PubMed

Pestic Biochem Physiol. 2024 Dec;206:106208. doi: 10.1016/j.pestbp.2024.106208. Epub 2024 Nov 8.ABSTRACTThe high toxicity of thiamethoxam (Thi) to foragers has threatened the development of bee populations and the use of neonicotinoid pesticides. In this study, we explored the mechanism of selective feeding on azadirachtin (Aza) by foragers to reduce the feeding of Aza-Thi and improve foragers' safety. The results showed that foragers under selective feeding significantly reduced the Aza sucrose solution intake. The Thi content in foragers was significantly lower, and the mortality rate was significantly reduced. In order to further analyze the selective feeding of foragers on Aza, the classic proboscis extension response (PER) experiment showed that Aza did not affect the learning ability of foragers, and the expression of related genes was not significantly different from the regular PER foragers. Further analysis of transcriptomics and metabolomics showed that compared with the regular PER foragers, treated with Aza were significantly affected in metabolic pathways and peroxisome and 67 differentially expressed genes (DEGs) were up-regulated and 136 were down-regulated. Differential metabolite analysis showed that metabolites primarily enriched in caffeine metabolism and microbial metabolism in diverse environments, and only dibucaine was up-regulated in response to Aza treatment. It is worth noting that dibucaine was significantly positively correlated with differentially expressed genes. Thus, our findings revealed that Aza does not affect the expression of memory genes in foragers. Aza affected the regular metabolic levels of foragers, leading to selective feeding of foragers on Aza, reduced intake of Aza-Thi, and increased safety for foragers. This study provides a reference for applying Aza to selective mechanisms in foragers.PMID:39672620 | DOI:10.1016/j.pestbp.2024.106208

Pestic Biochem Physiol. 2024 Dec;206:106178. doi: 10.1016/j.pestbp.2024.106178. Epub 2024 Oct 18.ABSTRACTAcetamiprid (ACE) is widely used in agriculture to control pests. However, its accumulation in soil and subsequent translocation to plants can impact plant growth and development through mechanisms that remain unclear. This study evaluated the comprehensive effects of residual ACE from soil on cultivated pak choi and lettuce at environmental levels. Results showed that more than 90 % of ACE residues in the soils dissipated within 14 days. The average root concentration factor (RCF) values of pak choi and lettuce were 1.442 and 0.318, respectively, while the average translocation factor (TF) values were 2.145 for pak choi and 5.346 for lettuce. Seedling height increased by 6.32 % in pak choi but decreased by 8.54 % in lettuce. Furthermore, chlorophyll content decreased by 14.6 % in pak choi and increased by 23.7 % in lettuce. Non-targeted metabolomics analysis showed significant disturbances in carbohydrates, amino acids, and secondary metabolite levels. Additionally, KEGG pathway analysis revealed the down-regulation of amino acid metabolites in both vegetables, alongside an up-regulation of flavone and flavonol biosynthesis in pak choi. This research enhances the understanding of the effects and underlying metabolic mechanism of ACE on different vegetables.PMID:39672607 | DOI:10.1016/j.pestbp.2024.106178

Int J Biol Macromol. 2024 Dec 11:138698. doi: 10.1016/j.ijbiomac.2024.138698. Online ahead of print.ABSTRACTAn imbalance in the microbiota-gut-brain axis exerts an essential effect on the pathophysiology of depressive and anxiety disorders. Our previous research revealed that the timing of inulin administration altered its effects on chronic unpredictable mild stress (CUMS)-induced anxiety and depression. However, it is still unclear if the gut-brain axis is primarily responsible for these effects. In this study, fecal microbiota transplantation (FMT) confirmed that inulin administration at different times alleviated CUMS-induced anxiety- and depression-like behaviors via the gut-brain axis. The time of administration seemed to modify the anxiolytic and antidepressant effects of inulin, and inulin intervention in the evening was more pronounced in inhibiting the inflammatory response than that of morning inulin intervention. Serum metabolomics analysis showed that the main differential metabolites, including fenofibric acid, 4'-Hydroxyfenoprofen glucuronide and 5-(4-Hydroxybenzyl)thiazolidine-2,4-dione may be vital for the anxiolytic and antidepressant effects of different inulin treatment times. Our results suggested that inulin administration in the evening was more effective in alleviating the inflammatory response and improving amino acids metabolism. This study provides a new potential link between the microbiota-gut-brain axis and chrono-nutrition, demonstrating that a more appropriate administration time results in a better intervention effect.PMID:39672439 | DOI:10.1016/j.ijbiomac.2024.138698

