PubMed

J Agric Food Chem. 2025 Jan 2. doi: 10.1021/acs.jafc.4c08612. Online ahead of print.ABSTRACTBotrytis cinerea infections of grapes significantly reduce yield and quality and increase phenolic compound oxidation, resulting in color loss, off-flavors, and odors in wine. In this study, metabolites were extracted from grape homogenates comprising healthy or infected grapes from different vintages, cultivars, regions, and maturity stages. Samples were randomly analyzed by direct injection into an ion trap mass spectrometer, with data collected from 50 to 2000 m/z for 1 min. Molecular feature abundances from 0.1 to 0.4 min were normalized prior to Principal Components Analysis assessment of workflow. Samples were randomly assigned to a calibration and independent test sample set, with feature reduction, a two-class model Partial Least Squares-Discriminant Analysis, cross-validation, and permutation testing performed with the calibration data set. Prediction of sample class in the independent test samples demonstrated an overall predictive error of less than 5%. Feature importance was assessed using a combined variable importance in projection and selectivity ratio plot. Annotation of important molecular features using a high-resolution LC-QTOF mass spectrometry MS/MS of selected samples enabled key metabolites palmitic, oleic, linoleic and linolenic acids, succinate, and epicatechin to be identified and associated with infection. The proposed workflow establishes sensitive high-throughput rapid MS-based methods for phytosanitary testing of grape and fruit samples.PMID:39746708 | DOI:10.1021/acs.jafc.4c08612

Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2024 Dec 20;42(12):911-917. doi: 10.3760/cma.j.cn121094-20240422-00180.ABSTRACTObjective: To investigate the changes of metabolites in urine of automobile manufacturing workers with muscle fatigue using metabolomics technology, and to explore potential biomarkers and disrupted metabolic pathways. Methods: In July 2022, urine samples were collected from 35 male workers in a certain automobile manufacturing industry before and after muscle fatigue, and metabolite analysis was conducted. Subsequently, multivariate statistical analysis was used for data processing to screen differential metabolites. Metabolic pathway enrichment was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database (http: //www.kegg.jp), and potential biomarkers were screened through the receiver operating characteristic (ROC) curve. Results: Metabolomics analysis revealed that compared to pre-fatigue samples, a total of 363 differential metabolites were identified in the post-fatigue urine samples of the subjects. Among these, 201 metabolites (55.4%) showed increased relative expression, while 162 metabolites (44.6%) showed decreased relative expression. The metabolic pathways involved mainly included histidine metabolism, tryptophan metabolism, valine, leucine and isoleucine biosynthesis, caffeine metabolism, niacin and nicotinamide metabolism, and oxidative phosphorylation. The ROC curve analysis results showed that the areas under the ROC curves for 1-methylnicotinamide, 2-piperidinone, kojic acid and diferuloyl Putrescine were 0.992, 0.959, 0.937 and 0.902, respectively. Conclusion: Muscle fatigue could cause changes in urine metabolite profiles of automobile manufacturing workers. The metabolites represented by 1-methylnicotinamide in urine can be used as potential biomarkers of muscle fatigue in automobile manufacturing workers.PMID:39746681 | DOI:10.3760/cma.j.cn121094-20240422-00180

Mol Metab. 2024 Dec 31:102092. doi: 10.1016/j.molmet.2024.102092. Online ahead of print.ABSTRACTThe peroxisome proliferator-activated receptor-alpha (PPARα) plays a central role in lipid metabolism in the liver by stimulating the expression of hundreds of genes. Accordingly, regulation by PPARα could be a screening tool to identify novel genes involved in hepatic lipid metabolism. Previously, the mitochondrial transporter SLC25A47 was suggested to play a role in energy metabolism and liver-specific uncoupling, but further research is lacking. Here, we identify SLC25A47 as a PPARα-regulated and fasting-induced gene in human and mouse hepatocytes. We explored the potential role of SLC25A47 using mice overexpressing and lacking SLC25A47. Adenoviral-mediated overexpression of SLC25A47 minimally impacted metabolic parameters during fasting and high-fat feeding. During high-fat feeding, SLC25A47 ablation also did not influence any metabolic parameters, apart from a minor improvement in glucose tolerance. In fasted mice, SLC25A47 ablation was associated with modest, reproducible, and likely indirect reductions in plasma triglycerides and glycerol. SLC25A47 ablation did not influence energy expenditure. Depending on the nutritional status, metabolomics showed modest alterations in plasma, liver, and hepatic mitochondrial levels of various metabolites related to amino acid metabolism, TCA cycle, and fatty acid metabolism. No major and consistent alterations in levels of specific metabolites were found that establish the substrate for and function of SLC25A47. Collectively, our results hint at a role of SLC25A47 in amino acid and fatty acid metabolism, yet suggest that SLC25A47 is dispensable for hepatic lipid homeostasis during fasting and high-fat feeding.PMID:39746607 | DOI:10.1016/j.molmet.2024.102092

