PubMed

Talanta. 2025 Feb 18;290:127770. doi: 10.1016/j.talanta.2025.127770. Online ahead of print.ABSTRACTGut microbiota produces a wide range of microbial metabolites with potential neuroactive properties. Among these, p-cresol, a by-product of tyrosine breakdown, has gained significant attention in various neuropsychiatric disorders, including autism spectrum disorder. However, current methods fail to detect p-cresol at trace levels in both the systemic circulation and brain, limiting the study of its role in neuropsychiatric disorders. There, the precise and accurate determination of p-cresol at low picogram levels is an unmet analytical need. To address this gap, we developed a highly-sensitive, validated method for quantifying p-cresol at low picogram levels in urine, plasma, and brain using chemical derivatization and liquid chromatography-tandem mass spectrometry (LC-MS/MS). We found that derivatization with 1,2-dimethylimidazole-5-sulfonyl chloride (5-DMIS-Cl or 5-DMISC) increased up to 40-fold the sensitivity compared to traditional dansyl derivatization. Therefore, a method based on 5-DMISC derivatization and sum of transitions was selected for validation. The method was accurate (recoveries 91-100 %) and precise (RSD <15 %) in all tested matrices, enabling detection down to100 pg/mL for urine, 20 pg/mL for plasma, and 0.04 pg/mg for brain tissue. The method was applied to plasma and brain samples from control and p-cresol-treated mice, revealing significant increases in p-cresol levels in treated animals. For the first time, we successfully quantified p-cresol levels in the brain, demonstrating its ability to cross the blood-brain barrier. In summary, this validated method offers a powerful tool for exploring the role of p-cresol -and potentially other phenolic compounds-in the microbiota-gut-brain axis and neuropsychiatric disorders.PMID:40010114 | DOI:10.1016/j.talanta.2025.127770

Phytomedicine. 2025 Feb 19;139:156543. doi: 10.1016/j.phymed.2025.156543. Online ahead of print.ABSTRACTBACKGROUND: The underlying pathogenesis of psoriasis was attributed to insufficient kidney qi and blood stasis arising from impeded blood circulation. Jinkui Shenqi decoction (JKSQD), was renowned for its capacity to warm and tonify kidney yang, as well as to invigorate blood circulation. However, there remains a dearth of studies on its specific therapeutic effects and underlying mechanisms of psoriasis.PURPOSE: Aiming to investigate the effectiveness and mechanism of JKSQD in the treatment of psoriasis.METHODS: Initially, we identified the compounds of JKSQD by UPLC-Q-TOF-MS/MS and constructed psoriasis-like mice to explore the effect of JKSQD on psoriasis. Subsequently, proteomic sequencing was conducted to identify key proteins and pathways involved in the therapeutic effect of JKSQD. Neutrophil extracellular traps (NETs) and peptidylarginine deiminase 4 (PAD4)-related indicators were detected to validate JKSQD mechanisms. At last, we analyzed metabolomic data to elucidate what metabolic pathway or metabolites worked during this procedure.RESULTS: We found that JKSQD effectively reversed the progression of psoriasis and associated inflammation in mice. Proteomic analysis further illuminated that PAD4 involved in NETosis was notably downregulated in psoriasis-like mice after JKSQD treatment. And a series of experiments further revealed that JKSQD inhibited NETs formation and PAD4 expression. Moreover, metabolomics demonstrated JKSQD influenced D-Arginine and D-ornithine metabolism, offering deeper insights into the mechanisms of JKSQD on psoriasis.CONCLUSIONS: This study unveiled that JKSQD could improve psoriasis progression by targeting PAD4 to inhibit NETs formation.PMID:40010032 | DOI:10.1016/j.phymed.2025.156543

Phytomedicine. 2025 Feb 14;139:156518. doi: 10.1016/j.phymed.2025.156518. Online ahead of print.ABSTRACTBACKGROUND: Drug discovery from nature has a long, ethnopharmacologically-based background. Today, natural resources are undeniably vital reservoirs of active molecules or drug leads. Advances in (bio)informatics and computational biology emphasized the role of herbal medicines in the drug discovery pipeline.PURPOSE: This review summarizes bioinformatic approaches applied in recent drug discovery from nature.STUDY DESIGN: It examines advancements in molecular networking, pathway analysis, network pharmacology within a systems biology framework and AI for assessing the therapeutic potential of herbal preparations.METHODS: A comprehensive literature search was conducted using Pubmed, SciFinder, and Google Database. Obtained data was analyzed and organized in subsections: AI, systems biology integrative approach, network pharmacology, pathway analysis, molecular networking, structure-based virtual screening.RESULTS: Bioinformatic approaches is now essential for high-throughput data analysis in drug target identification, mechanism-based drug discovery, drug repurposing and side-effects prediction. Large datasets obtained from "omics" approaches require bioinformatic calculations to unveil interactions, and patterns in disease-relevant conditions. These tools enable databases annotations, pattern-matching, connections discovery, molecular relationship exploration, and data visualisation.CONCLUSION: Despite the complexity of plant metabolites, bioinformatic approaches assist in characterization of herbal preparations and selection of bioactive molecule. It is perceived as powerful tool for uncovering multi-target effects and potential molecular mechanisms of compounds. By integrating multiple networks that connect gene-disease, drug-target and gene-drug-target, drug discovery from natural sources is experiencing a remarkable comeback.PMID:40010031 | DOI:10.1016/j.phymed.2025.156518