Environ Pollut. 2024 Dec 11:125522. doi: 10.1016/j.envpol.2024.125522. Online ahead of print.ABSTRACTNanoplastics, as emerging pollutants, have attracted worldwide concern for their possible environmental dangers. The ingestion and accumulation of nanoplastics in crops can contaminate the food chain and have unintended consequences for human health. In this study, we revealed the effects of polystyrene nanoplastics (PS-NPs; 80 nm) at different concentrations (0, 10, 100 mg L-1) on soybean (Glycine max L.) seedling growth, antioxidant enzyme system and secondary metabolism. Using laser confocal microscopy, we demonstrated that the absorption and translocation of PS-NPs in soybean. Plant growth inhibition was observed by changes in plant height, root length, and leaf area after 7 days of exposure to PS-NPs. The effect of PS-NPs on photosynthetic characteristics was reflected by a significant reduction in total chlorophyll content at 10 mg L-1. Activation of the antioxidant system was observed with increased malondialdehyde (MDA) content, and elevated activities of superoxide dismutase (SOD) and catalase (CAT). Non-targeted metabolomics analysis identified a total of 159 secondary metabolites, and exposure to 10 and 100 mg L-1 PS-NPs resulted in the production of 61 and 62 differential secondary metabolites. Metabolomics analysis showed that PS-NPs treatment altered the secondary metabolic profile of soybean leaves through the biosynthesis pathways of flavonoid, flavone flavonol, and isoflavones, which is expected to provide new insights into the tolerance mechanisms of plants to nanoplastics. Overall, the results of this study deepen our understanding of the negative impacts of nanoplastics in agricultural systems, which is crucial for assessing the risks of nanoplastics to ecological security.PMID:39672368 | DOI:10.1016/j.envpol.2024.125522

J Adv Res. 2024 Dec 11:S2090-1232(24)00558-7. doi: 10.1016/j.jare.2024.12.002. Online ahead of print.ABSTRACTINTRODUCTION: Ginseng demonstrates therapeutic potential in treating obesity, with both experimental and clinical studies suggesting its anti-obesity effects are mediated by gut microbiota. Nonetheless, the specific chemical components responsible for this effect remain largely unidentified.OBJECTIVES: This study aims to investigate the anti-obesity effects and mechanisms of ginseng polysaccharides (GP) and ginsenosides (GS), the primary chemical components of ginseng, with a focus on their impact on gut microbiota.METHODS: The impact of GP and GS on high-fat diet (HFD)-induced obesity was assessed using a mouse model. Molecular mechanisms were explored through a combination of chemical analysis, metagenomics, RT-qPCR, ELISA, and biochemical assays.RESULTS: GP or GS administration effectively prevented adiposity in HFD-fed mice, and both effects were mediated by gut microbiota. Chemical analysis revealed diverse glycosyl groups in GP and GS. Metagenomics data suggested that GP-enriched species, e.g., Bacteroides stercorirosoris and Clostridiales bacterium encoded carbohydrate-active enzymes GH35, GH43 and PL9_1, while GS-enriched Sulfurospirillum halorespirans encoded GH16_5. These enzymes facilitated the utilization of glycosyl groups in GP and GS, selectively stimulating bacterial growth and reshaping the gut microbiota. Furthermore, bacterial species enriched by GP or GS encoded specific functional genes involved in short-chain fatty acid (SCFA) synthesis (K00625 and K00925 for GP; K18118, K00100, and K18122 for GS) and intestinal gluconeogenesis (IGN) (K01678, K00024, and K01596 for GP; K18118 and K00278 for GS). Consequently, the SCFA-GLP-1/PYY signaling and IGN were activated by both GP and GS to ameliorate obesity phenotypes.CONCLUSION: GP and GS, containing diverse glycosyl groups, selectively stimulate specific gut bacteria, triggering mechanisms involved in SCFA-GLP-1/PYY signaling and IGN activation to reduce adiposity in HFD-fed mice. The study enhances understanding of the chemical components crucial for the gut microbiota-mediated anti-obesity effect of ginseng. The mechanistic understanding provides valuable insights for developing ginseng-based drugs or health products to combat obesity.PMID:39672231 | DOI:10.1016/j.jare.2024.12.002

