PubMed

Metabolomics. 2025 Feb 20;21(2):29. doi: 10.1007/s11306-024-02216-w.ABSTRACTINTRODUCTION: The identification of lipids is a cornerstone of lipidomics, and due to the specific characteristics of lipids, it requires dedicated analysis workflows. Identifying novel lipids and lipid species for which no reference spectra are available is tedious and often involves a lot of manual work. Integrating high-resolution mass spectrometry with enhancements from chromatographic and ion mobility separation enables the in-depth investigation of intact lipids.OBJECTIVES: We investigated phosphorylated glycosphingolipids from the nematode Caenorhabditis elegans, a biomedical model organism, and aimed to identify different species from this class of lipids, which have been described in one particular publication only. We checked if these lipids can be detected in lipid extracts of C. elegans.METHODS: We used UHPLC-UHR-TOF-MS and UHPLC-TIMS-TOF-MS in combination with dedicated data analysis to check for the presence of phosphorylated glycosphingolipids. Specifically, candidate features were identified in two datasets using Mass Spec Query Language (MassQL) to search fragmentation data. The additional use of retention time (RT) and collisional cross section (CCS) information allowed to filter false positive annotations.RESULTS: As a result, we detected all previously described phosphorylated glycosphingolipids and novel species as well as their biosynthetic precursors in two different lipidomics datasets. MassQL significantly speeds up the process by saving time that would otherwise be spent on manual data investigations. In total over 20 sphingolipids could be described.CONCLUSION: MassQL allowed us to search for phosphorylated glycosphingolipids and their potential biosynthetic precursors systematically. Using orthogonal information such as RT and CCS helped filter false positive results. With the detection in two different datasets, we demonstrate that these sphingolipids are a general part of the C. elegans lipidome.PMID:39979652 | DOI:10.1007/s11306-024-02216-w

Metabolomics. 2025 Feb 20;21(2):30. doi: 10.1007/s11306-025-02225-3.ABSTRACTINTRODUCTION: Maternal tobacco smoking in the perinatal period increases the risk for adverse outcomes in offspring.OBJECTIVE: To better understand the biological pathways through which maternal tobacco use may have long-term impacts on child metabolism, we performed a high-resolution metabolomics (HRM) analysis in newborns, following an untargeted metabolome-wide association study workflow.METHODS: The study population included 899 children without cancer diagnosis before age 6 and born between 1983 and 2011 in California. Newborn dried blood spots were collected by the California Genetic Disease Screening Program between 12 and 48 h after birth and stored for later research use. Based on HRM, we considered mothers to be active smokers if they were self- or provider-reported smokers on birth certificates or if we detected any cotinine or high hydroxycotinine intensities in newborn blood. We used partial least squares discriminant analysis and Mummichog pathway analysis to identify metabolites and metabolic pathways associated with maternal tobacco smoking.RESULTS: A total of 26,183 features were detected with HRM, including 1003 that were found to be associated with maternal smoking late in pregnancy and early postpartum (Variable Importance in Projection (VIP) scores > = 2). Smoking affected metabolites and metabolic pathways in neonatal blood including vitamin A (retinol) metabolism, the kynurenine pathway, and tryptophan and arachidonic acid metabolism.CONCLUSION: The smoking-associated metabolites and pathway perturbations that we identified suggested inflammatory responses and have also been implicated in chronic diseases of the central nervous system and the lung. Our results suggest that infant metabolism in the early postnatal period reflects smoking specific physiologic responses to maternal smoking with strong biologic plausibility.PMID:39979646 | DOI:10.1007/s11306-025-02225-3