J Chromatogr A. 2025 Feb 20;1746:465804. doi: 10.1016/j.chroma.2025.465804. Online ahead of print.ABSTRACTFissistigma polyanthum is a renowned medicinal plant traditionally used by over 10 ethnic groups in China to treat various ailments, including inflammation. However, research on its chemical composition and bioactivity remains limited. This study investigated the chemical profiles and biological activities across different parts of F. polyanthum, aiming to identify the bioactive molecules associated with anti-inflammatory and anti-Alzheimer's effects. To ensure accurate metabolite identification, an in-house Fissistigma compound library containing 654 chemicals was constructed and integrated with the Progenesis QI informatics platform. Using UPLC-ESI-QTOF-MS-based metabolomics, 97 compounds, including alkaloids, flavonoids and terpenoids, were identified, of which 86 were reported for the first time in this species. Heatmap analysis revealed significant content variations of these constituents across different plant parts: leaves were rich in flavonoids and terpenoids, while the root without bark was abundant in alkaloids. PCA and PLS-DA analyses confirmed significant metabolite differences among the plant parts, with 31 key differential compounds explaining the chemical variations. Comparative bioactivity assays showed that the root without bark exhibited strong anti-butyrylcholinesterase activity, with an IC50 value of 54.22 μg/mL, while the root bark and leaves demonstrated the strongest inhibition of NO production, with IC50 values of 62.64 and 71.85 μg/mL, respectively. The S-plot analysis further identified 25 potential bioactive compounds, primarily alkaloids and flavonoids, responsible for the observed bioactivities, including known anti-inflammatory and anti-Alzheimer's agents. These findings underscore the pharmaceutical potential of F. polyanthum and the effectiveness of integrating metabolomics and chemometrics to discover bioactive molecules in medicinal plants.PMID:40009970 | DOI:10.1016/j.chroma.2025.465804

Ecotoxicol Environ Saf. 2025 Feb 25;292:117948. doi: 10.1016/j.ecoenv.2025.117948. Online ahead of print.ABSTRACTDi(2-ethylhexyl) phthalate (DEHP) is recognised as a pollutant with multiple health risks. In this study, multi-omics approaches were used to examine the alterations in immunity, gut microbiota and metabolome, and liver transcriptome in the rats with DEHP-induced subacute liver injury. Following short-term subacute DEHP exposure, the rats exhibited decreased body weight, increased liver weight, impaired liver function and immunity, and signs of liver injury. DEHP exposure reduced the richness, diversity, and evenness of gut microbiota, resulting in elevated levels of Lactobacillus, Romboutsia, and Alistipes and decreased levels of unclassified Muribaculaceae, Oscillibacter, and Akkermansia in the intestine. Multiple gut metabolic pathways were altered by DEHP, among which sphingolipid metabolism was enriched with the most differentially expressed metabolites. In the liver tissues of rats exposed to DEHP, lipid metabolism-related pathways were altered, including downregulated steroid biosynthesis and upregulated fatty acid degradation. In conclusion, the relevant findings suggest that DEHP can cause immune alteration, gut microbiota dysbiosis, gut metabolome disruption, liver transcriptome dysregulation, and result in liver injury in rats. These results could benefit the clinical diagnosis of DEHP-induced subacute liver injury.PMID:40009945 | DOI:10.1016/j.ecoenv.2025.117948

