PubMed

Cell Metab. 2024 Oct 25:S1550-4131(24)00409-1. doi: 10.1016/j.cmet.2024.10.013. Online ahead of print.ABSTRACTHepatic de novo lipogenesis (DNL) is a fundamental physiologic process that is often pathogenically elevated in metabolic disease. Treatment is limited by incomplete understanding of the metabolic pathways supplying cytosolic acetyl-CoA, the obligate precursor to DNL, including their interactions and proportional contributions. Here, we combined extensive 13C tracing with liver-specific knockout of key mitochondrial and cytosolic proteins mediating cytosolic acetyl-CoA production. We show that the mitochondrial pyruvate carrier (MPC) and ATP-citrate lyase (ACLY) gate the major hepatic lipogenic acetyl-CoA production pathway, operating in parallel with acetyl-CoA synthetase 2 (ACSS2). Given persistent DNL after mitochondrial citrate carrier (CiC) and ACSS2 double knockout, we tested the contribution of exogenous and leucine-derived acetoacetate to acetoacetyl-CoA synthetase (AACS)-dependent DNL. CiC knockout increased acetoacetate-supplied hepatic acetyl-CoA production and DNL, indicating that ketones function as mitochondrial-citrate reciprocal DNL precursors. By delineating a mitochondrial-cytosolic DNL substrate supply network, these findings may inform strategies to therapeutically modulate DNL.PMID:39471817 | DOI:10.1016/j.cmet.2024.10.013

EBioMedicine. 2024 Oct 28;109:105427. doi: 10.1016/j.ebiom.2024.105427. Online ahead of print.ABSTRACTBACKGROUND: The influence of the gut microbiota on long-term immune checkpoint inhibitor (ICI) efficacy and immune-related adverse events (irAEs) is poorly understood, as are the underlying mechanisms.METHODS: We performed gut metagenome and metabolome sequencing of gut microbiotas from patients with lung cancer initially treated with anti-PD-1/PD-L1 therapy and explored the underlying mechanisms mediating long-term (median follow-up 1167 days) ICI responses and immune-related adverse events (irAEs). Results were validated in external, publicly-available datasets (Routy, Lee, and McCulloch cohorts).FINDINGS: The ICI benefit group was enriched for propionate (P = 0.01) and butyrate/isobutyrate (P = 0.12) compared with the resistance group, which was validated in the McCulloch cohort (propionate P < 0.001, butyrate/isobutyrate P = 0.002). The acetyl-CoA pathway (P = 0.02) in beneficial species mainly mediated butyrate production. Microbiota sequences from irAE patients aligned with antigenic epitopes found in autoimmune diseases. Microbiotas of responsive patients contained more lung cancer-related antigens (P = 0.07), which was validated in the Routy cohort (P = 0.02). Escherichia coli and SGB15342 of Faecalibacterium prausnitzii showed strain-level variations corresponding to clinical phenotypes. Metabolome validation reviewed more abundant acetic acid (P = 0.03), propionic acid (P = 0.09), and butyric acid (P = 0.02) in the benefit group than the resistance group, and patients with higher acetic, propionic, and butyric acid levels had a longer progression-free survival and lower risk of tumor progression after adjusting for histopathological subtype and stage (P < 0.05).INTERPRETATION: Long-term ICI survivors have coevolved a compact microbial community with high butyrate production, and molecular mimicry of autoimmune and tumor antigens by microbiota contribute to outcomes. These results not only characterize the gut microbiotas of patients who benefit long term from ICIs but pave the way for "smart" fecal microbiota transplantation. Registered in the Chinese Clinical Trial Registry (ChiCTR2000032088).FUNDING: This work was supported by Beijing Natural Science Foundation (7232110), National High Level Hospital Clinical Research Funding (2022-PUMCH-A-072, 2023-PUMCH-C-054), CAMS Innovation Fund for Medical Sciences (CIFMS) (2022-I2M-C&T-B-010).PMID:39471749 | DOI:10.1016/j.ebiom.2024.105427