Acta Pharmacol Sin. 2025 Feb 20. doi: 10.1038/s41401-025-01495-w. Online ahead of print.ABSTRACTNon-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD encompasses a spectrum of liver damage starting with liver steatosis and lipid disorders presented as the hallmark. Cannabinoid-2 receptor (CB2R) is the receptor of endocannabinoids mainly expressed in immune cells. Our preliminary study revealed the preventative role of CB2R in liver injury related to lipid metabolism. In this study, we aimed to explore the role of CB2R in NAFLD and the underlying mechanism related to microbial community. High-fat diet-induced NAFLD model was established in mice. We found that hepatic CB2R expression was significantly reduced in NAFLD mice and CB2R-/- mice fed with normal chow. Interestingly, cohousing with or transplanted with microbiota from WT mice, or treatment with an antibiotic cocktail ameliorated the NAFLD phenotype of CB2R-/- mice. The gut dysbiosis in CB2R-/- mice including increased Actinobacteriota and decreased Bacteroidota was similar to that of NAFLD patients and NAFLD mice. Microbial functional analysis and metabolomics profiling revealed obviously disturbed tryptophan metabolism in NAFLD patients and NAFLD mice, which were also seen in CB2R-/- mice. Correlation network showed that the disordered tryptophan metabolites such as indolelactic acid (ILA) and xanthurenic acid in CB2R-/- mice were mediated by gut dysbiosis and related to NAFLD severity indicators. In vitro and in vivo validation experiments showed that the enriched tryptophan metabolites ILA aggravated NAFLD phenotypes. These results demonstrate the involvement of CB2R in NAFLD, which is related to gut microbiota-mediated tryptophan metabolites. Our findings highlight CB2R and the associated microbes and tryptophan metabolites as promising targets for the treatment of NAFLD.PMID:39979552 | DOI:10.1038/s41401-025-01495-w

Metabolomics. 2025 Feb 20;21(2):28. doi: 10.1007/s11306-025-02230-6.ABSTRACTNeoadjuvant therapy is a standard treatment for breast cancer, but its effectiveness varies among patients. This highlights the importance of developing accurate predictive models. Our study uses metabolomics and machine learning to predict the response to neoadjuvant therapy in breast cancer patients.OBJECTIVE: To develop and validate predictive models using machine learning and circulating metabolites for forecasting responses to neoadjuvant therapy among breast cancer patients, enhancing personalized treatment strategies.METHODS: Based on pathological analysis after neoadjuvant chemotherapy and surgery, this retrospective study analyzed 30 young women breast cancer patients from a single institution, categorized as responders or non-responders. Utilizing liquid chromatography-tandem mass spectrometry, we investigated the plasma metabolome, explicitly targeting 40 metabolites, to identify relevant biomarkers linked to therapy response, using machine learning to generate a predictive model and validate the results.RESULTS: Eighteen significant biomarkers were identified, including specific acylcarnitines and amino acids. The most effective predictive model demonstrated a remarkable accuracy of 90.7% and an Area Under the Curve (AUC) of 0.999 at 95% confidence, illustrating its potential utility as a web-based application for future patient management. This model's reliability underscores the significant role of circulating metabolites in predicting therapy outcomes.CONCLUSION: Our study's findings highlight the crucial role of metabolomics in advancing personalized medicine for breast cancer treatment by effectively identifying metabolite biomarkers correlated with neoadjuvant therapy response. This approach signifies a critical step towards tailoring treatment plans based on individual metabolic profiles, ultimately improving patient outcomes in breast cancer care.PMID:39979511 | DOI:10.1007/s11306-025-02230-6

EMBO Rep. 2025 Feb 20. doi: 10.1038/s44319-025-00397-6. Online ahead of print.ABSTRACTThe maternal-to-zygotic transition (MZT) is a conserved developmental process where the maternally-derived protein and mRNA cache is replaced with newly made zygotic gene products. We have previously shown that in Drosophila the deposited RNA-binding proteins ME31B, Cup, and Trailer Hitch are ubiquitylated by the CTLH E3 ligase and cleared. However, the organization and regulation of the CTLH complex remain poorly understood in flies because Drosophila lacks an identifiable substrate adaptor, and the mechanisms restricting the degradation of ME31B and its cofactors to the MZT are unknown. Here, we show that the developmental regulation of the CTLH complex is multi-pronged, including transcriptional control by OVO and autoinhibition of the E3 ligase. One major regulatory target is the subunit Muskelin, which we demonstrate is a substrate adaptor for the Drosophila CTLH complex. Finally, we find that Muskelin has few targets beyond the three known RNA-binding proteins, showing exquisite target specificity. Thus, multiple levels of integrated regulation restrict the activity of the embryonic CTLH complex to early embryogenesis, during which time it regulates three important RNA-binding proteins.PMID:39979464 | DOI:10.1038/s44319-025-00397-6