Neoplasia. 2025 Feb 25;62:101146. doi: 10.1016/j.neo.2025.101146. Online ahead of print.ABSTRACTOral squamous cell carcinoma (OSCC) is characterized by aggressiveness and a poor prognosis, in part because most patients are diagnosed during the later stages of the disease. B cell-specific Moloney murine leukemia virus integration site 1 (BMI1), part of polycomb repressive complex 1 (PRC1), is a key transcription factor overexpressed in OSCC. Although increased BMI1 has been linked to tumor formation in mouse models of the disease, the molecular mechanisms have not been elucidated. Here we used a transgenic mouse line (KrTB) that selectively overexpresses BMI1 in the tongue basal epithelial stem cells (SCs) to delineate BMI1 actions during oral tumorigenesis. By tumor pathological classification after 4-nitroquinoline 1-oxide (4-NQO)-induced carcinogenesis we detected more severe tumors in mice with ectopic BMI1 expression. Genome-wide transcriptomics indicated that mRNAs associated with human OSCC, including SOX9, HIF1A, MMP9, INHBB, and MYOF, were further increased by ectopic BMI1 expression in murine tongue epithelia. mRNAs encoding multiple metabolic targets, such as SLC2A1 (GLUT1), PKM, LDHA, and HK2, were also increased upon BMI1 overexpression in 4-NQO-treated tongue epithelia. Furthermore, we detected BMI1, SOX9, and GLUT1 proteins in the infiltrating cells of invasion fronts identified by markers of invasive SCCs. Finally, metabolomic data show that BMI1 overexpression in tongue epithelia promotes glycolysis during 4-NQO-induced carcinogenesis. Thus, our data demonstrate that BMI1 causes OSCC cells to alter cell metabolism, as changes in many of these transcripts are linked to increased glycolysis and metabolic reprograming that occurs during carcinogenesis.PMID:40009939 | DOI:10.1016/j.neo.2025.101146

Proc Natl Acad Sci U S A. 2025 Mar 4;122(9):e2421489122. doi: 10.1073/pnas.2421489122. Epub 2025 Feb 26.ABSTRACTAldosterone-producing adenomas (APA), a major endocrine tumor and leading subtype of primary aldosteronism, cause secondary hypertension with high cardiometabolic risks. Despite potentially producing multiple steroid hormones, detailed cellular mechanisms in APA remain insufficiently studied. Our multiomics analysis focusing on APA with KCNJ5 mutations, which represent the most common genetic form, revealed marked cellular heterogeneity. Tumor cell reprogramming initiated from stress-responsive cells to aldosterone-producing or cortisol-producing cells, with the latter progressing to proliferative stromal-like cells. These cell subtypes showed spatial segregation, and APA exhibited genomic intratumor heterogeneity. Among the nonparenchymal cells, lipid-associated macrophages, which were abundant in APA, might promote the progression of cortisol-producing and stromal-like cells, suggesting their role in the tumor microenvironment. Intratumor cortisol synthesis was correlated with increased blood cortisol levels, which were associated with the development of vertebral fractures, a hallmark of osteoporosis. This study unveils the complex cellular ecosystem with clinical relevance in APA with KCNJ5 mutations, providing insights into tumor biology that could inform future clinical approaches.PMID:40009643 | DOI:10.1073/pnas.2421489122

Blood. 2025 Feb 26:blood.2024025924. doi: 10.1182/blood.2024025924. Online ahead of print.ABSTRACTMicrobial dysbiosis and metabolite changes in the gastro-intestinal (GI) tract have been linked to pathogenesis and severity of many diseases, including graft-versus-host disease (GVHD), the major complication of allogeneic hematopoietic stem cell transplantation (HCT). However, published studies have only considered the microbiome and metabolome of excreted stool and do not provide insight into the variability of microbial community and metabolite composition throughout the GI tract or the unique temporal dynamics associated with different gut locations. Because such geographical variations are known to influence disease processes, we utilized a multi-omics approach to characterize the microbiome and metabolite profiles of gut contents from different intestinal regions in well-characterized mouse models of GVHD. Our analysis validated analyses from excreted stool, but importantly, uncovered new biological insights from the microbial and metabolite changes between syngeneic and allogeneic hosts that varied by GI location and time after transplantation. Our integrated analysis confirmed the involvement of known metabolic pathways, including SCFA synthesis and bile acid metabolism, and identified additional functional genes, pathways, and metabolites, such as amino acids, fatty acids, and sphingolipids, linked to GI GVHD. Finally, we validated a biological relevance for one such newly identified microbial metabolite, phenyl lactate, that heretofore had not been linked to GI GVHD. Thus, our analysis of the geographic variability in the intestinal microbiome and metabolome offers new insights into GI GVHD pathogenesis and potential for novel therapeutics.PMID:40009444 | DOI:10.1182/blood.2024025924