Mult Scler Relat Disord. 2024 Oct 15;92:105942. doi: 10.1016/j.msard.2024.105942. Online ahead of print.ABSTRACTMultiple sclerosis (MS) remains a challenging neurological condition for diagnosis and management and is often detected in late stages, delaying treatment. Artificial intelligence (AI) is emerging as a promising approach to extracting MS information when applied to different patient datasets. Given the critical role of metabolites in MS profiling, metabolomics data may be an ideal platform for the application of AI to predict disease. In the present study, a machine-learning (ML) approach was used for a detailed analysis of metabolite profiles and related pathways in patients with MS and healthy controls (HC). This approach identified unique alterations in biochemical metabolites and their correlation with disease severity parameters. To enhance the efficiency of using metabolic profiles to determine disease severity or the presence of MS, we trained an AI model on a large volume of blood-based metabolomics datasets. We constructed this model using an artificial neural network (ANN) architecture with perceptrons. Data were divided into training, validation, and testing sets to determine model accuracy. After training, accuracy reached 87 %, sensitivity was 82.5 %, specificity was 89 %, and precision was 77.3 %. Thus, the developed model seems highly robust, generalizable with a wide scope and can handle large amounts of data, which could potentially assist neurologists. However, a large multicenter cohort study is necessary for further validation of large-scale datasets to allow the integration of AI in clinical settings for accurate diagnosis and improved MS management.PMID:39471746 | DOI:10.1016/j.msard.2024.105942

Talanta. 2024 Oct 21;283:127083. doi: 10.1016/j.talanta.2024.127083. Online ahead of print.ABSTRACTEndometrial cancer (EC) is the most prevalent cancer within the female reproductive system in developed countries. Despite its high incidence, there is currently no established laboratory screening test for EC, making early detection challenging. This study introduces an innovative, minimally invasive, and cost-effective method utilizing three-dimensional fluorescence analysis combined with machine learning algorithms to enhance early EC detection. Intrinsic fluorescence of blood serum samples was measured using a luminescence spectrophotometer, which captured fluorescence spectra as synchronous excitation spectra and visualized them through wavelength contour matrices. The spectral data were processed using machine learning algorithms, including Random Forest (RF), Logistic Regression (LR), Support Vector Machine (SVM), and Stochastic Gradient Descent (SGD), along with exploratory techniques such as Principal Component Analysis (PCA) and Partial Least Squares Discriminant Analysis (PLS-DA). Fluorescence ratios R300/330 and R360/490, indicative of altered tryptophan metabolism and redox state changes, were identified as fluorescent spectral markers and represent key metabolic biomarkers. These ratios demonstrated high diagnostic efficacy with AUC values of 0.88 and 0.91, respectively. Among the ML algorithms, LR and RF exhibited high sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), showing significant promise for clinical application. After optimization, LR achieved a sensitivity of 0.94, specificity of 0.89, and an impressive AUC value of 0.94. The application of this novel approach in laboratory diagnostics has the potential to significantly enhance early detection and improve prognosis for EC patients.PMID:39471720 | DOI:10.1016/j.talanta.2024.127083

Redox Biol. 2024 Oct 18;78:103401. doi: 10.1016/j.redox.2024.103401. Online ahead of print.ABSTRACTRheumatoid arthritis (RA) is an inflammatory autoimmune disease mediated by immune cell dysfunction for which there is no universally effective prevention and treatment strategy. As primary effector cells, neutrophils are important in the inflammatory joint attack during the development of RA. Here, we used single-cell sequencing technology to thoroughly analyze the phenotypic characteristics of bone marrow-derived neutrophils in type II collagen (COL2)-induced arthritis (CIA) models, including mice primed and boosted with COL2. We identified a subpopulation of neutrophils with high expression of neutrophil cytoplasmic factor 1 (NCF1) in primed mice, accompanied by a characteristic reactive oxygen species (ROS) response, and a decrease in Ncf1 expression in boosted mice with the onset of arthritis. Furthermore, we found that after ROS reduction, arthritis occurred in primed mice but was attenuated in boosted mice. This bidirectional effect of ROS suggested a protective role of ROS during immune priming. Mechanistically, we combined functional assays and metabolomics identifying Ncf1-deficient neutrophils with enhanced migration, chemotactic receptor CXCR2 expression, inflammatory cytokine secretion, and Th1/Th17 differentiation. This alteration was mainly due to the metabolic reprogramming of Ncf1-deficient neutrophils from an energy supply pathway dominated by gluconeogenesis to an inflammatory immune pathway associated with the metabolism of histidine, glycine, serine, and threonine signaling, which in turn induced arthritis. In conclusion, we have systematically identified the functional and inflammatory phenotypic characteristics of neutrophils under ROS regulation, which provides a theoretical basis for understanding the pathogenesis of RA, to further improve prevention strategies and identify novel therapeutic targets.PMID:39471640 | DOI:10.1016/j.redox.2024.103401