J Hazard Mater. 2024 Dec 9;485:136833. doi: 10.1016/j.jhazmat.2024.136833. Online ahead of print.ABSTRACTFine particulate matter (PM2.5) is related to embryo growth arrest (EGA). In this study, we collected demographic information from EGA cases and early pregnancy controls in Taiyuan, China, between 2022 and 2023 and obtained villi and serum samples from these participants. We employed multilevel mixed-effects logistic regression models to estimate the odds ratios (ORs). Subsequently, we examined the associations between PM2.5 and its components and the EGA-related biomarkers in the serum of the case-control groups. Additionally, we performed spatial metabolomics on villi using mass spectrometry imaging. Our results indicated that PM2.5 levels during pregnancy were higher in the EGA group compared to the control, increasing the risk by 17 % (OR=1.17, 95 %CI: 1.06-1.30, p = 0.001). PM2.5 and its components (Ni, Pb, ANY, NAP, ANT, PYR, and BaP) showed significant negative correlations with biomarkers (PAPP-A, VEGF, and PROG). Furthermore, EGA induced histopathological changes in the villi alongside differential spatial distribution of metabolites. Key metabolites, including 2'-deoxyinosine triphosphate, cytidine triphosphate, uridine triphosphate, guanosine-5'-triphosphate, guanosine diphosphate, and deoxyguanosine-5'-triphosphate, were predominantly involved in purine and pyrimidine metabolism pathways. It provides evidence of the association between PM2.5 and EGA and demonstrates the utility of spatial metabolomics in elucidating the metabolic alterations induced by PM2.5 in EGA.PMID:39672068 | DOI:10.1016/j.jhazmat.2024.136833

Food Chem. 2024 Dec 6;468:142394. doi: 10.1016/j.foodchem.2024.142394. Online ahead of print.ABSTRACTPimpinella brachycarpa Nakai is a perennial plant that has been widely used as a traditional medicine. However, the comprehensive analysis of primary and secondary metabolites and antioxidant activities in different organs (flowers, leaves, stems, and roots) has not been extensively studied. A comprehensive analysis using GC-qMS, GC-TOFMS, and HPLC metabolomic analyses identified 66 known metabolites in different organs of P. brachycarpa. The heat map showed that most metabolites were high in flowers and leaves. KEGG enrichment analysis based on plant metabolic pathways showed that six pathways were significantly impacted based on -log p-value and pathway impact scores. The in vitro antioxidant activities, such as DPPH, ABTS, and SOD-like, reducing power activities, IC50 values for DPPH, ABTS, and SOD were highest in flower and leaf extracts. This study elucidated the metabolites and medicinal and edible value of different P. brachycarpa organs, promoting the effective utilisation of different P. brachycarpa organs.PMID:39671916 | DOI:10.1016/j.foodchem.2024.142394

Food Chem. 2024 Dec 6;468:142393. doi: 10.1016/j.foodchem.2024.142393. Online ahead of print.ABSTRACTGhee, a traditional fermented dairy product and dietary staple for inhabitants of the Tibet Plateau, has unclear lipid profiles and flavor formation mechanisms. This study aims to characterize superior ghee varieties and elucidate factors driving the production of beneficial lipids and flavor compounds. Through a comprehensive analysis of lipidomic profiles, volatile organic compound (VOC) release and microbial dynamics during ghee production from Holstein milk (HM) and Jersey milk (JM), A total of 126 differential lipids were identified, primarily associated with glycerophospholipid and sphingolipid metabolism. Additionally, 69 VOCs were detected, with 23 recognized as critical to flavor development. Key microbial species, including Lactococcus, Lactobacillus, Acetobacter, and Lacticaseibacillus, enriched during fermentation, were found to drive both VOC release and free fatty acid (FFA) production, particularly of eicosapentaenoic acid (EPA) and long-chain fatty acids. Notably, ghee derived from JM exhibited higher levels of functional lipids, beneficial FFAs, and critical VOCs compared to Holstein ghee (HG). The fermentation process, supported by microbial activity and enzyme production, significantly enriched these compounds, underscoring the pivotal role of microbes in enhancing both health benefits and flavor. These findings have potential implications for improving the quality of fermented dairy products in the food industry.PMID:39671915 | DOI:10.1016/j.foodchem.2024.142393