Appl Biochem Biotechnol. 2025 Feb 26. doi: 10.1007/s12010-025-05200-9. Online ahead of print.ABSTRACTColorectal cancer (CRC) is one of the common deadliest cancers worldwide. In Malaysia, the numbers of new CRC cases were horrific and worrisome. Telomerase is both prognostic indicator and predictor of carcinogenesis in CRC patients. Berberine, a telomerase inhibitor, was used in clinical trials and metabolomic studies; however, the association of telomerase with metabolites and metabolic pathways was not fully understood. Colorectal cancer cell line HCT 116 was cultured and treated with 10.54 µg/mL berberine. The cells were harvested at different time points to conduct subsequent analyses. The methods used in this research were real time-polymerase chain reaction (RT-PCR) to assess RNA expressions; Western blot to determine protein levels; TELOTAGGG Telomerase PCR ELISA to determine relative telomerase activity (RTA); 4',6-diamidino-2-phenylindole (DAPI) staining to determine percentage of nuclei damage; fluorescence microscopy for cell area; spectrophotometric potassium iodide assay for intracellular hydrogen peroxide concentration [H2O2]; as well as liquid chromatography mass spectrometry (LCMS) and tandem mass spectrometry (MS/MS) to investigate the intracellular metabolites. Partial least square-discriminant analysis (PLS-DA) score plot exhibited an improved separation compared to principal component analysis (PCA) when metabolomic data analysis of HCT 116 at various berberine treatment durations was conducted. Time and berberine treatment had an impact on RTA in HCT 116. RTA was discovered to be positively and negatively correlated to 14 and 2 metabolites, respectively. Glutamic acid was consistently found correlated to RTA. Other four metabolites, i.e., MG(14:0), [3-[hydroxy(phosphonooxy)phosphoryl]oxyphenyl] phosphono hydrogen phosphate), (3S,6S)-6-[[(3S,6R)-6-[(2S,3S,5S)-2,5-diiodo-4-methoxy-6-methyloxan-3-yl]oxy-3,4,5-trihydroxyoxan-2-yl]methoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid, and 1-[5-O-(5'-adenylyloxyphosphonyl)-beta-D-ribofuranosyl]-5-amino-1H-imidazole-4-carboxamide, were newly discovered to be connected to RTA in HCT 116. Four metabolic pathways that majorly affected shared glutamic acid and glutamine. Nitrogen metabolism, D-glutamine and D-glutamate metabolism, glyoxylate and dicarboxylate metabolism, and aminoacyl-tRNA biosynthesis have been identified to be associated with RTA. Network analyses hinted that glutamic acid was also associated with oxidative stress mechanism. The multiple roles glutamic acid acted in diverse metabolic pathways and interaction networks emphasized the importance of glutamic acid in HCT 116 regarding RTA. This research establishes the association between RTA and several chosen RNAs, proteins, metabolites, and oxidative stress mechanisms, consequential in morphological alteration in HCT 116, to expand the knowledge of the intricate biological relationships and telomerase mechanism in CRC.PMID:40009339 | DOI:10.1007/s12010-025-05200-9

Theor Appl Genet. 2025 Feb 26;138(3):59. doi: 10.1007/s00122-025-04849-4.ABSTRACTA missense mutation that causes premature termination of the CmEGY1 protein leads to golden fruit in melon. Melon (Cucumis melo L.) is an economically important fruit crop that has been cultivated for thousands of years. Fruit color, a crucial trait influencing the appearance quality and economic value of melons, is primarily determined mainly by the type and concentration of pigments such as chlorophyll, carotenoids, and flavonoids. Identifying the genetic loci that govern melon fruit color contributes to breeding efforts aimed at enhancing melon rind coloration. This study reports an EMS-induced mutant, designated as gf1 (golden fruit 1), which produces fruit with both golden peel and flesh. Through MutMap and map-based cloning, we localized the gf1 locus to an 862 kb region containing 42 SNPs. Of these, a single SNP in the coding region caused a stop-gained mutation in the gene Cme13C08g017690, which exhibits the highest sequence similarity to Arabidopsis ETHYLENE-DEPENDENT GRAVITROPISM-DEFICIENT AND YELLOW-GREEN 1 (EGY1). Genome editing of CsEGY1, the cucumber homolog, confirmed its role in golden-fruit formation. Transcriptome and metabolome analyses revealed reduced flavonoid and carotenoid contents, accompanied by the downregulation of related biosynthetic genes. The identification and characterization of egy1 provide novel genetic insights and a valuable resource for improving melon appearance through breeding.PMID:40009196 | DOI:10.1007/s00122-025-04849-4