Sci Data. 2025 Feb 20;12(1):306. doi: 10.1038/s41597-025-04563-2.ABSTRACTSeed development, which depends on parent plants genetic background and mother plant environmental conditions, is a major component determining seed composition. Seed quality is a main agricultural concern, impacting both food and non-food applications, while also playing a central role in biodiversity conservation and environment protection. Climate change, in particular the emergence of extremely high temperatures, constitute a critical global threat to agriculture. Specialized metabolites (SMs) play crucial roles in the interactions of plants and seeds with their environments. Several SMs are known to be protective compounds involved in seed stress responses, thus impacting their quality. In this study, we performed untargeted metabolomic (LC-MS/MS) and transcriptomic (RNA-Seq) analyses of Arabidopsis thaliana seeds harvested at six developmental stages (Globular, Transition, Torpedo, Bent cotyledon, Mature green and Dry seed), and developed under control and warm temperature conditions. Those data provide an original and valuable resource that could be used to identify SMs and genes involved in seed heat stress responses and for the study of their regulation and functions during seed development.PMID:39979379 | DOI:10.1038/s41597-025-04563-2

Nat Commun. 2025 Feb 20;16(1):1817. doi: 10.1038/s41467-025-56940-5.ABSTRACTIn plant cells, ALMTs are key plasma and vacuolar membrane-localized anion channels regulating plant responses to the environment. Vacuolar ALMTs control anion accumulation in plant cells and, in guard cells, they regulate stomata aperture. The activation of vacuolar ALMTs depends on voltage and cytosolic malate, but the underlying molecular mechanisms remain elusive. Here we report the cryo-EM structures of ALMT9 from Arabidopsis thaliana (AtALMT9), a malate-activated vacuolar anion channel, in plugged and unplugged lipid-bound states. In all these states, membrane lipids interact with the ion conduction pathway of AtALMT9. We identify two unplugged states presenting two distinct pore width profiles. Combining structural and functional analysis we identified conserved residues involved in ion conduction and in the pore lipid interaction. Molecular dynamics simulations revealed a peculiar anion conduction mechanism in AtALMT9. We propose a voltage-dependent activation mechanism based on the competition between pore lipids and malate at the cytosolic entrance of the channel.PMID:39979303 | DOI:10.1038/s41467-025-56940-5

Nephrol Dial Transplant. 2025 Feb 20:gfaf032. doi: 10.1093/ndt/gfaf032. Online ahead of print.ABSTRACTHereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is caused by heterozygous germline variants in the fumarate hydratase (FH) gene [1,2]. Inheritance follows an autosomal dominant pattern. Loss of FH confers a predisposition for various benign and malignant neoplasms, including cutaneous leiomyomas, uterine fibroids and FH-deficient renal cell carcinoma [3]. While benign, cutaneous and uterine manifestations have a relevant impact on quality of life and risk for complications [4]. The vast majority of FH-deficient RCC exhibit an aggressive behavior with invasive growth and potential for early metastatic spread [5]. Additionally, pathogenic germline FH variants have been associated with other neoplasms, such as adrenal gland [10] and Leydig cell tumors [28, 29]. The aggressive behavior of FH-deficient RCC challenges nephron-sparing resection strategies, as a wide margin is recommended. Even after early nephrectomy for surgical removal of FH-deficient renal cell carcinomas, there is a relevant risk for distant metastasis as well as the remaining predisposition for de novo primary renal tumors in the other kidney. Active screening is central to HLRCC care since no preventative HLRCC-specific treatment exists. VEGF/EGFR directed treatment regimes, such as Erlotinib/Bevacizumab demonstrate efficacy against HLRCC-associated RCC [6]. This emphasizes the importance of establishing the correct diagnosis in HLRCC early on to guide therapeutic decisions. Morphologic criteria as well as specific immunohistochemical (IHC) staining and molecular genetics allow the identification of FH-deficient RCC. Changes made in the recent 2022 WHO classification impact the diagnosis of HLRCC in multiple ways. This commentary aims to point out this impact and to raise awareness among pathologists as well as clinicians involved in the care of patients with HLRCC.PMID:39979023 | DOI:10.1093/ndt/gfaf032