Mol Metab. 2024 Dec 31:102090. doi: 10.1016/j.molmet.2024.102090. Online ahead of print.ABSTRACTMetabolic dysfunction-associated steatotic liver disease (MASLD) is characterised by lipid accumulation in the liver and is often associated with obesity and type 2 diabetes. The gut microbiome recently emerged as a significant player of liver metabolism and health through the production of bioactive compounds that are beneficial for its host - "postbiotics". Circulating hippurate, a host-microbial co-metabolite produced by conjugating microbial benzoate with glycine in the host-liver, is associated with human gut microbial gene richness and with metabolic health. Here, we first report significant associations among MASLD/MASH traits, plasma and hepatic hippurate in 318 individuals with obesity. Further analysis of the 318 patient's hepatic transcriptome showed that liver and plasma hippurate are inversely associated with MASLD, implicating lipid metabolism and regulation of inflammatory responses pathways. These observations strongly point towards a direct mechanistic role of hepatic hippurate in MASLD pathophysiology. To test a potential beneficial role for hippurate in hepatic insulin resistance, we profiled the metabolome of immortalised human hepatocytes (IHH) using ultra-high-performance liquid chromatography coupled to high-resolution tandem mass spectrometry (UHPLC-MS/MS), and characterised intracellular triglyceride accumulation and glucose internalisation after a 24h insulin exposure. Hippurate treatment inhibited lipid accumulation and rescued insulin resistance induced by 24-hour chronic insulin in IHH. Hippurate also improved hepatocyte metabolic profiles by increasing the abundance of metabolites involved in energy homeostasis (that are depleted by chronic insulin treatment) while decreasing those involved in inflammation. Altogether, our results further highlight hippurate as a mechanistic marker of metabolic health, by its ability to improve metabolic homeostasis as a postbiotic candidate.PMID:39746606 | DOI:10.1016/j.molmet.2024.102090

Ocul Surf. 2024 Dec 31:S1542-0124(24)00145-9. doi: 10.1016/j.jtos.2024.12.010. Online ahead of print.ABSTRACTDry eye disease (DED) is a multifactorial condition with complex and incompletely understood molecular mechanisms. Advances in multi-omics technologies, including genomics, transcriptomics, proteomics, metabolomics, and microbiomics, have provided new insights into the pathophysiology of DED. Genomic analyses have identified key genetic variants linked to immune regulation and lacrimal gland function. Transcriptomic studies reveal upregulated inflammatory pathways in ocular surface tissues, implicating these as core drivers of chronic inflammation. Proteomic research highlights significant alterations in tear protein composition, especially proteins involved in inflammation and tissue repair. Metabolomics studies focus on disrupted lipid metabolism and oxidative stress, which are crucial in maintaining tear film stability. Furthermore, microbiome research has demonstrated reduced microbial diversity and increased pathogenic bacteria, exacerbating inflammatory responses. The integration of multi-omics data allows for the identification of novel biomarkers and therapeutic targets, enabling precision diagnostics and personalized treatments. Therefore, this review highlights the critical importance of multi-omics approaches in deepening our understanding of DED's complex molecular mechanisms and their potential to transform clinical management and therapeutic innovations in this challenging field.PMID:39746576 | DOI:10.1016/j.jtos.2024.12.010

J Allergy Clin Immunol. 2024 Dec 31:S0091-6749(24)02473-4. doi: 10.1016/j.jaci.2024.12.1083. Online ahead of print.NO ABSTRACTPMID:39746555 | DOI:10.1016/j.jaci.2024.12.1083

