PubMed

Fitoterapia. 2025 May 14:106617. doi: 10.1016/j.fitote.2025.106617. Online ahead of print.ABSTRACTRubia cordifolia L. (RCL) is a widely used medicinal and food-related product with a long history. It exhibits anti-inflammatory and antioxidant properties and prevents apoptosis. While there is growing evidence that exhausted exercise (EE) might cause cardiac damage, RCL has been shown to provide cardioprotective effects. The effects and mechanisms of RCL on exercise-induced myocardial injury remain unclear. In this study, we tested the RCL extract using a rat model of exhausted swimming. We evaluated the therapeutic effect of RCL on exercise-induced myocardial damage using PCR, ELISA, hematoxylin-eosin (H&E) staining, DHE staining, and other methods. UPLC-Q-TOF-MS was employed to identify the components of the RCL extract and its blood-entry components, and network pharmacology was constructed. LC-MS was utilized to investigate left ventricular metabolomics. The two were combined in order to predict the possible metabolic pathways regulated by RCL. Finally, the targets of the metabolic pathway were verified using molecular docking and western blot analysis. The findings suggest that rubioncolin B, 4-hydroxy-2-carbexyanthraquinone, and 9-Oxo-9H-xanthene-4-carboxylic acid may be the primary active compounds of RCL. RCL promotes the degradation pathway of branched-chain amino acids (BCAA), including valine, leucine, and isoleucine, regulates the proteins BCAT2 and BCKDK, reduces pathological injuries, inflammation, oxidative stress, and collagen deposition, and mitigates the effects of exhaustion-induced myocardial injuries by influencing the key target AKR1C1 and the metabolite L-Valine. This study provides a foundation for the development of RCL as a sports supplement to alleviate EE-induced myocardial injury.PMID:40378926 | DOI:10.1016/j.fitote.2025.106617

Cell. 2025 May 9:S0092-8674(25)00458-1. doi: 10.1016/j.cell.2025.04.025. Online ahead of print.ABSTRACTThe amnion, an extra-embryonic tissue in mammalian embryos, is thought to provide crucial signaling, structural, and nutritional support during pregnancy. Despite its pivotal importance, studying human amnion formation and function has been hampered by the lack of accurate in vitro models. Here, we present an embryonic stem cell-derived 3D model of the post-gastrulation amnion, post-gastrulation amnioids (PGAs), that faithfully recapitulates extra-embryonic development up to 4 weeks post-fertilization, closely mimicking the functional traits of the human amniotic sac. PGAs self-organize, forming the amnion and the yolk sac, and are surrounded by the extra-embryonic mesoderm. Using PGAs, we show that GATA3 is required and sufficient for amniogenesis and that an autoregulatory feedback loop governs amnion formation, whereby extra-embryonic signals promote amnion specification. The reproducibility and scalability of the PGA system, with its precise cellular, structural, and functional integrity, opens avenues for investigating embryo-amnion interactions beyond gastrulation and offers an ideal platform for large-scale pharmacological and clinical studies.PMID:40378847 | DOI:10.1016/j.cell.2025.04.025

J Pharmacol Exp Ther. 2025 Apr 7;392(6):103578. doi: 10.1016/j.jpet.2025.103578. Online ahead of print.ABSTRACTCardiac fibrosis is a prevalent characteristic of various cardiovascular diseases and poses a significant global health challenge. Recent research has established a robust correlation between gut microbiota and cardiovascular diseases. Hesperidin has been shown to possess cardioprotective properties to some extent. Furthermore, studies suggest that hesperidin may enhance overall health by regulating intestinal flora. However, there is a lack of reports regarding the effects of hesperidin on cardiac fibrosis. This study aimed to investigate the mechanisms by which hesperidin ameliorates cardiac fibrosis through the regulation of gut microbiota and associated metabolites. Cardiac fibrosis was induced in C57BL/6 mice via subcutaneous injection of isoproterenol (5 mg/kg per day) for a duration of 7 days. Echocardiography was used to assess cardiac function, while Masson staining, western blot analysis, and real-time polymerase chain reaction were used to evaluate fibrosis-related indicators. Changes in gut microbiota were analyzed through 16S ribosomal RNA gene sequencing. Our findings indicate that hesperidin significantly mitigates cardiac fibrosis in mice. These beneficial effects are associated with improvements in the dysbiosis of intestinal microbiota observed in fibrotic mouse models. The involvement of gut microbiota in cardiac fibrosis was further corroborated by administering hesperidin therapy to mice depleted of gut microbiota. To our knowledge, this study provides the first evidence that the modulation of gut microbiota by hesperidin contributes to improved outcomes in cardiac fibrosis. The use of traditional Chinese medicine to modulate gut microbiota presents a promising strategy for the treatment of cardiac fibrosis. SIGNIFICANCE STATEMENT: The work is extremely interesting because it acts on a frontier of science that relates the influence of the intestinal microbiota with human physiological systems and associated pathologies. This study provides the first evidence that the modulation of gut microbiota by hesperidin contributes to improved outcomes in cardiac fibrosis.PMID:40378637 | DOI:10.1016/j.jpet.2025.103578