J Pharm Biomed Anal. 2024 Dec 4;255:116583. doi: 10.1016/j.jpba.2024.116583. Online ahead of print.ABSTRACTHura crepitans (Euphorbiaceae), is widespread in the Amazon rainforest and on plantations in sub-Saharan Africa. This tree produces an irritating milky latex rich in secondary metabolites, notably daphnane-type diterpenes and cerebrosides. Previous studies have shown that huratoxin, the main daphnane in the latex, significantly and selectively inhibited the growth of colorectal cancer cells through a unique mechanism involving the activation of PKCζ. One major challenge in isolating active molecules from natural products is the accessibility of the resource. This study explores the phytochemical composition and cytotoxic activities of latexes collected in Peru, Benin, and Togo using UHPLC-MS and metabolomics tools to identify a renewable source of bioactive compounds. Significant inter- and intra-continental differences in chemical composition have been highlighted, with daphnanes being concentrated in the Peruvian samples. Extracts form latexes collected in Peru showed cytostatic activity on Caco-2 cells, correlated with the presence of daphnanes, while some African samples exhibited cytotoxic activity on Jurkat and Hela cancer cell lines, leading to the identification of potential other new bioactive compounds such as elasterol and cerebrosides. OBJECTIVE: To compare the composition of different Hura crepitans latex samples and determine their cytotoxic activity in order to identify new bioactive compounds CONCLUSIONS: Inter- and intra-continental variations in the phytochemical composition of latex were observed, leading to significant cytotoxic activities on different cell lines. Daphnanes were identified as responsible for the activity on Caco-2 cells, while elasterol and cerebrosides were putatively associated with the activity on Hela cells.PMID:39671907 | DOI:10.1016/j.jpba.2024.116583

Water Res. 2024 Dec 10;272:122954. doi: 10.1016/j.watres.2024.122954. Online ahead of print.ABSTRACTAnaerobic ammonium oxidation (anammox) process is a highly effective and economic technology for nitrogen removal from wastewater. However, the slow growth of anammox bacteria and sludge flotation often hinder its field application. Ion adsorption and crystal precipitation can potentially promote the sludge granulation and hence address the above issues. This study investigated two approaches to support anammox granulation through Mg2+ adsorption and magnesium ammonium phosphate (MAP) precipitation. Mg2+ addition improved the specific anammox activity (SAA) by 4.09 to 4.75-fold compared to MAP-mediated ones, which could be explained by the upregulations of nitrogen and inorganic carbon metabolisms. The active extracellular polymeric substances generation at metabolites level may also favor the granulation in Mg2+-mediated anammox. However, sludge loss halted the continuous size increase of sludge. Differently, MAP promoted granulation by physically increasing the granular density, which allowed for a greater retention of sludge within the reactor. However, the co-growth of MAP precipitates with anammox may lead to mass transfer limitations, resulting in down-regulated gene expressions and metabolites in inorganic carbon metabolism, which negatively impacted the SAA. Overall, both strategies achieved comparable nitrogen removal capacities. Nevertheless, the co-growth of MAP and anammox was promising for effectively mitigating sludge flotation. Our study provided strategies and omics-based evidences for anammox granulation and activity variations, benefiting anammox practical applications.PMID:39671866 | DOI:10.1016/j.watres.2024.122954