Plant Sci. 2024 Dec 31:112367. doi: 10.1016/j.plantsci.2024.112367. Online ahead of print.ABSTRACTThe rapid advancement in the field of omics approaches plays a crucial role in the development of improved industrial oil crops. Industrial oil crops play a crucial role across sectors like food processing, biofuels, cosmetics, and pharmaceuticals, making them indispensable contributors to global economies and these crops serve as vital elements in a multitude of industrial processes. Significant improvements in genomics have revolutionized the agricultural sector, particularly in the realm of oil crops. Cutting-edge advancements have facilitated the efficient sequencing of genomes for key commercial oil crops. This breakthrough not only enhances our understanding of the genetic makeup of these crops but also empowers breeders with invaluable insights for targeted genetic manipulation and breeding programs. Moreover, integrating transcriptomics with genomic data has assisted in a new era of precision agriculture. This approach provides an in-depth understanding of molecular mechanisms involved in traits of interest, such as oil content, yield potential, and resistance to biotic and abiotic stresses. Proteomics methods are instrumental in deciphering the intricacies of protein structure, interactions, and function, while metabolomics and ionomics shed light on the intricate network of metabolites and ions within biological systems. Each omics discipline offers unique insights, and their integration holds the promise of enriching our understanding and furnishing invaluable insights for enhancing oil crops. This review delves into the efficacy and constraints of various omics approaches in the context of refining industrial oil crops. Moreover, it underscores the importance of multi-omics strategies and explores their convergence with genetic engineering techniques to cultivate superior oil crop varieties.PMID:39746452 | DOI:10.1016/j.plantsci.2024.112367

J Ethnopharmacol. 2024 Dec 31:119308. doi: 10.1016/j.jep.2024.119308. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Drug-induced liver injury (DILI) is an important and common adverse drug event. Rhododendron molle Flos (RMF), as one of toxic Traditional Chinese medicines (TCMs), holds a prominent position in clinical practice for treating rheumatoid arthritis. However, the toxicity of RMF limits its safe. Most of the concerns are about its rapid neurotoxicity and cardiotoxicity, with less attention paid to its hepatotoxicity, and the mechanism of which is still unclear.AIM OF THE STUDY: To reveal the mechanism of RMF-induced hepatotoxicity by bioinformatics and multi-omics.MATERIALS AND METHODS: Rats were intragastric administered RMF at doses of 0.8 g/kg, 0.4 g/kg, and 0.2 g/kg once daily for 2 weeks. Initially, hepatotoxicity was then evaluated using liver function enzymes, antioxidant enzymes, and histopathology. Subsequently, network toxicology, transcriptomics, and metabolomics were used to identify the genes and metabolites. In addition, molecular docking and Western blot were employed to verify toxic components and key targets.RESULTS: RMF caused abnormal levels of ALT, γ-GT, TBIL, and TBA in the serum of rats, as well as abnormal levels of MDA, GSH-Px, and SOD in the liver, leading to inflammatory infiltration of liver cells, with a dose-dependent manner. RMF disordered the steroid hormone biosynthesis, pyruvate metabolism, fatty acid biosynthesis, and arachidonic acid metabolism. Six key targets were identified- UGT1A6, CYP2E1, ACOT1, ACSL5, CTH, and PKLR, along with their corresponding metabolites, namely 17β-estradiol, estriol, arachidonic acid, octadecanoic acid, and pyruvic acid. The hepatotoxicity could be attributed to five diterpenoid components, including grayanotoxin-III, rhodojaponin (RJ)-I, RJ-II, RJ-III, and RJ-V.CONCLUSIONS: This study comprehensively identified the toxic components, upstream targets, and downstream metabolites of RMF-induced liver toxicity, providing a basis for evaluating and monitoring liver function in patients during clinical application.PMID:39746411 | DOI:10.1016/j.jep.2024.119308