Phytomedicine. 2025 May 8;143:156828. doi: 10.1016/j.phymed.2025.156828. Online ahead of print.ABSTRACTPURPOSE: 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.METHODS: 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.RESULTS: 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.CONCLUSION: 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.PMID:40378592 | DOI:10.1016/j.phymed.2025.156828

Phytomedicine. 2025 May 8;143:156835. doi: 10.1016/j.phymed.2025.156835. Online ahead of print.ABSTRACTBACKGROUND: The NLRP3 inflammasome is a key regulator of innate immunity and plays a critical role in the pathogenesis of various inflammatory diseases. Regulating NLRP3 has emerged as a promising strategy for the development of anti-inflammatory therapies. Valtrate (Val), a natural compound derived from Valeriana officinalis Jones, has demonstrated significant anti-inflammatory activity. However, its precise mechanism of action remains unclear.PURPOSE: This study elucidates the molecular mechanisms of Val suppressing NLRP3 inflammasome activation.METHODS: We screened 100 natural compounds for anti-pyroptotic in lipopolysaccharide (LPS)/nigericin-stimulated THP-1 cells and bone marrow-derived macrophages (BMDMs) using lactate dehydrogenase (LDH) release assays. Val's effect on NLRP3 were assessed via immunoblotting and ELISA. Target identification employed DARTS, proteomics, thermal shift assay (TSA), microscale thermophoresis (MST), and molecular dynamics (MD) simulations. In vivo efficacy was evaluated in acetaminophen (APAP)- and LPS-induced liver injury models.RESULTS: Val potently inhibited pyroptosis (99.20 % LDH reduction) and selectively degraded NLRP3 via post-translation mechanisms (PTMs) without altering its mRNA. DARTS and CETSA confirmed that Val directly interacts with the C2 fragment of USP9X without inhibiting its enzymatic activity, while RMSD, RMSF, and Gibbs energy landscape analyses supported its stable binding to USP9X, which was further confirmed by MST. Mechanistically, Val downregulated USP9X protein expression and promoted K48- and K63-linked ubiquitination and proteasomal degradation of NLRP3. In vivo, Val exhibited therapeutic potential in murine models of acute liver injury induced by APAP and LPS. Val reduced serum ALT and AST levels, inflammatory cytokines, and liver injury (histopathological analysis (H&E) and TUNEL).CONCLUSION: This study uncovers an unrecognized mechanism by which Val attenuates NLRP3 inflammasome activation by disrupting the USP9X-NLRP3 axis, thereby promoting NLRP3 ubiquitination and proteasomal degradation. Notably, Val down-regulates USP9X protein levels without impairing its catalytic activity, representing a distinct mechanism from existing USP9X inhibitors. These findings not only deepen our understanding of Val's anti-inflammatory action but also underscore its promise as a lead compound for the development of novel therapeutics targeting NLRP3-driven inflammatory diseases.PMID:40378590 | DOI:10.1016/j.phymed.2025.156835