Phytomedicine. 2024 Nov 29;136:156299. doi: 10.1016/j.phymed.2024.156299. Online ahead of print.ABSTRACTBACKGROUND: The airway epithelium serves as the first line of defense between the lung's internal environment and the external environment, functioning through physical barriers and mucus-ciliary clearance to protect against external allergens and other harmful substances. Airway epithelial damage is a common feature of asthma, and research has shown that apoptosis plays a significant role in airway injury and inflammation in asthma. Although Kechuan Decoction (KCD) has demonstrated clinical efficacy in treating pediatric asthma, its precise mechanism of action remains unclear.OBJECTIVE: To elucidate the therapeutic mechanism of KCD in mitigating apoptosis of airway epithelial cells (AECs) in a house dust mite (HDM)-induced asthma mouse model.METHODS: To evaluate the effects of KCD on asthma-associated airway inflammation and AECs apoptosis, an asthma model was established in C57BL/6 J mice using HDM. The major chemical constituents of KCD were analyzed using LC-MS. Subsequently, we utilized network pharmacology approaches to predict the potential targets and mechanisms of KCD in asthma. Additionally, we conducted lipidomics analysis of lung tissue and mitochondria in the lung was conducted using LC-MS. Finally, the mechanisms underlying the effects of KCD on AECs apoptosis in asthmatic mice were investigated through Western blotting, qPCR, and Transmission electron microscopy (TEM) examination techniques.RESULTS: The efficacy of KCD has been shown to improve lung function, reduce airway inflammation, and prevent apoptosis of AECs in a HDM-induced asthma model. Through the use of UPLC-LTQ-Orbitrap-MS, we identified 24 potential active components of KCD. Network pharmacology analysis revealed that KCD shares 102 core targets with asthma. GO enrichment analysis, in conjunction with a literature review, indicated that the targets of KCD treatment for AECs apoptosis primarily focus on the mitochondrial membrane. Furthermore, lipidomics analysis of lung tissue and mitochondria in the lungs of mice with HDM-induced asthma revealed disruptions in lipid metabolism, with a decrease in phosphatidylcholine (PC) content in asthmatic mice, which was effectively restored by KCD treatment. KCD reinstates the expression of START domain-containing protein 7 (StarD7) and START domain-containing protein 10 (StarD10) in lung tissue, leading to increase in PC within the mitochondrial membrane. This regulation indirectly influences mitochondrial fusion and fission proteins, promoting mitochondrial membrane stability and reducing cytochrome c (Cyt c) release into the cytoplasm. Ultimately, this process helps mitigate mitochondria-mediated apoptosis of AECs.CONCLUSION: KCD can restore the content of PC in the mitochondria of AECs by regulating StarD7 and StarD10. It also restores proteins associated with mitochondrial fusion and fission, stabilizing mitochondrial structure, effectively reducing the release of Cyt c into the cytoplasm, and ultimately inhibiting mitochondria-mediated apoptosis of AECs induced by HDM in asthmatic mice.PMID:39671785 | DOI:10.1016/j.phymed.2024.156299

Ecotoxicol Environ Saf. 2024 Dec 12;290:117512. doi: 10.1016/j.ecoenv.2024.117512. Online ahead of print.ABSTRACTEnvironmental arsenic contamination is a serious issue that cannot be ignored, since arsenic levels in drinking water frequently exceed safety standards, and there is an increased prevalence of Helicobacter pylori (H. pylori) infection. This results in an increasing population at risk of simultaneous exposure to both harmful agents, yet whether a synergistic interaction exists between them remains unclear. Therefore, this study aims to investigate the combined effects and underlying pathogenic mechanisms of concurrent exposure to these two hazardous factors by establishing a mouse model that is infected with H. pylori and exposed to inorganic arsenic through drinking water. Analysis of intestinal flora revealed significant alterations in the composition, relative abundance (Akkermansia, Faecalibaculum, Ilieibacterium, etc.), and metabolic potential of the intestinal microflora (amino acid metabolism and energy metabolism) in the combinatory exposure group. Non-targeted metabolomics analysis identified that the combinatory exposure group exhibited greater fluctuations in metabolite content, particularly in triacylglycerol, fatty-acid, peptide and amino acid. Moreover, H. pylori infection and arsenic exposure had increased levels of metabolites associated with the intestinal microbiota in their livers (4-Ethylphenyl sulfate and Phenylacetylglycine). Further analysis revealed significant correlations between changes in the intestinal flora and alterations in liver metabolic profiles. Herein, we hypothesize that H. pylori infection may exacerbate the intestinal flora imbalance and hepatic metabolic disturbances caused by arsenic exposure, which may disrupt enterohepatic homeostasis and potentially increase biological susceptibility to heavy metal toxicity.PMID:39671763 | DOI:10.1016/j.ecoenv.2024.117512