J Hazard Mater. 2024 Oct 28;480:136306. doi: 10.1016/j.jhazmat.2024.136306. Online ahead of print.ABSTRACTF53B (6:2 chlorinated polyfluorinated ether sulfonate), a substitute for perfluorooctane sulfonate (PFOS), is widely used as a chromium mist inhibitor in the electroplating industry. However, significant concern has arisen owing to its biological toxicity. Several studies on F53B toxicity in mammals have focused on hepatotoxicity, immunotoxicity, developmental toxicity, and reproductive toxicity, while its neurotoxic effects, especially in relation to neurodegenerative diseases such as Parkinson's disease (PD), remain unclear. In this study, we investigated the neurotoxic effects of F53B on dopaminergic neurons and explored its potential risk associated with PD in a cellular model. Potential target prediction and validation experiments demonstrated that F53B induced apoptosis in dopaminergic neurons. We also discovered that F53B triggered oxidative stress and inflammatory responses, and stimulated nitric oxide (NO) generation in the PD cellular model. Subsequently, untargeted metabolomics and lipidomics approaches were integrated to explore the molecular mechanisms underlying the response of dopaminergic neurons to F53B exposure. The results suggested that F53B disrupted arginine and proline metabolism, energy metabolism, and caused lipid dysregulation, particularly promoting the hydrolysis of sphingomyelin (SM) into ceramide (Cer). Overall, this study provides evidence that F53B exposure could increase the potential risk of PD and offers novel insights into its neurotoxicity mechanisms.PMID:39471628 | DOI:10.1016/j.jhazmat.2024.136306

Microbiol Res. 2024 Oct 22;290:127933. doi: 10.1016/j.micres.2024.127933. Online ahead of print.ABSTRACTPseudomonads are well-known for their plant growth-promoting properties and biocontrol capabilities against microbial pathogens. Recently, their potential to protect crops from parasitic plants has garnered attention. This study investigates the potential of different Pseudomonas strains to inhibit broomrape growth and to protect host plants against weed infestation. Four Pseudomonas strains, two P. fluorescens JV391D17 and JV391D10, one P. chlororaphis JV395B and one P. ogarae F113 were cultivated using various carbon sources, including fructose, pyruvate, fumarate, and malate, to enhance the diversity of potential Orobanche growth inhibition (OGI)-specialized metabolites produced by Pseudomonas strains. Both global and targeted metabolomic approaches were utilized to identify specific OGI metabolites. Both carbon sources and Pseudomonas genetic diversity significantly influenced the production of OGI metabolites. P. chlororaphis JV395B and P. ogarae F113 produced unique OGI metabolites belonging to different chemical families, such as hydroxyphenazines and phloroglucinol compounds, respectively. Additionally, metabolomic analyses identified an unannotated potential OGI ion, M375T65. This ion was produced by all Pseudomonas strains but was found to be over-accumulated in JV395B, which likely explains its superior OGI activity. Then, greenhouse experiments were performed to evaluate the biocontrol efficacy of selected strains: they showed the efficacy of these strains, particularly JV395B, in reducing broomrape infestation in rapeseed. These findings suggest that certain Pseudomonas strains, through their metabolite production, can offer a sustainable biocontrol strategy against parasitic plants. This biocontrol activity can be optimized by environmental factors, such as carbon amendments. Ultimately, this approach presents a promising alternative to chemical herbicides.PMID:39471583 | DOI:10.1016/j.micres.2024.127933