J Pharm Biomed Anal. 2025 May 14;264:116955. doi: 10.1016/j.jpba.2025.116955. Online ahead of print.ABSTRACTThe global incidence of acute liver injury continues to rise, posing a significant threat to public health. While both raw and processed Rubus idaeus Linnaeus (RI) demonstrate hepatoprotective properties, their mechanisms require further elucidation. This study employed UPLC-Q-TOF/MS-based serum metabolomics to delineate the distinct liver-protective mechanisms of raw and processed RI in a murine model of acute liver injury. Following ten days of intragastric administration with low, medium, and high doses of raw and processed RI extracts, mice received intraperitoneal injection of 50 % carbon tetrachloride in olive oil. Serum levels of aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP), as well as liver levels of superoxide dismutase (SOD), malondialdehyde (MDA), and hydroxyproline (Hyp), were measured via ELISA. Liver histopathology was examined using Hematoxylin and Eosin (HE), Masson, and Sirius Red staining. Treatment with both raw and processed RI significantly reduced serum AST, ALT, and ALP levels while decreasing hepatic MDA and Hyp content compared to the model group. Conversely, SOD activity showed marked elevation. Metabolomic profiling identified 39 significantly altered endogenous metabolites in the model group, with subsequent characterization of 22, 23, and 7 distinctive biomarkers in the raw, salt-processed, and wine-processed RI treatment groups, respectively. These biomarkers predominantly associated with energy metabolism and arginine metabolism. Furthermore, the phenolic and flavonoid compounds in RI, known for their anti-inflammatory and antioxidant properties, played a key role in mitigating liver damage induced by CCl₄. These findings provide strong evidence supporting the potential use of both raw and processed RI in the development of hepatoprotective health products.PMID:40378529 | DOI:10.1016/j.jpba.2025.116955

Environ Int. 2025 May 8;200:109522. doi: 10.1016/j.envint.2025.109522. Online ahead of print.ABSTRACTThis study represents one of the first efforts to investigate the presence and environmental risk of contaminants of emerging concern (CECs) in surface water of the main watersheds of the Department of Lima (Rímac River, Chillón River, and Lurin River), Department of Arequipa (Chili-Quilca-Vítor River, Cámana-Majes River, and Tambo River), and Department of Puno (Lake Titicaca) from Peru. Water samples were collected during two sampling campaigns (June and September-October 2023) in Lima and Arequipa, and one sampling campaign (April-May 2023) in Puno. A strategy combining qualitative and quantitative analysis of CECs was applied, based on liquid chromatography coupled to ion mobility-high resolution mass spectrometry (LC-IMS-HRMS) and tandem mass spectrometry (LC-MS/MS), respectively. A total of 16 pharmaceutically active compounds (PhACs) and other compounds (sweeteners, stimulants, UV filters, and preservatives) and 16 metabolites were identified by LC-IMS-HRMS with a high level of confidence, in addition to the 39 target PhACs quantified by LC-MS/MS. The watersheds of Lima showed the highest pollution in terms of the number of pharmaceuticals and concentration levels compared to the watersheds of Arequipa and Lake Titicaca (Puno), with antibiotics persisting from the upper watersheds to the lower watersheds in the rivers and the lake. For the environmental risk assessment, five different scenarios were considered depending on the water uses/destinations, and the multicriteria scoring method allowed to identification of relevant/concerning PhACs. Azithromycin, clarithromycin, erythromycin, ciprofloxacin, flumequine, trimethoprim, diclofenac, acetaminophen, losartan, valsartan, atorvastatin and metabolite O-desmethyl venlafaxine posed a high level of risk/concern. This information will facilitate the design of a Watch List for CECs, with future monitoring programs and environment risk assessments to protect vulnerable areas most affected by anthropogenic pollution.PMID:40378476 | DOI:10.1016/j.envint.2025.109522