Ecotoxicol Environ Saf. 2024 Dec 12;290:117537. doi: 10.1016/j.ecoenv.2024.117537. Online ahead of print.ABSTRACTTriclosan (TCS) is a primary broad-spectrum antibacterial agent commonly present in the environment. As a new type of environmental endocrine disruptor, it causes range of toxicities, including hepatotoxicity and reproductive toxicity. However, few research has examined the toxicity of long-term TCS-induced exposure in zebrafish at ambient concentrations, in contrast to the early life stage investigations. In the present study, we investigated the behavioral effects of TCS at environmental concentrations (300 μg/L) during constant exposure in zebrafish adults；An integrated transcriptomic and metabolomic analysis was performed to analyze the molecular mechanism underlying behavioral effects of TCS. Our results show that TCS exposure significantly induces behavioral disruptions such as anxiety-like behavior, memory problems, and altered social preferences. Histopathological investigations and neural ultrastructural observations demonstrated that TCS could induce variable levels of pyknosis and vacuolation in the cytoplasm of neurons as well as torn mitochondrial membranes, shrinkage and broken or absent cristae. Transcriptomics indicated that immune- and metabolism-related gene expression patterns were severely disturbed by TCS. Metabolomic analysis revealed 82 distinct metabolites in adult zebrafish exposed to TCS. Lipid metabolism, especially glycerophospholipid metabolism, and amino acid regulation pathways were co-enriched by multi-omics combinatorial analysis. Hence, this study highlights a number of biomarkers for the risk assessment of TCS against non-target organisms, offering a reference dataset for the behavioral toxicity of TCS to zebrafish, and strengthening the early warning, management, and control of TCS pollution.PMID:39671762 | DOI:10.1016/j.ecoenv.2024.117537

Sci Immunol. 2024 Dec 13;9(102):eadl4613. doi: 10.1126/sciimmunol.adl4613. Epub 2024 Dec 13.ABSTRACTThe rapid proliferation of germinal center (GC) B cells requires metabolic reprogramming to meet energy demands, yet these metabolic processes are poorly understood. By integrating metabolomic and transcriptomic profiling of GC B cells, we identified that asparagine (Asn) metabolism was highly up-regulated and essential for B cell function. Asparagine synthetase (ASNS) was up-regulated after B cell activation through the integrated stress response sensor GCN2. Conditional deletion of Asns in B cells impaired survival and proliferation in low Asn conditions. Removal of environmental Asn by asparaginase or dietary restriction compromised the GC reaction, impairing affinity maturation and the humoral response to influenza infection. Furthermore, metabolic adaptation to the absence of Asn required ASNS, and oxidative phosphorylation, mitochondrial homeostasis, and synthesis of nucleotides were particularly sensitive to Asn deprivation. These findings demonstrate that Asn metabolism acts as a key regulator of B cell function and GC homeostasis.PMID:39671468 | DOI:10.1126/sciimmunol.adl4613

J Vis Exp. 2024 Nov 29;(213). doi: 10.3791/67319.ABSTRACTMetabolomics is emerging as a significant approach to reflect the individual's response to pathophysiological conditions. Nuclear magnetic resonance (NMR) spectroscopy has evolved as a tool to identify metabolic dysregulations in critically ill patients afflicted with conditions like acute respiratory distress syndrome (ARDS), severe acute pancreatitis (SAP), acute kidney injury (AKI), and sepsis. The spectral data from the serum sample of the study and control group are recorded using an 800 MHz NMR spectrometer and processed using NMR processing and analysis tools. Furthermore, a rigorous statistical analysis, such as univariate and multivariate tests, is performed to pinpoint significant metabolites, which are then accurately identified and quantified using NMR metabolite quantification software. Additionally, pathway analysis highlights the deranged biochemical cycles that result in the severity of illness. Through this comprehensive approach, researchers aim to gain deeper insights into the metabolic alterations associated with these critical illnesses, potentially paving the way for a better understanding of the disease and improved diagnostics and treatment strategies.PMID:39671341 | DOI:10.3791/67319