Food Chem. 2024 Oct 21;464(Pt 2):141740. doi: 10.1016/j.foodchem.2024.141740. Online ahead of print.ABSTRACTThis study aimed to unraveling the color evolution and metabolic pathways of pelargonidin-3-O-glucoside (P3G) during lactic acid fermentation of the strawberry juice color simulation system. The results revealed that fermentation with both Lactobacillus plantarum and Lactobacillus acidophilus caused a decline in pH of the strawberry juice color simulation system and significantly accelerated the decrease in P3G content. The CIELAB space model pointed out that parameters a⁎ and b⁎ of the group treated with both lactic acid bacteria and P3G initially increased to a peak level and then gradually decreased, shifting the overall color towards orange and then gradually fading. Furthermore, untargeted metabolomics results revealed that P3G was progressively degraded and converted to pyruvate, methylparaben, 3,4-dihydroxybenzoic acid, p-anisic acid, and terephthalic acid, affecting the metabolic pathways of glycolysis, d-amino acids, benzoate degradation, aromatic compounds degradation, and aminobenzoate degradation in lactic acid bacteria.PMID:39471556 | DOI:10.1016/j.foodchem.2024.141740

Protein Cell. 2024 Oct 29:pwae063. doi: 10.1093/procel/pwae063. Online ahead of print.NO ABSTRACTPMID:39471360 | DOI:10.1093/procel/pwae063

J Agric Food Chem. 2024 Oct 29. doi: 10.1021/acs.jafc.4c07362. Online ahead of print.ABSTRACTThe antioxidant dipeptides (Ala-His, AH; Thr-Tyr, TY; and Phe-Cys, FC) significantly enhanced the lager yeast tolerance of ethanol stress. The enhancement mechanisms were further elucidated through physiological responses and metabolomics analysis. The results indicated that antioxidant dipeptides significantly increased the lager yeast biomass and budding rate. The primary mechanisms by which antioxidant dipeptides improved lager yeast tolerance involved decreasing intracellular reactive oxygen species (ROS) levels and increasing energy metabolism. Specifically, the addition of FC resulted in a 27.44% reduction in intracellular ROS content and a 26.14% increase in the ATP level compared to the control. Metabolomics analysis further explored the potential mechanisms underlying the protective effects of FC, identifying 63 upregulated and 103 downregulated metabolites. The analysis revealed that FC altered intracellular metabolites related to glutathione metabolism, purine metabolism, starch and sucrose metabolism, and ABC transporters, thereby enhancing yeast stress tolerance. The results suggest that FC is an effective enhancer for improving lager yeast tolerance to ethanol stress.PMID:39470994 | DOI:10.1021/acs.jafc.4c07362

J Nat Med. 2024 Oct 29. doi: 10.1007/s11418-024-01856-5. Online ahead of print.ABSTRACTAcacia confusa Merr. (Fabaceae) (A. confusa) is a native tree species of Taiwan, commonly found in the low-altitude mountains and hilly areas of the Hengchun Peninsula. This evergreen, perennial, and large-sized tree was the focus of a study that employed various chromatographic and spectroscopic methods to analyze the hot water extract of its flowers. The analysis revealed that the major components of the extract were myricitrin, quercitrin, europetin-3-O-rhamnoside, and chalconaringenin-2'-xyloside, with respective concentrations of approximately 0.22, 0.02, 0.26, and 0.10 mg/g of the flowers. Subsequent cell assays were conducted to assess the inhibitory effect of the extract on lipid synthesis in fat cells. Oil Red O staining results indicated that the extract significantly suppressed fatty acid accumulation in 3T3-L1 cells, with the most pronounced effect observed at a concentration of 180 μg/ml. Furthermore, the hot water extract of A. confusa flowers was found to increase the phosphorylation of AMP-activated protein kinase (AMPK), decrease the phosphorylation of cAMP response element-binding protein (CREB), and reduce the expression of glucocorticoid receptor (GR) protein. This, in turn, inhibited the expression of downstream transcription factors such as CCAT/ehancer binding proteins α (C/EBPα), CCAT/ehancer binding proteins β (C/EBPβ), CCAT/ehancer binding proteins δ (C/EBPδ), peroxisome proliferation-actived receptor γ (PPARγ), and sterol regulatory element binding proteins-1 (SREBP-1). Consequently, the expression of lipid synthesis-related proteins acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and fatty acid translocase (CD36) was reduced, ultimately inhibiting lipid generation. Therefore, the hot water extract of A. confusa flowers shows potential for development as a weight-loss tea.PMID:39470961 | DOI:10.1007/s11418-024-01856-5