J Proteome Res. 2025 May 16. doi: 10.1021/acs.jproteome.5c00120. Online ahead of print.ABSTRACTMost colorectal cancer (CRC) patients experience changes in tongue coating morphology, but the underlying mechanisms remain unclear. While the human-derived proteome of tongue coatings in gastric cancer and healthy individuals has been characterized, research on CRC patients remains lacking. The tongue coating collection process is painless and noninvasive, providing a more favorable examination experience. This study aims to preliminarily explore the composition and changes in the human-derived proteome of tongue coatings in CRC patients, providing insights into abnormal morphology and potential new CRC screening methods. Utilizing a "bottom-up" strategy and data-independent acquisition (DIA) mode, the human-derived proteome of tongue coating in healthy controls, colorectal hyperplastic polyps patients, and CRC patients was detected using the EASY-nLC 1200 chromatograph coupled with the Orbitrap Fusion Lumos Tribrid mass spectrometer. Differentially expressed proteins were validated by Western blot, and the diagnostic efficacy of tongue coating proteins compared with CRC serum markers was assessed. Our results indicate that the human tongue coating proteome undergoes significant changes in CRC, with upregulated proteins potentially involved in remodeling the tongue coating morphology. Hemopexin (HPX), fibrinogen β chain (FGB), and cystatin C (CST3) in the tongue coating are promising indicators for CRC screening.PMID:40378345 | DOI:10.1021/acs.jproteome.5c00120

Mol Neurobiol. 2025 May 16. doi: 10.1007/s12035-025-05004-2. Online ahead of print.ABSTRACTCrack cocaine has a high addictive power that stimulates the central nervous system (CNS), and its high consumption by women of reproductive age has generated many challenges for public health. Crack cocaine use by pregnant women has been correlated with CNS malformations, cell damage, and changes in the immune system. Our purpose was to evaluate the effects of gestational exposure to crack cocaine in pregnant rats on ectoplacental cone cells, immune organs, maternal behavior, anxiety-like phenotype, metabolites, and sensorimotor reflex development of offspring. Pregnant rats were exposed to air or crack cocaine (200 mg) from the 5th gestational day (5thGD) to the 9th GD or until the end of pregnancy. Our findings showed that gestational exposure to crack cocaine increased trophoblast cell death, associated with reduced ectoplacental cone outgrowth in vitro. Furthermore, anxiogenic-like behavior in pregnant rats and negligence in maternal care were observed after exposure to crack cocaine. The development of motor reflexes in the offspring remained unchanged. In addition, exposure to crack cocaine during pregnancy reduced the relative weight of the spleen and CD8 + T lymphocyte subsets. No changes were observed in the thymus. Finally, we observed a series of changes in the metabolites of lactating rats exposed to crack cocaine during pregnancy. Taken together, our findings provide new insight into gestational changes promoted following exposure to crack cocaine and support future clinical interventions and treatments.PMID:40377894 | DOI:10.1007/s12035-025-05004-2

J Physiol Biochem. 2025 May 16. doi: 10.1007/s13105-025-01085-8. Online ahead of print.ABSTRACTOur aim was to study the metabolic effects of eight weeks of high-intensity interval training (HIIT) on the liver of rats with type 2 diabetes (T2D) using untargeted metabolomics. Twenty male Wistar rats, were divided into four groups (n = 5 per group): control (CTL), type 2 diabetes (DB), HIIT (EX), and type 2 diabetes + HIIT (DTX). A two months of a high-fat diet followed by a single dose of streptozotocin (35 mg/kg body weight) was used to induce T2D. Animals in the EX and DTX groups were trained for eight weeks (5 times per week, 4-10 running intervals at 80-100% of their maximum velocity). Metabolomic data were collected using proton nuclear magnetic resonance (¹H-NMR) to assess metabolic changes in the liver after training. Data were then pre-processed using ProMetab (MATLAB) for baseline correction, normalisation and binning. Fasting blood glucose (FBG) levels were analysed using a repeated-measures mixed ANOVA [i.e., time as the within-subject factor (Baseline - Month 0, Post-induction - Month 2, and Post-intervention - Month 4) and gruop (CTL, DB, HIIT, DTX) as the between-subject factor]. A one-way ANOVA with Tukey's post hoc test (p < 0.05) was applied to assess differences in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Multivariate analysis - using sparse partial least squares discriminant analysis (sPLS-DA) - was performed to identify key metabolites, followed by pathway analysis (MetaboAnalyst) to determine significantly affected metabolic pathways. DB group showed higher HOMA-IR than CTL and DTX groups (p < 0.05). Furthermore, distinct clustering patterns was shown for metabolites by multivariate analysis. Key altered metabolic pathways included valine, leucine, and isoleucine biosynthesis; glutathione metabolism; pantothenate and coenzyme A biosynthesis; fructose and mannose metabolism; glycine, serine, and threonine metabolism; cysteine and methionine metabolism; arginine biosynthesis; tyrosine metabolism; histidine metabolism; beta-alanine metabolism; propanoate metabolism; glycolysis/gluconeogenesis; phenylalanine, tyrosine, and tryptophan biosynthesis; arginine and proline metabolism; and thiamine metabolism. These results suggest that eight weeks of HIIT may reverse metabolic changes induced by T2D in the rat liver, potentially contributing to reduced FBG and HOMA-IR levels. Clinical trial number: Not applicable.PMID:40377860 | DOI:10.1007/s13105-025-01085-8