J Ethnopharmacol. 2024 Dec 31:119312. doi: 10.1016/j.jep.2024.119312. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Alangium chinense (Lour.) Harms, commonly known as A. chinense, is a member of the Alangiaceae family. This plant is traditionally utilized by the Miao nationality of Guizhou as a medicinal remedy for rheumatic discomfort, employing a method that targets and eliminates toxins. Research has demonstrated its efficacy in dispelling wind, reducing dampness, breaking up blood stagnation, and alleviating pain. Nonetheless, there have been indications that A. chinense may possess toxic properties; however, the exact mechanism underlying its toxicity remains not fully understood.AIM OF THE STUDY: Employing an integrated strategy that combines serum metabolomics and network pharmacology, this work intends to elucidate the toxic elements and comprehensively explore the fundamental processes of toxicity connected to A. chinense.MATERIALS AND METHODS: Rats were divided into thirteen groups, including normal control group and low-medium-high dose groups of water extract and ethanol extract of fibrous root and root, over 14 consecutive days. Toxic effects were evaluated through serum biochemistry and pathohistological examinations. Serum metabolomics were analyzed using UPLC-MS/MS to identify the main blood-absorbed constituents of A. chinense. Additionally, hepatotoxicity-related targets were compiled from OMIM, CTD, GeneCards, and DisGeNET databases alongside primary blood-absorbed component targets sourced from TCMSP and Swiss Target Prediction databases. We elucidated the toxic mechanism of A. chinense through compound-target and target-pathway networks. Finally, we verified the mechanism of A. chinense-induced hepatotoxicity in rats by molecular docking, qRT-PCR , western blotting and in vitro experiments .RESULTS: In vivo experiments revealed that A. chinense increased the levels of AST and ALT in serum. The sectioning results indicated that different medicinal parts and different extracts of A. chinense caused varying degrees of liver damage in a dose-dependent manner, with the water extract of fibrous root resulting in the greatest damage. The UPLC-MS/MS analysis revealed 75 blood-absorbed components in A. chinense, with 18 significantly linked to liver injury factors, such as Anabasine, Brucine, Tricin, and quercetin-3,4'-dimethyl ether. Additionally, network pharmacology revealed 123 potential targets associated with A. chinense-induced hepatotoxicity. KEGG pathway analysis revealed 247 signaling pathways associated with these common targets, emphasizing key pathways such as the PI3K-Akt signaling pathway, lipid and atherosclerosis signaling pathway, and chemical carcinogenesis-receptor activation signaling pathway. Molecular docking studies demonstrated that Mansonone D, Sudachitin, Mansonone E, Tricin, Brucine, and (-)-Anabasine exhibit strong affinity and low binding energy with PIK3CA, AKT1, mTOR, MAP2K1, and MAPK1 among the identified blood-absorbed ingredients. In addition, qRT-PCR combined with Western blotting analysis showed that compared with the control group, A. chinense water extract significantly increased the mRNA expression of PIK3CA, AKT1, mTOR, MAP2K1, MAPK1 and rheb in rat liver tissue. Abnormal activation of pmTOR/mTOR, pPI3K/PI3K, pAKT/AKT protein expression levels and the enzyme activity levels of caspase3/7 and caspase1, thereby activating PI3K/ALT/mTOR pathway to play hepatotoxic role through autophagy or apoptosis. This suggests an intensive activation of this specific biochemical transformation channel. Finally, the in vitro experiment showed that Anabasine, the alkaloids of fibrous root and root could significantly increase AST and ALT levels in mouse AML-12 cells.CONCLUSIONS: Through network pharmacology and serum metabolomics analysis, we investigated the possible mechanism of A. chinense's hepatotoxicity and confirmed that A. chinense may be caused by abnormal activation of PI3K/AKT/mTOR signaling pathway. This study elucidates the potential mechanism of A. chinense-related hepatotoxicity, provides a theoretical basis for in-depth exploration of its toxicity mechanism and mitigation strategies, and provides valuable insights and scientific support for understanding the intrinsic toxicity mechanism of ethnomedicine from a holistic perspective.PMID:39746409 | DOI:10.1016/j.jep.2024.119312