Carbohydr Polym. 2025 Apr 15;354:123314. doi: 10.1016/j.carbpol.2025.123314. Epub 2025 Jan 24.ABSTRACTCassava is a significant starchy root crop providing staple foods for millions of people globally. However, the metabolic differences and regulatory mechanisms underlying starch accumulation remain largely elusive in cassava. In this work, scanning electron microscopy, metabolome, and transcriptome were analyzed in parallel between starchy cassava (SC205) and sugary cassava (SM) during storage root (SR) development. Many carbohydrate-related metabolites (including fructose-6-phosphate and glucose-6-phosphate) were differentially accumulated between SC205 and SM. Further analysis unveiled coordinated metabolomic and transcriptomic changes in sucrose and starch metabolism, glycolysis and TCA cycle, lipid metabolism, and lignin and flavonoid biosynthesis during SR development, but with distinct abundance patterns between SC205 and SM. Specifically, bZIP2 could directly bind to the promoters of APL1, ISA1, and GBSS1 and promote their expression levels in SC205, but these interactions were absent in SM. Transient silencing of APL1, ISA1, or GBSS1 resulted in significant decreases in starch contents. Transient silencing of bZIP2 suppressed the expression of APL1, ISA1, and GBSS1, and accordingly, decreased the starch contents. These results suggest a crucial contribution of coordinated regulation of carbohydrate-related pathways/genes to the difference of starch accumulation between starchy cassava and sugary cassava, providing useful information for starch improvement in the future.PMID:39978918 | DOI:10.1016/j.carbpol.2025.123314

J Proteomics. 2025 Feb 18:105411. doi: 10.1016/j.jprot.2025.105411. Online ahead of print.ABSTRACTCannabidiol (CBD), the primary non-psychoactive cannabinoid isolated from cannabis, exhibits promising antibacterial effects. However, the antibacterial mechanism of CBD remains poorly understood. In this study, the mechanism was investigated using bacterial inhibition assays, label-free proteomics, and untargeted metabolomics, with Bacillus licheniformis (B. licheniformis), Staphylococcus aureus (S. aureus), and Enterococcus faecium (E. faecium) selected as representative Gram-positive bacteria. The results revealed that CBD caused significant damage to bacterial cell walls and membranes, leading to notable changes in proteomic and metabolic profiles. Specifically, 437, 120, and 195 proteins, as well as 52, 153, and 94 metabolites, were differentially expressed in B. licheniformis, S. aureus, and E. faecium, respectively. The antimicrobial mechanism of CBD shares similarities with previously known antibacterial agents, such as penicillin and cephalosporins, particularly in affecting the bacterial cell wall, but differs in its detailed mode of action. CBD disrupted the biosynthesis of primary and secondary metabolites and altered bacterial metabolism, contributing to its antibacterial activity. This study provides valuable insights into the antibacterial mechanism of CBD, supporting its potential development as an antibiotic alternative and its application in food safety. SIGNIFICANCE: It is crucial to find alternatives to antibiotics to mitigate the impact of pathogenic bacteria on food safety and reduce the use of antibiotics. CBD is the primary non-psychoactive cannabinoid derived from cannabis, and it has shown promising antibacterial effects. However, the antimicrobial mechanisms of CBD have not been well elucidated. This study provides a deep understanding of the antibacterial mechanism from the cellular to molecular level, which will contribute to the development of CBD as a novel antibacterial agent.PMID:39978755 | DOI:10.1016/j.jprot.2025.105411

Exp Cell Res. 2025 Feb 18:114466. doi: 10.1016/j.yexcr.2025.114466. Online ahead of print.ABSTRACTBrown hares (Lepus europaeus) and mountain hares (Lepus timidus) frequently hybridize in regions where their range overlaps, producing fertile offspring and enabling gene flow between the species. Despite this, no hybrid species has emerged, suggesting that hybrid backcrosses may incur fitness costs. One potential mechanism for such costs involves the interactions between mitochondrial and nuclear gene products, where incompatibilities between species-specific alleles may reinforce species barriers and lead to hybrid breakdown. However, direct experimental evidence for this hypothesis remains limited. In this study, we used fibroblasts derived from skin biopsies of wild-caught hares to generate cytoplasmic hybrid (cybrid) cell lines, wherein mitochondria and mtDNA from one species were transferred to mitochondria-depleted cells of the other species, creating novel mitonuclear gene combinations while preserving the original diploid nuclear background. Employing a range of techniques - including transcriptomics, metabolomics, microscopy, and respirometry - we explored the consequences of mitochondrial transfer between these hare species. Our results reveal that in the studied species mitonuclear incompatibilities exhibit strong effects on cellular fitness but are limited to specific genotypes. We propose mechanisms of cellular-level incompatibility and their potential consequences for interspecific hybrids, offering new insights into the complexity of mitonuclear interactions.PMID:39978712 | DOI:10.1016/j.yexcr.2025.114466