J Membr Biol. 2025 Feb 26. doi: 10.1007/s00232-024-00332-1. Online ahead of print.ABSTRACTTrans-membrane water transport and co-transport is ubiquitous in cell biology. Integrated over all the cell's H2O transporters and co-transporters, the rate of homeostatic, bidirectional trans-cytolemmal water "exchange" is synchronized with the metabolic rate of the crucial Na+,K+-ATPase (NKA) enzyme: the active trans-membrane water cycling (AWC) phenomenon. Is AWC futile, or is it consequential? Conservatively representative literature metabolomic and proteinomic results enable comprehensive free energy (ΔG) calculations for the many transport reactions with known water stoichiometries. Including established intracellular pressure (Pi) magnitudes, these reveal an outward trans-membrane H2O barochemical ΔG gradient comparable to that of the well-known inward Na+ electrochemical ΔG gradient. For most co-influxers, these two gradients are finely balanced to maintain intracellular metabolite concentration values near their consuming enzyme Michaelis constants. Our analyses include glucose, glutamate-, gamma-aminobutyric acid (GABA), and lactate- transporters. 2%-4% Pi alterations can lead to disastrous metabolite concentrations. For the neurotransmitters glutamate- and GABA, very small astrocytic Pi changes can allow/disallow synaptic transmission. Unlike the Na+ and K+ electrochemical steady-states, the H2O barochemical steady-state is in (or near) chemical equilibrium. The analyses show why the presence of aquaporins (AQPs) does not dissipate trans-membrane pressure gradients. A feedback loop inherent in the opposing Na+ electrochemical and H2O barochemical gradients regulates AQP-catalyzed water flux as integral to AWC. A re-consideration of the underlying nature of Pi is also necessary. AWC is not a futile cycle but is inherent to the cell's "NKA system"-a new, fundamental aspect of biology. Metabolic energy is stored in the trans-membrane water barochemical gradient.PMID:40009106 | DOI:10.1007/s00232-024-00332-1

Food Funct. 2025 Feb 26. doi: 10.1039/d4fo06449f. Online ahead of print.ABSTRACTObesity is a major global public health challenge, affecting billions and serving as a primary risk factor for many chronic diseases. Certain probiotics have shown promise in regulating energy balance and enhancing fat metabolism, offering potential strategies for managing obesity. In this study, we evaluated three strains of Bifidobacterium adolescentis and identified B. adolescentis FJSSZ23M10 as the most effective in alleviating high-fat diet (HFD)-induced obesity. This strain significantly reduced weight gain, improved abnormal serum biochemical indicators, decreased lipid accumulation in adipocytes, and enhanced energy expenditure. Furthermore, B. adolescentis FJSSZ23M10 treatment modulated the gut microbiota, notably increasing the abundance of Bifidobacterium and Faecalibaculum. Untargeted metabolomic analysis revealed that B. adolescentis FJSSZ23M10 uniquely upregulated beneficial metabolites, such as butyrate and pyruvic acid, suggesting its superior metabolic impact. Genomic analysis indicated that B. adolescentis FJSSZ23M10 harbored the highest abundance of unassigned genes and carbohydrate-active enzymes (CAZymes) compared to the other strains, highlighting its superior functional potential. Combining the shared and unique modifications in gut microbiota, metabolites, and genomic annotations, the study highlights that genomic differences among probiotics could shape their effects on gut microbiota and metabolites. Conclusively, the study underscores the critical role of probiotic genomic characteristics in determining their functional efficacy and suggests that the intake of the B. adolescentis FJSSZ23M10 strain with enriched genomic features, such as CAZymes, could represent a novel genomic-based strategy for alleviating obesity through gut microbiota modulation and metabolic regulation.PMID:40008925 | DOI:10.1039/d4fo06449f

Anal Chem. 2025 Feb 26. doi: 10.1021/acs.analchem.4c05560. Online ahead of print.ABSTRACTDefinitive structural elucidation of lipids is pivotal for unraveling the functions of lipids in biological systems. Despite advancements in mass spectrometry (MS) for lipid analysis, challenges in annotation scope and efficiency remain, especially in resolving isomers. Herein, we introduce an optimized method using liquid chromatography coupled with electron impact excitation of ions from organic tandem mass spectrometry (LC-EIEIO-MS/MS) for comprehensive analysis and structural annotation of lipids. This approach integrates a six-step analytical protocol for precise lipid annotation, including (1) extracting MS information, (2) classifying lipids, (3) aligning sum composition, (4) determining sn-positions, (5) locating C═C positions, and (6) ascertaining annotation levels. In analyzing 34 lipid standards spiked into serum, our method achieved 100% and 82.4% annotation accuracy at the sn- and C═C isomer levels, respectively, compared to 26.5% and 0% in the CID mode using MS-DIAL. A total of 1312 sn-positions and 1033 C═C locations of lipids were annotated in quality control plasma pooled from healthy individuals and patients with Alzheimer's disease. The isomers of lipids revealed more pronounced differences between the healthy and diseased groups compared to the sum compositions of the lipids. Overall, the LC-EIEIO-MS/MS approach provides a comprehensive profiling and efficient annotation method for lipidomics, promising to shed new light on lipid-related biological pathways and disease mechanisms.PMID:40008860 | DOI:10.1021/acs.analchem.4c05560

