregulating tight junction proteins and reducing plasma Diamine Oxidase (DAO)/D-lactate (D-Lac)/Endotoxin (ET). PKPs suppressed pro-inflammatory cytokines (TNF-α/IL-1β/IL-6) while elevating IL-10, activated the Nrf2/HO-1/NQO1 antioxidant pathway, and reduced oxidative stress (MDA decreased, SOD/GSH increased). Multi-omics revealed PKPs enriched beneficial bacteria (Blautia, Odoribacter, Rikenellaceae_RC9_gut_group), restored SCFAs (acetate/propionate/butyrate), and modulated metabolic pathways (sphingolipid/linoleic acid metabolism). Conclusions: PKPs ameliorate DSS-induced colitis through multi-target mechanisms: (1) preserving intestinal barrier function, (2) suppressing inflammation and oxidative stress via Nrf2 activation, (3) restoring gut microbiota balance and SCFA production, and (4) regulating host-microbiota metabolic interactions. These findings support PKPs as a promising dietary supplement for UC management. Full article

The health impacts of atmospheric fine particulate matter (PM_2.5) in plateau regions have attracted concerns, along with local population growth and rapid urbanization. This study collected PM_2.5 samples at summer and winter in Xining, a city located in the northeastern Tibetan Plateau. The chemical composition of PM_2.5 and its cytotoxicity on human lung epithelial cells (A549) are characterized, and composition–cytotoxicity correlation is discussed. The toxic mechanisms of PM_2.5 in different seasons were further investigated through metabolomic analysis using high-resolution mass spectrometry. The average PM_2.5 mass concentration in Xining during winter was 2.10 times higher than that during summer. The carbonaceous components in PM_2.5 were dominated by OC, while the main water-soluble ions were SO₄²⁻, NO₃⁻, and NH₄⁺, with Mg, Al, Fe, and Ca also present in high concentrations in metal elements. LDH and ROS emerged as the most PM_2.5-affected toxicity indices in summer (34.59 ± 4.86 ng/L, 1.19× control) and winter (8.62 ± 1.25 ng/mL, 1.77× control), respectively. OC, Cl⁻, F⁻, Sn, Cr, SO₄²⁻, Pb, Zn, Mg, NO₃⁻, and NH₄⁺ may synergistically exacerbate oxidative stress and inflammatory responses on A549 cells in Xining. Furthermore, glutathione metabolism, amino acid metabolism, and sphingolipid metabolism were identified as key pathways influencing cellular oxidation and inflammation. Thimonacic, 9-(2,3-dihydroxypropoxy)-9-oxononanoic acid, and hypoxanthine were common metabolites in both seasons. Our findings greatly enhance the understanding of health risks associated with PM_2.5 in the plateau city. Full article

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

The effects of long-term adjustments in body weight on the lipid balance in patients with severe obesity are not well understood. This study aimed to evaluate a non-invasive lipidomic approach to identifying biomarkers that could help predict which patients may require additional therapies before and after weight loss. Using mass spectrometry, 275 lipid species were analysed in non-obese controls, patients with severe obesity, and patients one year after bariatric surgery. The results showed that severe obesity disrupts lipid pathways, contributing to lipotoxicity, inflammation, mitochondrial stress, and abnormal lipid metabolism. Although weight loss improved these disturbances, surgery did not fully normalise the lipid profiles of all patients. Outcomes varied depending on their baseline liver health and genetic differences. Persistent alterations in cholesterol handling, membrane composition, and mitochondrial function were observed in partial responders. Elevated levels of sterol lipids, glycerophospholipids, and sphingolipids emerged as markers of complete metabolic recovery, identifying candidates for targeted post-surgical interventions. These findings support the use of lipidomics to personalise obesity treatment and follow-up. Full article