J Chromatogr B Analyt Technol Biomed Life Sci. 2024 Dec 28;1252:124445. doi: 10.1016/j.jchromb.2024.124445. Online ahead of print.ABSTRACTChronic kidney disease (CKD) is recognized as a common disorder worldwide. Protein-binding uremic toxins that cannot be efficiently removed by extracorporeal renal replacement therapies, such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS), are associated with high risks of cardiovascular complications and high mortality in CKD population. This study aimed to explore the therapeutical effects of Huangkuisiwu formula (HKSWF) on CKD rats. Moreover, the underlying mechanisms of HKSWF to inhibit the biosynthesis of IS and PCS were studied. Untargeted metabolomics based on UHPLC-QTOF/MS was conducted to analyze the alterations of endogenous metabolites in plasma. Levels of IS and PCS in plasma and peripheral tissues, as well as levels of amino acids in colonic contents were analyzed by UHPLC-TQ/MS. Levels of indole and p-cresol, the precursors of IS and PCS, in feces and colonic contents were quantified by HPLC-FLD. mRNA and protein expression of sulfotransferase 1 a1 (SULT1A1) were determined by qPCR and Western blotting, respectively. The ability of colonic microbiota to metabolize amino acids into precursors, as well as the activity of sulfotransferase to catalyze precursors into uremic toxins were evaluated by detecting corresponding products from specific substrates. 16S rRNA sequencing were conducted to analyze the profile of gut microbiota. The results showed that HKSWF significantly alleviated the structural and functional impairment of kidney, as well as improved the global metabolic disorders in CKD rats. IS and PCS were identified as the key differential metabolites that contributed to the effects of HKSWF. HKSWF significantly reduced the levels of IS and PCS in plasma, kidney, liver and heart of CKD rats. HKSWF showed no significant effects on the expression of SULT1A1 or the activity of sulfotransferase. HKSWF significantly decreased the levels of indole and p-cresol in the colonic contents and feces of CKD rats, by inhibiting the ability of colonic microbiota to metabolize tryptophan and tyrosine into indole and p-cresol. Alterations in the profile of amino acids and gut microbiota in CKD rats were significantly improved by HKSWF treatment. Conclusively, HKSWF inhibited gut-microbiota mediated biosynthesis of indole and p-cresol, to alleviate the accumulation of IS and PCS in CKD rats.PMID:39746293 | DOI:10.1016/j.jchromb.2024.124445

J Clin Anesth. 2025 Jan 1;101:111736. doi: 10.1016/j.jclinane.2024.111736. Online ahead of print.ABSTRACTCognitive impairment following surgery is a significant complication, affecting multiple neurocognitive domains. The term "perioperative neurocognitive disorders" (PND) is recommended to encompass this entity. Individuals who develop PND are typically older and have increases in serum and brain pro-inflammatory cytokines notwithstanding the type of surgery undergone. Surgical trauma induces production of small biomolecules, damage-associated molecular patterns (DAMP), particularly the DAMP known as high molecular group box 1 protein (HMGB1). Mechanistically, peripheral surgical trauma promotes pro-inflammatory cytokines that stimulate central nervous system (CNS) inflammation by disrupting the blood-brain barrier (BBB) causing functional neuronal disruption that leads to PND. PND is strongly linked to elevations in serum and CNS pro-inflammatory cytokines interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα); these cytokines cause further release of HMGB1 creating a positive feedback loop that amplifies the inflammatory response. The cytokine IL-6 is necessary and sufficient for PND. Dehydroepiandrosterone (DHEA) is a principal component of the steroid metabolome and is involved in immune homeostasis. DHEA has been shown to suppress expression of several pro-inflammatory cytokines by regulation of the NF-kB pathway. Bromo-epi-androsterone (BEA) is a potent synthetic analog of DHEA; unlike DHEA, it is non-androgenic, non-anabolic and is an effective modulator of immune dysregulation. In a randomized, placebo-controlled clinical trial, BEA effected significant and sustained decreases in IL-1β, TNFα and IL-6. This article presents BEA as a potential candidate for clinical trials targeting PND and further suggests the use of BEA in elective total hip arthroplasty as a well-documented surgical entity relevant to the management of PND.PMID:39746239 | DOI:10.1016/j.jclinane.2024.111736