Brain Behav Immun. 2025 Feb 18:S0889-1591(25)00051-0. doi: 10.1016/j.bbi.2025.02.011. Online ahead of print.ABSTRACTOBJECTIVE: This study explores the behavioral and molecular biological impacts of Fecal Microbiota Transplantation (FMT) on depressive mice unresponsive to treatment with Selective Serotonin Reuptake Inhibitors (SSRIs).METHODS: Healthy male C57BL/6 mice were used to establish a depression model through chronic restraint stress, treated with fluoxetine, and categorized into Response and Non-response groups. An FMT treatment was added to the Non-response group. Behavioral tests were conducted to assess symptoms of depression. The gut microbiome, plasma metabolites, and hippocampal tissue gene expression and function changes were analyzed using 16S rRNA gene sequencing, LC-MS, and RNA sequencing.RESULTS: FMT significantly improved the depressive symptoms in SSRIs-resistant mice. There was a partial restoration in the diversity and structure of the gut microbiota in the FMT group. Compared to the Non-response group, significant changes were noted in the metabolomic profiles of the FMT group, identifying various differential metabolites. Functional annotations indicated that these metabolites are involved in multiple metabolic pathways. In the Non-response group, certain gene expression levels were significantly restored. GO and KEGG enrichment analyses revealed that these differential genes mainly involve cytokine activity, receptor signaling regulation, and NOD-like receptor signaling pathways. Joint analysis suggested that FMT may exert its effects through an increase in the abundance of g__Paraprevotella, leading to decreased baicalin content and increased Tal2 expression.CONCLUSION: FMT has potential in improving depressive symptoms unresponsive to SSRIs treatment. Its mechanism may be related to the modulation of the gut microbiota and its metabolites, subsequently affecting gene expression.PMID:39978693 | DOI:10.1016/j.bbi.2025.02.011

J Allergy Clin Immunol. 2025 Feb 18:S0091-6749(25)00207-6. doi: 10.1016/j.jaci.2025.02.011. Online ahead of print.ABSTRACTInflammation is a pathogenic driver of many diseases, including atherosclerosis and rheumatoid arthritis. 'Hyperinflammation' can be seen as any inflammatory response that is deleterious to the host, regardless of cause. In medicine, hyperinflammation is defined as severe, deleterious, fluctuating, systemic or local inflammation with presence of a cytokine storm. It has been associated with rare auto-inflammatory disorders. However, advances in omics technologies, including genomics, proteomics, and metabolomics, have revealed it to be more common, occurring in sepsis and severe COVID-19. Focusing on proteomics, this review highlights the key role of omics in this shift. Through an exploration of research, we present how omics technologies have contributed to improved diagnostics, prognostics, and targeted therapeutics in the field of hyperinflammation. We also discuss the integration of advanced technologies, multiomics approaches and artificial intelligence (AI), in analyzing complex datasets to develop targeted therapies, and their potential for revolutionizing clinical aspects of hyperinflammation. We emphasize personalized medicine approaches for effective treatments and outline challenges, including the need for standardized methodologies, robust bioinformatics tools, and ethical considerations regarding data privacy. This review aims to provide comprehensive understanding of the molecular mechanisms underpinning hyperinflammation and underscores the potential of omics technologies in enabling successful clinical management.PMID:39978687 | DOI:10.1016/j.jaci.2025.02.011