Clin Exp Med. 2024 Oct 29;24(1):248. doi: 10.1007/s10238-024-01505-x.ABSTRACTColorectal cancer (CRC) ranks among the most prevalent malignant tumors worldwide, with a multifactorial etiology encompassing genetic, environmental, and life-style factors, as well as the intestinal microbiota and its metabolome. These risk factors often work together in specific groups of patients, influencing how CRC develops and progresses. Importantly, alterations in the gut microbiota act as a critical nexus in this interplay, significantly affecting susceptibility to CRC. This review highlights recent insights into unmodifiable and modifiable risk factors for CRC and how they might interact with the gut microbiota and its metabolome. Understanding the mechanisms of these interactions will help us develop targeted, precision-medicine strategies that can adjust the composition of the gut microbiota to meet individual health needs, preventing or treating CRC more effectively.PMID:39470880 | DOI:10.1007/s10238-024-01505-x

Medicine (Baltimore). 2024 Oct 25;103(43):e40093. doi: 10.1097/MD.0000000000040093.ABSTRACTErectile dysfunction (ED) is a common male sexual health problem that can be associated with obesity. This study aimed to identify serum metabolic differences and pathways related to ED in obese men using non-targeted metabolomics techniques. We included 54 obese male patients with (n = 27) and without (n = 27) ED. We collected 5 mL of fasting elbow vein blood and analyzed serum metabolites using ultra-high-performance liquid chromatography-mass spectrometry. Multivariate statistical methods (principal component analysis and orthogonal partial least squares discriminant analysis) were used to identify differential metabolites between the groups. Finally, pathway analysis using the Kyoto encyclopedia of genes and genomes database identified 4 differential metabolic pathways in obese men with ED compared to obese men without ED. A total of 77 differential metabolites were identified in obese men with ED compared to the control group (obese men without ED) using a threshold of variable importance in the projection > 1 and P < .05. Pathway analysis revealed 4 main differences: glycine, serine and threonine metabolism, glycerophospholipid metabolism, aminoacyl-tRNA biosynthesis, and D-glutamine and D-glutamate metabolism. Specific metabolites associated with these pathways included betaine aldehyde, choline, L-threonine, phosphatidylcholine, L-serine, and D-glutamine. Our findings suggest abnormalities in fatty acid metabolism, phospholipid metabolism, and amino acid metabolism between obese men with and without ED. Metabolites such as betaine aldehyde, choline, L-threonine, phosphatidylcholine, L-serine, and D-glutamine may be potential biomarkers for distinguishing obese men with ED.PMID:39470567 | DOI:10.1097/MD.0000000000040093