Diabetes Care. 2025 Jan 2:dc241412. doi: 10.2337/dc24-1412. Online ahead of print.ABSTRACTOBJECTIVE: Progression of prediabetes to type 2 diabetes has been associated with β-cell dysfunction, whereas its remission to normoglycemia has been related to improvement of insulin sensitivity. To understand the mechanisms and identify potential biomarkers related to prediabetes trajectories, we compared the proteomics and metabolomics profile of people with prediabetes progressing to diabetes or reversing to normoglycemia within 1 year.RESEARCH DESIGN AND METHODS: The fasting plasma concentrations of 1,389 proteins and the fasting, 30-min, and 120-min post-oral glucose tolerance test (OGTT) plasma concentrations of 152 metabolites were measured in up to 134 individuals with new-onset diabetes, prediabetes, or normal glucose tolerance. For 108 participants, the analysis was repeated with samples from 1 year before, when all had prediabetes.RESULTS: The plasma concentrations of 14 proteins were higher in diabetes compared with normoglycemia in a population with prediabetes 1 year before, and they correlated with indices of insulin sensitivity. Higher levels of dicarbonyl/L-xylulose reductase and glutathione S-transferase A3 in the prediabetic state were associated with an increased risk of diabetes 1 year later. Pathway analysis pointed toward differences in immune response between diabetes and normoglycemia that were already recognizable in the prediabetic state 1 year prior at baseline. The area under the curve during OGTT of the concentrations of IDL particles, IDL apolipoprotein B, and IDL cholesterol was higher in new-onset diabetes compared with normoglycemia. The concentration of glutamate increased in prediabetes progressing to diabetes.CONCLUSIONS: We identify new candidates associated with the progression of prediabetes to diabetes or its remission to normoglycemia. Pathways regulating the immune response are related to prediabetes trajectories.PMID:39746149 | DOI:10.2337/dc24-1412

Elife. 2025 Jan 2;13:RP100427. doi: 10.7554/eLife.100427.ABSTRACTNon-inheritable antibiotic or phenotypic resistance ensures bacterial survival during antibiotic treatment. However, exogenous factors promoting phenotypic resistance are poorly defined. Here, we demonstrate that Vibrio alginolyticus are recalcitrant to killing by a broad spectrum of antibiotics under high magnesium. Functional metabolomics demonstrated that magnesium modulates fatty acid biosynthesis by increasing saturated fatty acid biosynthesis while decreasing unsaturated fatty acid production. Exogenous supplementation of unsaturated and saturated fatty acids increased and decreased bacterial susceptibility to antibiotics, respectively, confirming the role of fatty acids in antibiotic resistance. Functional lipidomics revealed that glycerophospholipid metabolism is the major metabolic pathway remodeled by magnesium, where phosphatidylethanolamine biosynthesis is reduced and phosphatidylglycerol production is increased. This process alters membrane composition, increasing membrane polarization, and decreasing permeability and fluidity, thereby reducing antibiotic uptake by V. alginolyticus. These findings suggest the presence of a previously unrecognized metabolic mechanism by which bacteria escape antibiotic killing through the use of an environmental factor.PMID:39745871 | DOI:10.7554/eLife.100427

Nat Prod Bioprospect. 2025 Jan 2;15(1):6. doi: 10.1007/s13659-024-00491-7.ABSTRACTThe Plectranthinae clade, which includes genera such as Plectranthus, Ocimum, and Aeollanthus, is well known for its diverse array of diterpenoids. While numerous studies have deepened the understanding of diterpene diversity across the clade, Aeollanthus species remain underexplored, with only two studies focusing on their diterpene profiles. The NMR-based chemical profiling of the EtOAc leaf extract of the rocky and succulent species Aeollanthus buchnerianus Briq. reveals a range of diterpenes with isopimarane and abietane skeletons including several previously unreported analogues. Interestingly, the isolated compounds provided insights into the breakdown patterns of both diterpene classes by examining the product ions in their MS2 spectra. These data offer valuable information for evaluating the taxonomic position of this species in relation to other species within the clade.PMID:39745518 | DOI:10.1007/s13659-024-00491-7

J Agric Food Chem. 2025 Jan 2. doi: 10.1021/acs.jafc.4c09878. Online ahead of print.ABSTRACTPlant-based foods with low methionine contents have gained increasing interest for their potential health benefits, including neuroprotective effects. Methionine restriction (MR) linked to a plant-based diet has been shown to mitigate neurodegenerative diseases such as Alzheimer's disease (AD) through mechanisms that involve the gut microbiota. In this study, a 16-week MR diet (0.17% methionine, w/w) improved working memory and reduced neuronal damage exclusively in 4-month-old male APP/PS1 AD mice. Transcriptomic analysis revealed the activation of serum- and glucose-corticoid-regulated kinase 1 (SGK1) and peroxisome proliferator-activated receptor α (PPARα) pathways. Furthermore, metabolomics demonstrated increased serum indole-3-propionic acid (IPA) levels and an enhanced expression of gut barrier proteins Claudin-1 and MUC2 in male mice. MR significantly altered the gut microbiota composition, notably increasing indole-producing bacteria such as Lactobacillus reuteri (L. reuteri). Multiomics integration linked L. reuteri, IPA, and PPARα signaling to improved cognitive outcomes. Molecular docking and RT-qPCR analyses confirmed IPA's interaction with PPARα, leading to the activation of neuroprotective targets (Bdnf, Pparα, Acsbg1, Scd2, and Scd3). These results highlight the role of methionine restriction in modulating gut microbiota and metabolites, offering a promising dietary approach to managing neurodegenerative diseases with sex-specific effects.PMID:39745486 | DOI:10.1021/acs.jafc.4c09878