Fitoterapia. 2025 Feb 18:106407. doi: 10.1016/j.fitote.2025.106407. Online ahead of print.ABSTRACTShengui Yangrong Decoction (SGYR) is a traditional Chinese herbal prescription that has been used for the treatment of polycystic ovary syndrome (PCOS). However, there is a consensus on the clinical efficacy of SGYR in treating PCOS, yet the underlying pharmacological mechanisms remain unclear.This study aim to investigate the effects of SGYR on insulin resistance in rats with PCOS and its modulation of follicular development through the epidermal growth factor receptor (EGFR)/PI3K/AKT signaling cascade by integrating metabolomics and network pharmacology and in vivo and in vitro experimental validation.Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry, network pharmacology, and molecular docking, were used to identify key components of SGYR and predict its potential targets. Subcutaneous dehydroepiandrosterone injections and a fat-rich diet were used to create a rat model for PCOS. This was followed by the in vitro growth of human granulosa cells and subsequent treatment with dihydrotestosterone and the epidermal growth factor (EGF). Subsequently, the recovery mechanism of SGYR was analyzed using an enzyme-linked immunosorbent assay, hematoxylin and eosin staining, immunofluorescence, and western blot assays.A total of 112 compounds were identified in SGYR, and 147 potential PCOS targets were found. The core targets were screened using a cluster analysis, and seven gene clusters and five core genes were identified. The core genes included ERBB2, SDHB, EGFR, IL6ST, and PIK3CD, and the EGFR/PI3K/AKT signaling cascade was investigated in depth based on component-target-pathway screening and in conjunction with literature studies. Molecular docking confirmed that the EGF receptor had good binding activity with these compounds. In vivo and in vitro experiments confirmed that SGYR effectively regulated sex hormone levels, improved insulin resistance, attenuated pathological changes in rat ovaries, and verified the localization and expression of EGFR, ERBB2, IGF-1, follicle-stimulating hormone receptor, and luteinizing hormone/chorionic gonadotropin receptor in the ovaries. The complex mechanism of SGYR in treating PCOS by inhibiting the EGFR/PI3K/AKT signaling cascade was revealed.PMID:39978644 | DOI:10.1016/j.fitote.2025.106407

J Allergy Clin Immunol Pract. 2025 Feb 18:S2213-2198(25)00169-2. doi: 10.1016/j.jaip.2025.02.006. Online ahead of print.ABSTRACTBACKGROUND: Increasing cases of vaccine-related severe cutaneous adverse reactions (SCARs) are reported in the literature.OBJECTIVES: To provide comprehensive information regarding the clinical spectrum of vaccine-associated SCARs.METHODS: This was a systematic review and meta-analysis on case reports, case series, cohort studies, case-control studies, and post-market surveillance of SCARs following vaccination. Data on demographic information, classes of vaccination, past medical history and medications, and types, manifestations, management, and prognosis of SCARs, including acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and generalized bullous fixed drug eruptions (GBFDE), were extracted.RESULTS: A total of 255 cases of SCARs following vaccination were identified. 231 (91%) of the reported cases of vaccine-associated SCARs were identified as SJS/TEN. The pooled incidence of SCARs following vaccination was 1.676 per million (95% confidence interval=0.136-20.668; I2 = 97%). The H1N1 vaccine (n=52), coronavirus disease 2019 (COVID-19) vaccines (n=38; 23 [61%] from mRNA vaccines), and influenza vaccine (n=33) contributed to most of these cases. AGEP and DRESS were frequently reported with COVID-19 vaccines, particularly the mRNA vaccines (57.1% [4/7] and 83.3% [5/6], respectively) and viral vector vaccines (28.6% [2/7] and 16.7% [1/6]). No SCAR was reported for protein-based COVID-19 vaccines. Six cases of fatal SJS/TEN were reported, with two cases associated with the COVID-19 vaccine.CONCLUSIONS: SCARs following vaccination were extremely rare, with a high proportion of these cases SJS/TEN. Most suspected culprits included the H1N1 vaccine, the influenza vaccine, the varicella vaccines, and COVID-19 vaccines especially mRNA vaccines. However, concurrent medication use may confound underlying attribution of SCARs to vaccines.PMID:39978545 | DOI:10.1016/j.jaip.2025.02.006