Plant Foods Hum Nutr. 2025 May 16;80(3):121. doi: 10.1007/s11130-025-01362-3.ABSTRACTCajanus scarabaeoides, a wild relative of Cajanus cajan, is renowned for its medicinal properties and rich bioactive compounds, particularly within its seeds, which are valuable for their storage of primary and secondary metabolites with potential pharmacological applications. This study aimed to comprehensively analyze physical properties, nutritional content, and the metabolic profile of Cajanus scarabaeoides seeds to understand their medicinal potential. Physical characteristics such as seed weight, volume, density, hydration capacity, and swelling index were measured, alongside a detailed nutritional assessment that quantified moisture, ash, crude fat, fiber, protein, carbohydrate, and vitamin content (A, C, E), as well as essential minerals. Metabolic profiling was conducted using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS), identifying 117 non-volatile and 135 volatile metabolites. The chloroform extract showed the highest concentration of volatile metabolites (55), while the chloroform and ethyl acetate extracts were rich in non-volatile compounds (45 and 43, respectively), including flavonoids, polyphenols, and organic acids, which are associated with antioxidant and anti-inflammatory properties. Multivariate analysis, using supervised partial least squares discriminant analysis (PLS-DA), identified differential metabolites, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed the involvement of metabolic pathways such as unsaturated fatty acid biosynthesis, metabolism of xenobiotics by cytochrome P450, and Drug metabolism - other enzymes. The rich composition of bioactive metabolites, especially flavonoids and polyphenols, underscores the medicinal value of Cajanus scarabaeoides seeds, suggesting significant potential for developing antioxidant and anti-inflammatory treatments.PMID:40377812 | DOI:10.1007/s11130-025-01362-3

Cell Mol Life Sci. 2025 May 16;82(1):205. doi: 10.1007/s00018-025-05656-2.ABSTRACTNeuroendocrine neoplasms (NENs) are a group of highly heterogeneous neoplasms originating from neuroendocrine cells with a gradually increased incidence. Metabolic change is one of the recognized markers of tumor progression, which has been extensively and systematically studied in other malignant tumors. However, metabolic change in NENs has been relatively poorly studied, and systematic reviews are lacking. We reviewed the relationship between metabolic changes and NENs from the aspects of glucose metabolism, lipid metabolism, metabolic syndrome, amino acid metabolism and metabolomics, and discussed the potential therapeutic strategies of metabolic changes for NENs.PMID:40377669 | DOI:10.1007/s00018-025-05656-2

J Proteome Res. 2025 May 16. doi: 10.1021/acs.jproteome.4c00947. Online ahead of print.ABSTRACTHeteromeric acetyl-CoA carboxylase (ACCase) catalyzes the ATP-dependent carboxylation of acetyl-CoA to produce malonyl-CoA, which is the committed step for de novo fatty acid synthesis. In plants, ACCase activity is controlled at multiple levels, including negative regulation by biotin attachment domain-containing (BADC) proteins, of which the badc1/3 double mutant leads to increased seed triacylglycerol accumulation. Unexpectedly, the Arabidopsis badc1/3 mutant also accumulated more protein. The metabolic consequences from both higher oil and protein were investigated in developing badc1/3 seed using global transcriptomics, translatomics, proteomics, metabolomics, and other biomass measurements. Changes included increased storage proteins and lipid droplet-packaging proteins, increased SDP1 lipase, altered organic acid metabolism, and reduced extracellular lipid synthesis perhaps offsetting the increase in TAG. We present a model of how Arabidopsis adapted to deregulated ACCase, resulting in more oil, and altered flux through pathways that partition carbon and propose targets for future bioengineering of seed storage reserves.PMID:40377540 | DOI:10.1021/acs.jproteome.4c00947