Clin Kidney J. 2024 Nov 23;18(1):sfae366. doi: 10.1093/ckj/sfae366. eCollection 2025 Jan.ABSTRACTBACKGROUND: Sarcopenia and frailty are often overlooked in assessing kidney transplant (KT) candidates with chronic kidney disease (CKD), potentially leading to poor post-transplant outcomes. This study aimed to identify metabolites associated with frailty and sarcopenia in KT candidates from the FRAILMar study.METHODS: Between June 2016 and June 2020, we evaluated frailty and sarcopenia in 173 KT candidates using the Physical Frailty Phenotype and EGWSOP-2 criteria, respectively. Seventy-five metabolic markers from targeted pathways, previously linked to CKD, sarcopenia or frailty, were measured in serum samples. These markers were analyzed using adjusted and weighted generalized linear models. Metabolomic data were integrated with multi-modal data, such as comorbidities, using a factor-based integration algorithm to identify metabolic phenotypes.RESULTS: Increased metabolites related to energy metabolism and essential amino acids were associated with frailty, mainly Krebs cycle intermediates. Sarcopenic KT candidates showed lower levels of aromatic amino acids, and lower protein/muscle metabolism, energy metabolism and neurotransmission compared with non-sarcopenic patients. Unsupervised multi-modal integration revealed a high-risk metabolic phenotype characterized by the presence of sarcopenia, diabetes mellitus and low body mass index, with alterations in branched-chain amino acids and high activity of lactate dehydrogenase enzyme.CONCLUSIONS: Frailty and sarcopenia are common among KT candidates, and their metabolic status reveals notable disruptions in energy and amino acid metabolism. These findings highlight the value of a detailed metabolic assessment to more accurately evaluate patient health status prior to transplantation.PMID:40008357 | PMC:PMC11852263 | DOI:10.1093/ckj/sfae366

Brain Commun. 2025 Feb 8;7(1):fcaf063. doi: 10.1093/braincomms/fcaf063. eCollection 2025.ABSTRACTMetabolic imbalance is associated with amyotrophic lateral sclerosis progression. Impaired glucose oxidation and increased reliance on fatty acid oxidation contribute to reduced metabolic flexibility and faster disease progression in amyotrophic lateral sclerosis. We sought to evaluate the safety and tolerability, and explore the pharmacodynamic response of trimetazidine, a partial fatty acid oxidation inhibitor, on oxidative stress markers and energy expenditure in amyotrophic lateral sclerosis. The study was conducted between June 29, 2021 and May 24, 2023. People living with amyotrophic lateral sclerosis, recruited in Australia and the Netherlands, received open-label oral trimetazidine for 12 weeks after an initial 4-week lead-in period. The primary outcome measures were safety and tolerability, as well as the change from baseline in oxidative stress markers malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Secondary outcome measures were change from baseline in energy expenditure, amyotrophic lateral sclerosis functional rating scale-revised, and slow vital capacity (SVC). Linear mixed effects were used to estimate the mean difference in MDA and 8-OHdG between the on- and off-treatment periods. This trial is registered under ClinicalTrial.gov National Clinical Trial (NCT) number NCT04788745 and European Union Drug Regulating Authorities Clinical Trials (EudraCT) number 2020-005018-17. Twenty-one participants received trimetazidine; 19 (90%) completed the treatment period. Trimetazidine was well tolerated; there were 57 adverse events reported, of which 7 (11%) were deemed potentially drug-related, including hot flushes (2), nausea (2), paraesthesia (2) and fatigue (1). MDA was numerically lower during treatment [-0.29 uM; 95% confidence interval (CI) -0.90 to 0.33, P = 0.36]; 8-OHdG was significantly lower during treatment (-0.12 nM; 95% CI -0.23 to -0.01, P = 0.0245). The decrease in oxidative stress markers was accompanied by a reduction in resting energy expenditure (95 kcal, 95% CI 36.8-154, P = 0.0014). The absence of a placebo group prevented the interpretation of the clinical parameters. Oral trimetazidine was safe and well tolerated among patients with amyotrophic lateral sclerosis. This, combined with the significant reduction in markers of oxidative stress and resting energy expenditure, warrants a larger double-blind placebo-controlled efficacy study.PMID:40008327 | PMC:PMC11851067 | DOI:10.1093/braincomms/fcaf063