J Proteome Res. 2024 Dec 13. doi: 10.1021/acs.jproteome.4c00592. Online ahead of print.ABSTRACTChronic dacryocystitis (CD) can result in severe complications and vision impairment due to ongoing microbial infections and persistent tearing. Tear fluid, which contains essential components vital for maintaining ocular surface health, has been investigated for its potential in the noninvasive identification of ocular biomarkers through metabolomics analysis. In this study, we employed UHPLC-MS/MS to analyze the tear metabolome of CD patients. UHPLC-MS/MS analysis of tear samples from CD patients revealed significant metabolic alterations. Compared with the control group, 298 metabolites were elevated, while 142 were decreased. KEGG pathway analysis suggested that these changes primarily affected arginine and proline metabolism, biosynthesis of amino acids, and phenylalanine biosynthesis in CD. Notably, 3-dehydroquinic acid, anthranilic acid, citric acid, and l-isoleucine emerged as potential biomarker candidates of CD with high diagnostic accuracy (AUC = 0.94). These findings suggest that tear fluid metabolism, particularly amino acid biosynthesis, plays a significant role in the pathogenesis of CD. Uncovering these metabolic products and pathways provides valuable insights into the mechanisms underlying CD and paves the way for the development of diagnostic tools and targeted therapies.PMID:39670809 | DOI:10.1021/acs.jproteome.4c00592

J Proteome Res. 2024 Dec 13. doi: 10.1021/acs.jproteome.4c00530. Online ahead of print.ABSTRACTMetabolic rewiring is required for cancer cells to survive in harsh microenvironments and is considered to be a hallmark of cancer. Specific metabolic adaptations are required for a tumor to become invasive and metastatic. Cell division and metabolism are inherently interconnected, and several cell cycle modulators directly regulate metabolism. Here, we report that TBK1, which is a noncanonical IKK kinase with known roles in cell cycle regulation and TLR signaling, affects cellular metabolism in cancer cells. While TBK1 is reported to be overexpressed in several cancers and its enhanced protein level correlates with poor prognosis, the underlying molecular mechanism involved in the tumor-promoting role of TBK1 is not fully understood. In this study, we show a novel role of TBK1 in regulating cancer cell metabolism using combined metabolomics, transcriptomics, and pharmacological approaches. We find that TBK1 mediates the regulation of nucleotide and energy metabolism through aldo-keto reductase B10 (AKRB10) and thymidine phosphorylase (TYMP) genes, suggesting that this TBK1-mediated metabolic rewiring contributes to its oncogenic function. In addition, we find that TBK1 inhibitors can act synergistically with AKRB10 and TYMP inhibitors to reduce cell viability. These findings raise the possibility that combining these inhibitors might be beneficial in combating cancers that show elevated levels of TBK1.PMID:39670797 | DOI:10.1021/acs.jproteome.4c00530

Transl Vis Sci Technol. 2024 Dec 2;13(12):23. doi: 10.1167/tvst.13.12.23.ABSTRACTPURPOSE: Identify optimal metabolic features and pathways across diabetic retinopathy (DR) stages, develop risk models to differentiate diabetic macular edema (DME), and predict anti-vascular endothelial growth factor (anti-VEGF) therapy response.METHODS: We analyzed 108 aqueous humor samples from 78 type 2 diabetes mellitus patients and 30 healthy controls. Ultra-high-performance liquid chromatography-high-resolution-mass-spectrometry detected lipidomics and metabolomics profiles. DME patients received ≥3 anti-VEGF treatments, categorized into strong and weak response groups. Machine learning (ML) screened prospective metabolic features, developing prediction models.RESULTS: Key metabolic features identified in the metabolomics and lipidomics datasets included n-acetyl isoleucine (odds ratio [OR] = 1.635), cis-aconitic acid (OR = 3.296), and ophthalmic acid (OR = 0.836) for DR. For early-DR, n-acetyl isoleucine (OR = 1.791) and decaethylene glycol (PEG-10) (OR = 0.170) were identified as key markers. L-kynurenine (OR = 0.875), niacinamide (OR = 0.843), and linoleoyl ethanolamine (OR = 0.941) were identified as significant indicators for DME. Trigonelline (OR = 1.441) and 4-methylcatechol-2-sulfate (OR = 1.121) emerged as predictors for strong response to anti-VEGF. Predictive models achieved R² values of 99.9%, 97.7%, 93.9%, and 98.4% for DR, early-DR, DME, and strong response groups in the calibration set, respectively, and validated well with R² values of 96.3%, 96.8%, 79.9%, and 96.3%.CONCLUSIONS: This research used ML to identify differential metabolic features from metabolomics and lipidomics datasets in DR patients. It implies that metabolic indicators can effectively predict early disease progression and potential weak responders to anti-VEGF therapy in DME eyes.TRANSLATIONAL RELEVANCE: The identified metabolic indicators may aid in predicting the early progression of DR and optimizing therapeutic strategies for DME.PMID:39671223 | DOI:10.1167/tvst.13.12.23