Microbiol Spectr. 2024 Oct 29:e0180824. doi: 10.1128/spectrum.01808-24. Online ahead of print.ABSTRACTDysregulation of immune and inflammatory cells around blood vessels and metabolic dysfunction are key mechanisms in the development of pulmonary arterial hypertension (PAH). The homeostasis of the human microbiome plays a crucial role in regulating immune responses and the progression of diseases. For pulmonary arterial hypertension associated with congenital heart disease involving body-lung shunt (PAH-CHD), the potential impact of the microbiome on the "gut-lung axis" remains underexplored. This study recruited 15 healthy individuals and 15 patients with pulmonary arterial hypertension due to congenital heart disease from Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences, and Kunming Children's Hospital. We performed differential analyses of metabolites and microbiota from both the gut and lower respiratory tract for these two groups. The goal was to investigate the "gut-lung axis" microbiome and metabolome profiles in children with PAH-CHD and to analyze the interrelationships between these profiles. Ultimately, we aim to propose the potential value of these profiles in aiding diagnosis. The results indicated that the gut and pulmonary microbiota of children with PAH-CHD are characterized by an increased abundance of beneficial symbionts, which are closely linked to changes in the metabolome. Metabolite functional enrichment analysis revealed energy metabolism reprogramming in the PAH-CHD group, with active metabolic pathways associated with bile acid secretion and carnitine homeostasis. Moreover, the differential expression of metabolites was correlated with right heart function and growth development.IMPORTANCEPrevious studies have primarily focused on the relationship between the gut microbiome and PAH. However, the impact of microbial homeostasis on the progression of PAH-CHD from the perspective of the gut-lung axis has not been adequately elucidated. Our study utilizes an integrated multi-omics approach to report on the differential characteristics of gut and lung microbiota between children with PAH-CHD and reference subjects. We found that microbiota influence the pathological changes and disease manifestations of PAH-CHD through their metabolic activity. Additionally, alterations in metabolites impact the microbial ecological structure. Our findings suggest that modulating the microbiome composition may have positive implications for maintaining and regulating the immune environment and pathological progression of PAH-CHD.PMID:39470277 | DOI:10.1128/spectrum.01808-24

J Psychoactive Drugs. 2024 Oct 29:1-10. doi: 10.1080/02791072.2024.2420059. Online ahead of print.ABSTRACTAyahuasca is a brew traditionally prepared with a mixture of Psychotria viridis leaves and Banisteriopsis caapi vine and has demonstrated therapeutic properties for depression. Knowledge of the brew composition is important to improve the therapeutic potential and decrease side effects if ayahuasca becomes an option for refractory depression treatment. Ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) was applied to analyze 126 ayahuasca samples collected from different ayahuasqueiro groups and geographic origins. We were able to observe a differentiation in the metabolite composition of ayahuasca samples prepared by diverse ayahuasqueiro groups. These samples presented different antioxidant effects based on FRAP and ORAC assays. Exploratory statistical analysis demonstrated a trend of separating the samples according to the religious group. The most important identified compounds for differentiation of the brew prepared by distinct religious groups are glycosylated and/or phenolic compounds. The comparison based on the mode of ayahuasca preparation presented more variability than the comparison based on the botanical variety of B. caapi used. We conclude that ayahuasca samples prepared with "caupuri" or "tucunacá" separately exhibited differences in the analysis of L-glutamate and the metabolism of arginine and proline. This suggests that a possible variation in this pathway could explain the occurrence of swollen stem nodes in "caupuri," one of the B. caapi varieties.PMID:39470142 | DOI:10.1080/02791072.2024.2420059