Plant Cell Environ. 2025 May 16. doi: 10.1111/pce.15623. Online ahead of print.ABSTRACTEngineering plants with reduced lignin content can result in pleiotropic growth defects. In stems of Arabidopsis plants with reduced expression of hydroxycinnamoyl CoA: shikimate hydroxycinnamoyl transferase (HCT), the plastidial glucose 6-phosphate: phosphate co-transporter GPT2 is highly overexpressed, and this coincides with reduced lignin levels and extensive transcriptional and metabolic reprogramming. To explore the potential relationship between GPT2 expression and lignin accumulation, GPT2 transcript levels were evaluated in a suite of Arabidopsis thaliana and Medicago truncatula lignin-defective lines. We also examined lignin levels and composition, and transcriptomic and metabolic profiles in GPT2 loss-of-function, GPT2 overexpression, and wild-type Arabidopsis plants. Loss of GPT2 had no effect on lignin, but its overexpression caused a decrease in stem lignin levels due to reduced accumulation of both guaiacyl and syringyl lignins and their associated monolignol pools. HCT transcript levels were diminished in 35S-GPT2 lines, indicating a potential transcriptional regulatory connection between lignin biosynthesis and GPT2. Based on our transcriptomic and metabolomic analyses, we suggest that GPT2 operates to balance the flux between the biosynthesis of lignin and light-protective phenylpropanoid derivatives.PMID:40377235 | DOI:10.1111/pce.15623

Comb Chem High Throughput Screen. 2025 May 15. doi: 10.2174/0113862073379369250513115909. Online ahead of print.ABSTRACTBACKGROUND: The mechanisms of chemotherapy sensitivity and toxicity are complex. Metabolomics can better reflect the status of anticancer drugs, tumors, and hosts simultaneously.AIM: To identify metabolites and metabolic pathways linked to varying sensitivity and toxicity to chemotherapy in gastric cancer.METHODS: Mice were implanted with human gastric cancer cells through subcutaneous xenografting, and then treated with the PF (platinum-fluorouracil) regimen, with saline serving as the control. Tumor growth was monitored by measuring tumor volume, and body weight was recorded on Days 0, 2, 4, 6, and 8. Kidney damage was assessed using H&E staining. To analyze differential responses, PF-treated mice were grouped separately according to chemotherapy sensitivity (high/medium/low via tumor response) and toxicity (high/medium/low via body weight changes). Serum metabolomics was evaluated using Mass Spectrometry.RESULTS: Platinum-Fluorouracil (PF) chemotherapy significantly reduced tumor weight in mice (164.7 ± 73.5 mg vs. 334.0 ± 107.5 mg; 54.4% inhibition rate), although it also induced notable body weight loss and renal toxicity compared to controls. Serum metabolomic analysis revealed significant differences between PF and control groups, involving metabolites like deoxymethacin and dehydrocorticosterone, associated with AMPK and cortisol synthesis/secretion pathways. Further comparisons highlighted: (1) High- vs. low-sensitivity subgroups differed significantly in metabolites, such as palmitoyl-CoA and indoleacetic acid (linked to AGE-RAGE, insulin resistance, and AMPK pathways). (2) High- vs. low-toxicity subgroups displayed significant metabolic differences, including methylguanosine and methylcytidine (implicated in ferroptosis, ether lipid, and fatty acid metabolism pathways).CONCLUSION: The PF regimen effectively inhibits the growth of subcutaneous tumors in nude mice, while causing varying levels of sensitivity and toxicity in tumor chemotherapy. These observed effects of sensitivity and toxicity are linked to underlying metabolic mechanisms.PMID:40377160 | DOI:10.2174/0113862073379369250513115909