Hepatol Commun. 2024 Dec 11;9(1):e0599. doi: 10.1097/HC9.0000000000000599. eCollection 2025 Jan 1.ABSTRACTBACKGROUND: Alcohol-associated liver disease (ALD) is a major clinical issue characterized by progressive stages, including hepatic steatosis, liver fibrosis, cirrhosis, and HCC. Patients with long-term chronic alcoholism often present with gut microbiota dysbiosis and reduced plasma levels of vitamin B6. This study aimed to verify that gut microbiota disruption in ALD significantly contributes to reduced in vivo production of vitamin B6 and to investigate the role of this reduction in the pathogenesis of ALD.METHODS: The ALD was investigated utilizing the Gao-binge mouse model. Fecal microbial composition was analyzed in pair-fed mice and ALD mice to identify alcohol-induced functional changes in the microbiota. Additionally, liver protein expression profiles and liver and plasma metabolomic profiles were characterized to elucidate the role of vitamin B6 in ALD pathogenesis through integrated proteomic and metabolomic analyses. The findings were further validated using animal models and clinical patient samples.RESULTS: Alcohol consumption disrupted the gut microbiota in the mice, impairing the vitamin B6 synthesis by intestinal microorganisms. Vitamin B6 deficiency aggravated the disorder of amino acid metabolism in the liver and inhibited ornithine aminotransferase expression, thereby worsening oxidative stress damage. In patients with ALD, significant disturbances of gut microbiota were observed, along with decreased intestinal vitamin B6 levels, which were negatively correlated with serum biochemical markers.CONCLUSIONS: The imbalance of gut microbiota in ALD mice reduces vitamin B6 synthesis, which affects amino acid metabolism and glutathione synthesis in the liver, thereby exacerbating ALD. These findings suggest that vitamin B6 may play a critical protective role in ALD progression by regulating amino acid metabolism.PMID:39670862 | DOI:10.1097/HC9.0000000000000599

Microbiol Spectr. 2024 Dec 13:e0199924. doi: 10.1128/spectrum.01999-24. Online ahead of print.ABSTRACTThe gut microbiome plays a key role in bile acid (BA) metabolism, where a diversity of metabolic products contribute to human health and disease. In particular, Inflammatory Bowel Disease (IBD) is characterized by a low concentration of secondary bile acids (SBAs), whose transformation from primary bile acids (PBAs) is an essential function performed solely by gut bacteria. BA-transformation activity mediated by the bile acid inducible (bai) operon has been functionally characterized in the genus Clostridium, and homologous bai gene sequences have been found in metagenome-assembled genomes (MAGs) belonging to other taxa in the human gut, but it is unclear which species of bai-carrying bacteria perform physiologically significant amounts of bile acid transformation in healthy and sick individuals. Here, we analyzed hundreds of stool samples with paired metagenomic and metabolomic data from IBD patients and controls and found that the abundance of the bai operon in metagenomic samples was highly predictive of that sample's high- or low-SBA metabolic state. We further found that bai genes from the Clostridium species best characterized as BA transformers were more prevalent in IBD patients than in non-IBD controls, while bai genes from uncharacterized taxa known only from MAGs were much more physiologically relevant in non-IBD samples. These un-isolated clades of BA-transforming bacteria merit further research; as beyond their prevalence in the human population, we found some cases in which they engrafted in IBD patients who had undergone fecal microbiota transplantation and experienced a clinical response.IMPORTANCEIn this paper, we identify specific bacteria that perform an important metabolic function in the human gut and demonstrate that in the guts of a large subset of patients with IBD, these bacteria are missing and the function is defective. This is a rare example where the correlation between the absence of specific bacteria and the dysfunction of metabolism is directly observed, not in mice nor in the lab, but in physiologic microbial communities in the human gut. Our results point to a path for studying how a small but important set of bacteria is affected by conditions in the IBD gut and perhaps to the development of interventions to mitigate the loss of these bacteria in IBD.PMID:39670752 | DOI:10.1128/spectrum.01999-24