J Ethnopharmacol. 2025 Feb 18:119511. doi: 10.1016/j.jep.2025.119511. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Qingjie Fuzheng Granules (QFG), a herbal formula, has been employed as an adjuvant therapy for colitis-associated colorectal cancer (CAC), yet the underlying mechanisms by which QFG operates remain unclear.AIMS OF THE STUDY: The aim of this study is to investigate whether the potential mechanism of QFG against CAC is associated with macrophage polarization.MATERIALS AND METHODS: Non-targeted metabolomics and molecular docking assessed potential compounds of QFG to interact with targets associated with macrophage polarization. A model of AOM/DSS-induced CAC mice was established to analyze the effects of QFG on macrophage polarization using flow cytometry and immunohistochemical staining. In vitro experiments involved models of Ana-1 macrophages, either induced by varying QFG concentrations or with MD2 knockdown, to analyze M1-like phenotype. Meanwhile, M2-like macrophages models induced by IL-4 or culture supernatant of CT26 cells were utilized to assess the effects of QFG on M2-like macrophages. Finally, the mRNA expression of M1-like phenotype related to TLR4 pathways and the protein expression in IL-4R-mediated pathways were analyzed using RT-qPCR and western blot, respectively.RESULTS: Molecular docking confirmed the presence of binding sites between the ingredients of QFG and IL-4R or TLR4/MD2 receptor complex. QFG could induce a shift in macrophages towards an M1-like phenotype while inhibiting an M2-like phenotype in the colon with CAC mice and Ana-1 macrophages. QFG resulted in the upregulation of iNOS, IL-6, IL-1β, and TNF-α mRNA expression, which could be counteracted by TAK242, SR11302, INH14, PDTC, and LY294002, or by the knockdown of MD2. Meanwhile, QFG inhibited IL-4R-induced phosphorylation of STAT 6 and Akt.CONCLUSION: Various monomer components within QFG can bind to MD2 or IL-4R, respectively, thereby inducing macrophages towards an M1-like phenotype through TLR4-mediated NF-κB, MAPK, and PI3K/Akt pathway activation, or inhibiting macrophages towards an M2-like phenotype via IL-4R-mediated JAKs pathway inhibition, ultimately exerting an inhibitory effect on the occurrence and development of CAC.PMID:39978444 | DOI:10.1016/j.jep.2025.119511

Gastroenterology. 2025 Feb 17:S0016-5085(25)00329-4. doi: 10.1053/j.gastro.2025.01.224. Online ahead of print.ABSTRACTThe benefits of regular physical activity (PA) on disease prevention and treatment outcomes have been recognized for centuries. However, only recently has interorgan communication triggered by the release of "myokines" from contracting skeletal muscles emerged as a putative mechanism by which exercise confers protection against numerous disease states. Cross-talk between active skeletal muscles and the gut microbiota reveal how regular PA boosts host immunity, facilitates a more diverse gut microbiome and functional metabolome, and plays a positive role in energy homeostasis and metabolic regulation. In contrast, and despite the large interindividual variation in the human gut microbiome, reduced microbial diversity has been implicated in several diseases of the gastrointestinal (GI) tract, systemic immune diseases, and cancers. Although prolonged, intense, weight-bearing exercise conducted in extreme conditions can increase intestinal permeability, compromising gut-barrier function and resulting in both upper and lower GI symptoms, these are transient and benign. Accordingly, the gut microbiome has become an attractive target for modulating many of the positive effects of regular PA on GI health and disease, although the precise dose of exercise required to induce favourable changes in the microbiome and enhance host immunity is currently unknown. Future efforts should concentrate on gaining a deeper understanding of the factors involved in exercise-gut interactions through the generation of functional 'omics readouts (ie, metatranscriptomics, metaproteomics, and metabolomics) that have the potential to identify functional traits of the microbiome that are linked to host health and disease states, and validating these interactions in experimental and preclinical systems. A greater understanding of how PA interacts with the GI tract and the microbiome may enable targeted therapeutic strategies to be developed for individuals and populations at risk for a variety of GI diseases.PMID:39978410 | DOI:10.1053/j.gastro.2025.01.224

Cell Metab. 2025 Feb 14:S1550-4131(25)00007-5. doi: 10.1016/j.cmet.2025.01.007. Online ahead of print.ABSTRACTThe role of the intestinal microbiome in Crohn's disease (CD) treatment remains poorly understood. This study investigates microbe-host interactions in CD patients undergoing ustekinumab (UST) therapy. Fecal metagenome, metabolome, and host transcriptome data from 85 CD patients were analyzed using multi-omics integration and mediation analysis. Our findings reveal significant microbiome-metabolite-host interactions. Specifically, Faecalibacterium prausnitzii was linked to altered L-ornithine biosynthesis, resulting in higher L-ornithine levels in patients before UST therapy. In vivo and in vitro studies demonstrated that microbiome-derived L-ornithine enhances UST treatment sensitivity in CD by disrupting the host IL-23 receptor signaling and inhibiting Th17 cell stabilization through the IL-12RB1/TYK2/STAT3 axis. L-ornithine significantly enhances the therapeutic efficacy of UST in CD patients, as demonstrated in a prospective clinical trial. These findings suggest that targeting specific microbe-host metabolic pathways may improve the efficacy of inflammatory bowel disease (IBD) treatments.PMID:39978335 | DOI:10.1016/j.cmet.2025.01.007