FEBS Lett. 2025 May 16. doi: 10.1002/1873-3468.70067. Online ahead of print.ABSTRACTDuring cortical development, neural stem/precursor cells (NS/PCs) sequentially produce neurons, astrocytes, and oligodendrocytes. Before producing these cells, human (h) NS/PCs undergo prolonged self-renewal to form a larger cortex than other mammals, although the mechanisms are mostly unknown. Here, we performed a gene knockout screen using the CRISPR/Cas9 system to search for genes involved in hNS/PC self-renewal. We identified RMND5A, encoding an E3 ubiquitin ligase, among the candidate genes. We further demonstrated that knockdown of RMND5A decreased proliferation and promoted neuronal differentiation of hNS/PCs through the activation and suppression of the Wnt and mTOR signaling pathways, respectively. Taken together, our findings suggest that RMND5A participates in the maintenance of hNS/PC self-renewal by modulating the Wnt and mTOR signaling pathways. Impact statement During cortical development, human neural stem/precursor cells (hNS/PCs) undergo prolonged self-renewal to form a larger cortex than other mammals, although the mechanisms are mostly unknown. We identified RMND5A, an E3 ubiquitin ligase, as essential for maintaining self-renewal of hNS/PCs, providing valuable insights into the evolutionary expansion of the human brain.PMID:40377017 | DOI:10.1002/1873-3468.70067

Mol Med Rep. 2025 Jul;32(1):203. doi: 10.3892/mmr.2025.13568. Epub 2025 May 16.ABSTRACTHand‑foot syndrome (HFS) is defined as a major adverse reaction to capecitabine; however, the underlying mechanisms remain unclear. In total, 85 patients who were taking oral capecitabine were included in the present study and these patients were divided into HFS‑positive and HFS‑negative groups. Serum samples were collected from patients and an untargeted metabolomics analysis was conducted using ultra‑high performance liquid chromatography‑mass spectrometry/mass spectrometry. The present study aimed to investigate the presence of metabolites in the serum of patients that developed HFS in response to capecitabine treatment. A total of 193 differential metabolites were identified, with 134 upregulated and 59 downregulated. Bioinformatics analysis revealed four novel metabolites that may be associated with HFS. Subsequent in vitro experiments were conducted to explore the damaging effects of capecitabine and its associated metabolites on human adult keratinocyte cell line, TPA‑treated (HaCaT) cells. Results of the present study revealed that aciclovir and lamivudine affected cellular damage at the highest level. In conclusion, the present study aimed to systematically and comprehensively describe the metabolites present in patients with capecitabine‑induced HFS and may further the current understanding of the capecitabine pathways that play a key role in HFS.PMID:40377002 | DOI:10.3892/mmr.2025.13568

Phytochem Anal. 2025 May 16. doi: 10.1002/pca.3538. Online ahead of print.ABSTRACTINTRODUCTION: Natural products are among the main ingredients of medicinal plants, and strategies that enhance their bioactive profile by elemental supplementation have emerged recently. Manganese is involved in various plant secondary metabolism pathways among different micronutrients.OBJECTIVES: This study investigated the effects of ionic (MnSO₄, MnCl₂), bulk (Mn₂O₃), and nano (Mn₂O₃-NP) manganese forms on Artemisia annua's secondary metabolism. It also studied the influence of the application method (seed priming vs. seed priming + foliar).METHODS: For this purpose, untargeted UHPLC-QTOF-HRMS metabolomics was conducted.RESULTS: The findings revealed that Mn form and application method significantly influenced the metabolomic profile and secondary metabolite composition of the leaves and inflorescences, regardless of tissue type. Metabolomic profiling using untargeted analysis and multivariate statistical tools (PCA, PLS-DA, and VIP scoring) showed significant variation in bioactive compound accumulation. Mn₂O₃ and MnCl₂ were most effective in enhancing nitrogen-containing compounds, phenylpropanoids, flavonoids, and terpenoids, possibly via ROS-mediated biosynthesis. Mn₂O₃ strongly increased lignans, while Mn₂O₃-NP showed the highest artemisinin accumulation (3.2-3.7 mg g-1 FW) compared to MnCl₂ and Mn₂O₃ (0.2-1.7 mg g-1 FW). Key pharmacological metabolites such as vincristine, Momilactone A, and terbinafine were identified by VIP2 analysis.CONCLUSION: Mn₂O₃-NP application through seed priming is a promising and cost-effective approach to modulate bioactive metabolite production in Artemisia annua.PMID:40376941 | DOI:10.1002/pca.3538