Front Oral Health. 2025 Feb 11;6:1516025. doi: 10.3389/froh.2025.1516025. eCollection 2025.ABSTRACTINTRODUCTION: Salivary mucin MUC5B has been suggested to support eubiosis in early oral biofilms by regulating the attachment of commensals, while downregulating dysbiotic activities related to dental caries development, such as microbial carbohydrate transport and metabolism.METHODS: To investigate how the metabolism of glucose, a potential driver for dental caries, in early mono- and dual-species biofilms of oral Actinomyces naeslundii and Streptococcus gordonii clinical isolates was affected by the presence of the complex salivary mucin MUC5B, this study employed nuclear magnetic resonance (NMR)-based metabolomics with the interpretation of network integration.RESULTS AND DISCUSSION: MUC5B reduced early attachment in the presence of glucose compared with uncoated surfaces but maintained even species distribution. This suggests that MUC5B may represent an innate mechanism to regulate biofilm eubiosis by supporting early coadhesion while regulating total biomass. All annotated metabolites were intermediates in either carbohydrate metabolism, pyruvate conversion, or amino acid metabolism, which was not unexpected in biofilm glucose metabolomes from two saccharolytic species since pyruvate conversion represents a junction point between glycolysis and amino acid metabolic chains. The 10 metabolites present in all early biofilms represent a core metabolome shared by A. naeslundii and S. gordonii. Such core metabolomes can be used to detect deviations in future studies. Significant differences in metabolite abundance elicited by the presence of MUC5B were also detected. In early biofilms where they were each present, pyruvate, ethanol, and metabolite 134 were present in significantly higher abundance in the presence of 25% MUC5B with 20 mM glucose (MUC5B + G) compared with a physiologic buffer with 20 mM glucose (PBS + G), while metabolites 84, 97, and sarcosine were present at significantly lower abundance. Metabolite 72 was unique to biofilms grown in MUC5B + G, and eight unannotated metabolites were unique to biofilms grown in PBS + G. A pathway enrichment analysis of the metabolites that were differently expressed in early A. naeslundii, S. gordonii, and dual-species biofilms grown with 20 mM glucose with or without MUC5B showed that pyruvate metabolism was significantly over-represented. Studying the metabolic interactions between commensal members of oral biofilms and modulatory effects of host factors such as glycoproteins in saliva during the metabolism of substrates that are potential drivers of dysbiosis, such as glucose, is essential to understand the roles of oral microbial ecosystems in oral health and disease.PMID:40008185 | PMC:PMC11850524 | DOI:10.3389/froh.2025.1516025

Exp Biol Med (Maywood). 2025 Feb 11;250:10204. doi: 10.3389/ebm.2025.10204. eCollection 2025.ABSTRACTThe sex difference in depression has long been an unsolved issue. Women are twice as likely to suffer from depression as men. However, there were significant differences in the composition of gut microbiota between women and men. There is a lack of studies linking sex differences in depression to microbiota, and the specific mechanisms of this process have not been explained in detail. The main purpose of this study was to explore the gender differences in the intestinal tract of male and female depressed mice. In this study, chronic restraint stress (CRS) mouse models were used to simulate chronic stress, and behavioral tests were conducted, including the open field test (OFT), tail suspension test (TST) and forced swimming test (FST). Microbial diversity analysis and metabolomics were performed on collected mouse feces. The results showed that female mice were highly active and prone to anxious behavior before stress, and the levels of f-Rikenellaceae, f-Ruminococcaceae and 16α-hydroxyestrone were significantly different from those in male mice. After 21 days (Days) of stress, female mice showed depression-like behavior, and the levels of f-Erysipelotrichaceae, 5α-pregnane-3,20-dione, and 2-hydroxyestradiol were significantly different from those in male mice. After 14 days of stress withdrawal, the depression-like behavior continued to worsen in female mice, and the levels of 5α-pregnane-3,20-dione, estrone glucuronide and f-Erysipelotrichaceae were significantly different from those in male mice. In summary, female mice have stronger stress sensitivity and weaker resilience than male mice, which may be related to differences in bacterial diversity and estrogen metabolism disorders.PMID:40008145 | PMC:PMC11851196 | DOI:10.3389/ebm.2025.10204

Front Pharmacol. 2025 Feb 11;16:1528398. doi: 10.3389/fphar.2025.1528398. eCollection 2025.ABSTRACTINTRODUCTION: The extensively used Lindera communis Hemsl. (Lauraceae) in traditional Chinese medicine has been specifically employed for wound healing and treating skin diseases in cattle and horses, suggesting its potential antibacterial properties. To explore the antibacterial activities of L. communis plants, we investigated the chemicals, antibacterial activities and wound healing and of the n-hexane fraction of L. communis roots (LCH).METHODS: Our study included detecting phytochemical constituents, determining minimum inhibitory concentration (MIC) for different extract fractions, analyzing growth curves, assessing membrane integrity, monitoring potential changes in the membrane using scanning electron microscopy, and evaluating wound healing in rat excisional wounds.RESULTS: Based on our findings, humulene-type sesquiterpenes, guaiane-type sesquiterpenes, and lauric acid were identified from the LCH, responsible for antibacterial and wound healing activities. The results are that LCH affected the growth of methicillin-resistant Staphylococcus aureus (MIC: 0.1 mg/mL) through morphological alterations and disrupting cell surface structures, causing membrane hyperpolarization and altering membrane integrity. This result was subsequently validated through SEM analysis and cytotoxicity against HaCaT cells (IC50 1.83 ± 0.21 mg/mL). LCH also has exhibited remarkable effectiveness in healing rat excisional wounds, reinforcing its traditional use as a wound-healing agent.DISCUSSION: The findings substantiate the scientific essence of traditional applications, while also exhibiting significant potential as a promising candidate for the development of innovative and readily accessible wound healing agents.PMID:40008129 | PMC:PMC11851014 | DOI:10.3389/fphar.2025.1528398