Respiratory microbiota and lipids are closely associated with airway inflammation. This study aimed to analyze the correlations among the respiratory microbiome, the airway glycerophospholipid–sphingolipid profiles, and airway inflammation in patients with asthma. We conducted a cross-sectional study involving 61 patients with asthma and 17 healthy controls. Targeted phospholipidomics was performed on exhaled breath condensate (EBC) samples, and microbial composition was analyzed via the 16S rDNA sequencing of induced sputum. Asthma patients exhibited significant alterations in the EBC lipid profiles, with reduced levels of multiple ceramides (Cer) and glycerophospholipids, including phosphatidylethanolamine (PE) and phosphatidylcholine (PC), compared with healthy controls. These lipids were inversely correlated with the sputum interleukin-4 (IL-4) levels. Microbiome analysis revealed an increased abundance of Leptotrichia and Parasutterella in asthma patients, both positively associated with IL-4. Correlation analysis highlighted a potential interaction network involving PA, PE, ceramides, Streptococcus, Corynebacterium, Parasutterella, and Leptotrichia. Specific alterations in airway microbiota and phospholipid metabolism are associated with asthma-related inflammation, supporting the concept of a microbiota–phospholipid–immune axis and providing potential targets for future mechanistic and therapeutic studies. Full article

Background: Mass spectrometry imaging (MSI) lipidomics is a subset of spatially resolved techniques wherein lipids are detected by mass spectrometry, allowing their multiplexed detection and acquiring position-correlated spectra along a tissue section. Rapid advances in the field provide solid evidence demonstrating how specific and regulated lipid distribution is in any biological context. Objectives: Herein, we describe the MSI, particularly matrix-assisted laser desorption/ionization (MALDI-MSI), challenges and advantages in defining human lung pathophysiology, particularly in lung cancer and chronic obstructive pulmonary disease, leading causes of death. Methods: MALDI-MSI analysis of lung tissue sections at 25 μm of lateral resolution allowed associating specific lipid profiles with the main tissues present and independently assessing the impact on lipid composition of smoking, chronic inflammation, and lung cancer. Results: Consistent with MALDI-MSI studies in tumor epithelia, arachidonic acid-containing phospholipids increased, agreeing with its role as a precursor of numerous bioactive molecules participating in cell differentiation and malignization. Next, a gene expression dataset of epithelial human non-small cell lung cancer samples was analyzed using system biology approaches, revealing that, consistent with the most relevant changes in lipid profiles, the network dominated by the tumor-associated module included genes tightly involved in phosphatidylinositol and sphingolipid metabolism. Hence, despite the intrinsic difficulties entailed by lung tissue handling, the results strongly encourage future analysis at higher lateral resolutions so that the lipidome changes associated with each lung cellular type, even subtype, could be fully mapped. Therefore, MALDI-MSI lipidomics definitively broadens the options, some still rather unexplored, to delve into pathophysiology at the cell-type level. Full article

Background: Pulmonary fibrosis (PF) is a progressive interstitial lung disease characterized by chronic inflammation and excessive extracellular matrix deposition, with fibrocytes playing a pivotal role in fibrotic remodeling. This study aimed to identify upstream molecular mechanisms regulating fibrocyte recruitment and activation, focusing on the SPHK1 pathway as a potential therapeutic target. Methods: We utilized Mendelian Randomization and phenome-wide association analyses on genes involved in sphingolipid metabolism to identify potential regulators of idiopathic pulmonary fibrosis (IPF). A bleomycin-induced mouse model was employed to examine the role of the SPHK1-S1P axis in fibrocyte recruitment, using SKI-349 to target SPHK1 and FTY720 to antagonize S1PR1. Results: Our analyses revealed SPHK1 as a significant genetic driver of IPF. Targeting SPHK1 and S1PR1 led to a marked reduction in fibrocyte accumulation, collagen deposition, and histopathological fibrosis. Additionally, PAXX and RBKS were identified as downstream effectors of SPHK1. Our protein–protein interaction mapping indicated potential therapeutic synergies with existing anti-fibrotic drug targets. Conclusions: Our findings establish the SPHK1-S1P-S1PR1 axis as a key regulator of fibrocyte-mediated pulmonary fibrosis and support SPHK1 as a promising therapeutic target. Full article