CNS Neurosci Ther. 2025 May;31(5):e70424. doi: 10.1111/cns.70424.ABSTRACTOBJECTIVE: Metabolomics technology has been widely utilized to uncover the action mechanisms of Parkinson's Disease (PD) and to identify PD-related biomarkers. In this study, we compared plasma and fecal metabolite levels between PD patients and their healthy spouses (HS), aiming to identify the associations of differential metabolites with intestinal inflammation, intestinal barrier function, and clinical characteristics of PD.METHODS: Untargeted metabolomics techniques were used to characterize plasma and fecal metabolite profiles. We identified metabolites with elevated plasma levels in PD patients, while no significant differences were observed in fecal samples. Partial correlation analysis was employed to investigate the associations between these metabolites, markers of intestinal inflammation (calprotectin and lactoferrin), markers of intestinal permeability (α-1-antitrypsin and zonulin), and clinical characteristics of PD patients.RESULTS: The study identified ten metabolites that were significantly elevated in the plasma of PD patients compared to HS (p < 0.05), while their fecal concentrations did not differ significantly. Correlation analysis revealed that elevated levels of differential metabolites in the plasma of PD patients were associated with increased intestinal permeability and inflammation. Furthermore, five metabolites, including 3,4-Dihydroxyphenylglycol O-sulfate and Propyl gallate, were linked to PD symptoms. Receiver Operating Characteristic (ROC) curves demonstrated that these metabolites could effectively distinguish between PD patients and HS, with an area under the curve (AUC) of 0.94, indicating excellent predictive performance.CONCLUSIONS: This study identified significant metabolite alterations in PD patients and revealed their associations with intestinal barrier dysfunction and clinical characteristics of the disease.PMID:40376890 | DOI:10.1111/cns.70424

J Agric Food Chem. 2025 May 16. doi: 10.1021/acs.jafc.4c11988. Online ahead of print.ABSTRACTPectin, a class of dietary fiber, has received increasing attention in recent years for its ameliorative effects on metabolic diseases. However, the structural variability of pectin leads to differential effects on these diseases. The intrinsic mechanism by which pectin, derived from different sources, differentially influences metabolic syndrome by interacting with gut microbiota and host metabolism remains elusive and warrants thorough investigation. To address this, we investigated the effects of HG-type pectins from apple, citrus, and pomelo on phenotypic expressions, inflammatory factors, oxidative stress, and serum hormone levels in mice with metabolic syndrome. In addition, we sought to identify pivotal bacterial species and metabolites by integrating genomics and metabolomics approaches. Our exploration also extended to the relationship between structural characteristics of pectins, gut microbiota, and metabolic syndrome. Our findings revealed that the three pectins diversely improved metabolic syndrome in mice, which correlated with gut microbiota and their beneficial metabolites. Notably, all three pectins were closely associated with Bacteroides and Bacteroides acidifaciens. Besides, the potential mediators of the therapeutic effects included Bacteroides, Lactococcus, and Lachnoclostriclum for apple pectin; Colidextribacter, Bacteroides, Lachnospiraceae_NK4A136_group, and Lachnoclostriclum for citrus pectin; and Lachnospiraceae_NK4A136_group, Bacteroides, and Mucispirillum for pomelo pectin. Metabolites such as arachidonic acid, kynurenic acid, lithocholic acid, deoxycholic acid, and indoleacetic acid, linked to these microbes, may serve as the mediators of pectin's benefits. Ultimately, the molecular weight, degree of esterification, and monosaccharide composition of pectins significantly influenced the outcomes. This study may contribute to a more nuanced understanding that can inform targeted nutritional strategies to modulate gut microbiota for metabolic syndrome management.PMID:40376805 | DOI:10.1021/acs.jafc.4c11988