Front Cell Infect Microbiol. 2025 Feb 11;15:1444028. doi: 10.3389/fcimb.2025.1444028. eCollection 2025.ABSTRACTPreterm birth (PTB) is a major cause of infant morbidity and mortality. The aim of this study was to investigate the effect of vaginal microbiota and metabolites on the outcome of pregnant women. In this study, a total of 127 pregnant women provided written informed consent prior to enrollment in accordance with the approved institutional guidelines, but only 45 pregnancies met the experimental requirements, and then blood and cervical vaginal fluid (CVF) samples were collected before delivery (at the second week after cervical cerclage). Pregnant women with PTB exhibited high white blood cell and neutrophil contents, high neutrophil-to-lymphocyte ratio (NLR), and high systemic inflammation response index (SIRI) in the blood. Vaginal microbiome revealed that the proportion of beneficial bacteria (including Lactobacillus, [Ruminococcus] gnavus group, and Megamonas) significantly decreased in the PTB group, and the proportion of harmful bacteria (including Desulfovibrionaceae, Helicobacter, and Gardnerella) significantly increased, which is strongly related to the biochemical parameters of blood (white blood cells, neutrophils, NLR, and SIRI). In addition, vaginal metabolomics-based liquid chromatography-Orbitrap-tandem mass spectrometry (LC-Orbitrap-MS/MS) found that the alteration in vaginal metabolites in pregnant women with PTB is involved in starch and sucrose metabolism; arginine and praline metabolism; galactose metabolism; purine metabolism; arginine metabolism; tryptophan metabolism and N-glycan biosynthesis; cysteine and methionine metabolism; taurine and hypotaurine metabolism; amino acid metabolism; propanoate metabolism; valine, leucine, and isoleucine biosynthesis; glycine, serine, and threonine metabolism; and steroid hormone biosynthesis. These results elaborated that distinct vaginal microbiome and metabolome profiles in women with preterm delivery following cervical cerclage provide valuable information for establishing the prediction models for PTB.PMID:40007613 | PMC:PMC11850995 | DOI:10.3389/fcimb.2025.1444028

J Sci Food Agric. 2025 Feb 26. doi: 10.1002/jsfa.14190. Online ahead of print.ABSTRACTBACKGROUND: Tilia has a long history of cultivation and holds high ornamental and economic value. The volatile aroma compounds of Tilia flowers have significant characteristics that contribute to their ornamental appeal, and affect the flavor of floral tea. Here, widely targeted metabolomic analyses were conducted to investigate the aroma active compounds in the fresh inflorescences of Tilia cordata Mill. (Tc) and Tilia miqueliana Maxim. (Tm), and in samples prepared by freeze drying, air drying, and oven drying.RESULTS: We identified 442 volatile organic compounds by headspace solid-phase microextraction gas chromatography-mass spectrometry. Terpenoids were the most abundant and diverse group, while heterocyclic compounds were the main contributors to the aroma profile. Notably, 46 aroma compounds were identified as primary contributors to the characteristic aroma of Tilia, including abhexon, 2-isobutyl-3-methoxypyrazine, (Z)-6-nonenal, methyl benzoate, (E)-2-hexenal, 1-hexanol, 2-thiophenemethanethiol, p-cymene, furaneol, and (Z)-4-heptenal. The concentration of volatile organic compounds was higher in Tc than in Tm, indicating a more pronounced aroma character of Tc. For both Tc and Tm, the aroma compounds were better preserved and present at higher concentrations in freeze-dried samples than in air-dried and oven-dried samples.CONCLUSION: These results provide a foundation for further research on the molecular mechanisms of aroma formation in Tilia flowers and on aroma as a cue for insect pollination. Furthermore, the results provide a basis for the development and commercialization of Tilia floral teas and other related products. © 2025 Society of Chemical Industry.PMID:40007479 | DOI:10.1002/jsfa.14190