Endocr Connect. 2025 Jan 1:EC-24-0587. doi: 10.1530/EC-24-0587. Online ahead of print.ABSTRACTBACKGROUND: Prostate cancer therapy with surgical or chemical castration with GnRH agonists has been linked to elevated FSH levels, which may contribute to secondary health disorders, including atherosclerosis and diabetes. Although recent findings suggest a role for FSH beyond the reproductive system, its metabolic impact remains unclear and difficult to disentangle from that of androgens. In this study, we examined the metabolic changes induced by FSH and distinguished them from those caused by testosterone.METHODS: Plasma samples from temporarily medically castrated young men (n=33) treated with FSH and/or testosterone were characterized by proteomics and metabolomics approaches. All subjects received GnRH antagonists. Sixteen men were randomized to recombinant FSH (rFSH, 300 IU 3 times/week) for 5 weeks, while seventeen men served as controls. After 3 weeks, all men received 1000 mg testosterone undecanoate intramuscular. Blood samples were collected at the start, after 3 weeks, and after 5 weeks. The proteome and metabolome signatures were characterized in all samples.RESULTS: FSH significantly upregulates key proteins involved in the modulation of inflammatory response and innate immune system (p≤0.03) and dysregulates lipid metabolism, evidenced by downregulation of multiple apolipoproteins (p≤0.04) and increased levels of cholesterol and glycerophospholipids (p≤0.03). Additionally, low FSH levels were correlated with a reduction in the active form of vitamin D (p<0.02). These results highlight the short-term metabolic impacts of FSH in males.CONCLUSIONS AND CLINICAL IMPLICATIONS: Our findings underlined the FSH effect on extra-gonadal systems and its connection to metabolic disorders often seen as secondary effects of prostate cancer treatment.PMID:39745472 | DOI:10.1530/EC-24-0587

Anal Chem. 2025 Jan 2. doi: 10.1021/acs.analchem.4c05632. Online ahead of print.ABSTRACTMetabolite identification from 1D 1H NMR spectra is a major challenge in NMR-based metabolomics. This study introduces NMRformer, a Transformer-based deep learning framework for accurate peak assignment and metabolite identification in 1D 1H NMR spectroscopy. Unlike traditional approaches, NMRformer interprets spectra as sequences of spectral peaks and integrates a self-attention mechanism and peak height ratios directly into the Transformer encoder layer. It has the capability to recognize and interpret long-range dependencies between peaks and to quickly identify peaks corresponding to identical metabolites. The effectiveness of NMRformer has been rigorously validated by analyzing real 1D 1H NMR spectra from a variety of cellular and biofluid samples. NMRformer achieved peak assignment accuracies above 88% and metabolite identification accuracies above 80% in four types of cellular samples. It also achieved peak assignment accuracies above 88% and metabolite identification accuracies above 80% in three types of biofluid samples. These results underscore the ability of NMRformer to significantly improve the accuracy and efficiency of peak assignment and metabolite identification in NMR-based metabolomics studies.PMID:39745381 | DOI:10.1021/acs.analchem.4c05632