Phytomedicine. 2025 Feb 16;139:156495. doi: 10.1016/j.phymed.2025.156495. Online ahead of print.ABSTRACTBACKGROUND: Cholestatic liver injury is a hepatobiliary disorder primarily characterized by cholestasis, which significantly contributes to liver damage. The Yinzhihuang (YZH) oral preparation is an effective clinical treatment for cholestatic liver injury; however, the specific mechanism of action has not been clarified.PURPOSE: This study investigated YZH's pharmacological mechanisms associated with the microbe‒gut‒liver axis in cholestatic mice, offering new perspectives for the treatment of cholestasis.METHODS: YZH's protective effects were evaluated by evaluating serum liver injury indices and liver staining in an alpha-nephthyl isothiocyanate (ANIT)-induced intrahepatic cholestasis mouse model. Colon hematoxylin‒eosin (H&E) and alcian blue staining and FITC‒dextran leakage assays were performed to assess intestinal barrier integrity. Fluorescence in situ hybridization was employed to analyze bacterial translocation. Additionally, 16S rRNA sequencing, fecal microbiota transplantation, and bile acid metabolomics analysis were conducted to examine the relationships among the microbiome, bile acid metabolism, and YZH formula.RESULTS: We found that YZH administration alleviated symptoms of ANIT-induced hepatic pathological injury and fibrosis. In addition, YZH reduced the transfer of gut bacteria to liver tissue by maintaining an intact intestinal barrier. Notably, YZH influenced the intestinal microbiota composition, upregulated the abundance of bile acid metabolism-associated probiotic bacteria, including Clostridiales, Lachnospiraceae and Bifidobacterium pseudolongum; and downregulated the abundance of Escherichia-Shigella and Serratia, thereby promoting bile acid excretion.CONCLUSION: YZH protects against cholestatic liver damage by promoting bile excretion and maintaining intestinal mucosal barrier integrity. Furthermore, YZH alleviates cholestasis in a gut microbiota-dependent manner, and upregulation of probiotics may be crucial for YZH's influence on bile acid metabolism.PMID:39978276 | DOI:10.1016/j.phymed.2025.156495

Poult Sci. 2025 Feb 6;104(3):104885. doi: 10.1016/j.psj.2025.104885. Online ahead of print.ABSTRACTResidual feed intake (RFI) is a key indicator of feed efficiency, critical for enhancing the economic sustainability of poultry production. However, the genetic and metabolic regulatory mechanisms of RFI remain unclear. This study analyzed the genome, liver transcriptome, metabolome, and lipidome of hens with low and high feed efficiency (N = 60) from the previously established RFI divergent broiler lines (F15). Our results revealed pronounced genetic differentiation between low RFI (LRFI) and high RFI (HRFI) lines and identified genomic signatures of selection associated with feed efficiency. Transcriptomic analysis showed differential expression of genes involved in neural regulation and lipid metabolism. Notably, LRFI chickens exhibited reduced hepatic lipid accumulation, which was associated with decreased fatty acid metabolism and increased cholesterol metabolism (P < 0.05). The lipidomic analysis uncovered distinct profiles of glycerophospholipids (e.g., PE-P and PC-O) and sphingolipids (e.g., ceramides), which were more abundant in LRFI chickens (P < 0.05) and strongly correlated with key lipid metabolism processes (P < 0.05). Despite improved feed efficiency, LRFI chickens demonstrated signs of increased oxidative stress. Moreover, integrative analyses revealed that genes such as MGAT5, GABRA4, and LRRC4C, exhibiting strong selection signatures and higher expression in the LRFI line (P < 0.05), were identified as key regulators of lipid metabolism, potentially contributing to the observed differences in feed efficiency. This comprehensive study highlights the synergistic effect of genetics and lipid metabolism in driving feed utilization efficiency in chickens, establishing a scientific foundation for breeding strategies aimed at improving feed efficiency in poultry production.PMID:39978204 | DOI:10.1016/j.psj.2025.104885