Vet Q. 2025 Dec;45(1):1-15. doi: 10.1080/01652176.2024.2447601. Epub 2025 Jan 2.ABSTRACTChronic Kidney Disease (CKD) is one of the most common conditions affecting felines, yet the metabolic alterations underlying its pathophysiology remain poorly understood, hindering progress in identifying biomarkers and therapeutic targets. This study aimed to provide a comprehensive view of metabolic changes in feline CKD across conserved biochemical pathways and evaluate their progression throughout the disease continuum. Using a multi-biomatrix high-throughput metabolomics approach, serum and urine samples from CKD-affected cats (n = 94) and healthy controls (n = 84) were analyzed with ultra-high-performance liquid chromatography-high-resolution mass spectrometry. Significant disruptions were detected in tryptophan (indole, kynurenine, serotonin), tyrosine, and carnitine metabolism, as well as in the urea cycle. Circulating gut-derived uremic toxins, including indoxyl-sulfate, p-cresyl-sulfate, and trimethylamine-N-oxide, were markedly increased, primarily due to impaired renal excretion. However, alternative mechanisms, such as enhanced bacterial formation from dietary precursors like tryptophan, tyrosine, carnitine, and betaine, could not be ruled out. Overall, the findings suggest that metabolic disturbances in feline CKD are largely driven by the accumulation of gut-derived uremic toxins derived from precursors highly abundant in the feline diet. These insights may link the strict carnivorous nature of felines to CKD pathophysiology and highlight potential avenues for studying preventive or therapeutic interventions.PMID:39745207 | DOI:10.1080/01652176.2024.2447601

Mol Omics. 2025 Jan 2. doi: 10.1039/d4mo00140k. Online ahead of print.ABSTRACTThe present work aimed to examine the primary mechanisms of liver damage, namely the impact of gut-derived endotoxins along the gut-liver axis and adipose-derived free fatty acids along the adipose-liver axis. These processes are known to play a significant role in the development of hepatic inflammation and steatosis. Although possible overlapping in the pathogenesis was expected, these processes have unique pathophysiological consequences. Therefore, we used HepG2 cells as a model system to investigate the impact of lipopolysaccharides (LPS) and free fatty acid (FFA; albumin conjugated palmitic acid) on the intracellular metabolome. Although both LPS and FFA triggered the expression of nuclear factor κB (NFκB)-dependent inflammation, only LPS treatment was able to trigger a Toll-like receptor 4 (TLR4) dependent response. The intracellular cytoprotective enzymatic levels (catalase, peroxidase, glutathione) were increased due to FFA but lowered due to LPS. The free-radical neutralizing efficacies of cell-free metabolites of FFA-treated cells were better than those of the LPS-treated ones. The use of untargeted metabolomics allowed for the identification of distinct metabolic pathway enrichments, providing further insights into the differential effects of LPS and FFA on the metabolism of hepatocytes. Collectively, the current study highlights the distinct impacts of endotoxemia and lipotoxicity on the metabolome of hepatocytes, hence offering valuable insights into hepatocellular function.PMID:39744997 | DOI:10.1039/d4mo00140k

Mol Omics. 2025 Jan 2. doi: 10.1039/d4mo00207e. Online ahead of print.ABSTRACTBrevetoxins are a type of neurotoxin produced in red tide blooms. Northern quahogs (M. mercenaria) are extensively used in commercial aquaculture farming, and early-stage metabolomics studies can provide early warnings of brevetoxins for farmers. In this study, NMR-based metabolomics was performed to investigate the response of clam gills and digestive glands under a series of sublethal doses of brevetoxins. Our study showed that the brevetoxin PbTx-2 had minimal influence on the physical activities of M. mercenaria for a short exposure time (24 hours). However, major metabolic level perturbations were observed in the clam gill extracts from the 1 ppb treatment. In addition, in the low concentration (0.1 ppb) study, clam gills showed combinational metabolite perturbations, as observed by an OPLS-DA study. The highly disturbed metabolites in the gill samples were the upregulated serine, glucose, hypotaurine, and glycine and the downregulated lactate, leucine, isoleucine, threonine, biotin, taurine, and valine. The results indicated that the brevetoxin PbTx-2 potentially affects glycolysis, glycine, serine, and threonine metabolism, taurine and hypotaurine metabolism, and biotin metabolism. While the digestive gland had less significantly changed metabolites, the potential combinational metabolite changes from PCA were observed from the 5-ppb treatment. Glucose and glycine are the primary metabolites that showed high contributions to the OPLS-DA model, which indicates the potential influence of digestive activities. The study indicated that metabolomic analysis of the gills and digestive glands of M. mercenaria is a feasible method to monitor the toxicity of brevetoxins, especially under sublethal doses in marine water.PMID:39744881 | DOI:10.1039/d4mo00207e