Drug Des Devel Ther. 2024 Oct 24;18:4749-4778. doi: 10.2147/DDDT.S479341. eCollection 2024.ABSTRACTPURPOSE: Rodgersia sambucifolia Hemsl (also known as Yantuo ) is a traditional Chinese medicine commonly utilized as a medicinal herb with its rhizomes, mainly used to regulate the immune function of the human body. However, relatively few studies have investigated its active components and potential mechanisms of action in vivo.METHODS: First, the chemical composition in vitro was identified and analyzed using the UPLC-Q-TOF MS/MS technique. Cyclophosphamide (CTX) was then administered intraperitoneally to rats to establish an immunosuppression model. Physiological and biochemical parameters, organ indices, and histopathological findings were evaluated for efficacy. Subsequently, potential biomarkers in rat serum were identified using multivariate statistical analysis and enriched and topologized using online platforms such as MetaboAnalyst and KEGG to reveal the critical metabolic pathways and their roles in the immunomodulatory network. Finally, the integrated analysis of components in vivo and in vitro, along with metabolic pathways, was performed using network pharmacology and molecular docking technology to elucidate the mechanisms of their roles in organismal immunity.RESULTS: A total of 28 chemical components in vitro were identified, while pharmacodynamic experiments confirmed the immunomodulatory effects of Yantuo , especially in the high-dose administration group. Metabolomics analysis showed that 37 potential immune-related biomarkers were identified in positive and negative ion modes, involving 16 metabolic pathways such as arginine biosynthesis, pyrimidine metabolism, and riboflavin metabolism. The results of network pharmacology and molecular docking indicated that Yantuo may affect 7-O-galloyl-catechin, Cynaroside, Quercetin-7-O-beta-D-glucopyranoside, and 1.6-bis-O-galloyl-beta-D-glucose through interactions with the immune system, with significant pathways of action including galactose metabolism, glycolysis/gluconeogenesis, pyrimidine metabolism, and riboflavin metabolism.CONCLUSION: In our experiments, we confirmed the organismal modulatory effect of Yantuo on immunocompromised rats, clarified the key components, target proteins, and pathways of its possible action, and provided possibilities for follow-up studies.PMID:39469725 | PMC:PMC11514647 | DOI:10.2147/DDDT.S479341

Food Chem X. 2024 Oct 15;24:101904. doi: 10.1016/j.fochx.2024.101904. eCollection 2024 Dec 30.ABSTRACTPepper is a key agricultural crop susceptible to accumulating heavy metals like cadmium (Cd) and barium (Ba), posing significant health risks. To address these issues, this study investigated the effects of foliar applications of fulvic acid (FA), Zn-fulvic acid (Zn-FA), and Fe-fulvic acid (Fe-FA) on Ba and Cd uptake in pepper tissues, as well as their impact on nutritional quality, biomass, and leaf enzyme activity. Results indicated that Fe-FA application significantly reduced Cd and Ba in pepper fruit by 25 % and 93 %, respectively. Additionally, Fe-FA enhanced pepper growth, increasing vitamin C and phenolic compounds by 136 % and 13 %, respectively. Metabolomics analysis revealed that Fe-FA application up-regulated 857 metabolites and down-regulated 1045 metabolites. Furthermore, Fe-FA primarily influenced amino acid, carbohydrate, and lipid metabolism, promoting pepper growth. These findings suggest that Fe-FA foliar application offers a promising strategy for reducing Ba and Cd accumulation in pepper fruits while enhancing its nutritional quality.PMID:39469282 | PMC:PMC11513662 | DOI:10.1016/j.fochx.2024.101904

Aging Cell. 2024 Oct 29:e14370. doi: 10.1111/acel.14370. Online ahead of print.ABSTRACTThe unprecedented rise in global ambient temperatures in the last decade has significantly impacted human health, yet how heat exposure affects the development of sarcopenia remains enigmatic. Here, we demonstrate that chronic heat exposure induces skeletal muscle volume loss, leading to muscle strength and functional decline in mice. The microbiota composition of heat-exposed mice was analyzed using 16S ribosomal DNA analysis. Liquid chromatography-mass spectrometry (LC-MS) was used to explore the effects of heat exposure on the blood metabolome and to further analyze the correlation between blood metabolism and gut microbiota. Transplantation of microbiota from heat-exposed mice to germ-free mice was sufficient to increase adverse effects on skeletal muscle function in the host. Mechanistically, using an untargeted metabolomics strategy, we reveal that altered gut microbiota due to high temperatures is associated with elevated serum levels of homocitrulline. Homocitrulline causes mitochondrial dysfunction in myocytes by exacerbating ferroptosis levels. And Nrf2 activator (Oltipraz) supplementation alleviates muscle atrophy and dysfunction induced by heat exposure. Our findings reveal the detrimental effects of heat exposure on muscle function and provide new strategies for treating sarcopenia.PMID:39468887 | DOI:10.1111/acel.14370

Plant Cell Environ. 2024 Oct 28. doi: 10.1111/pce.15241. Online ahead of print.ABSTRACTMost terrestrial plants can establish a reciprocal symbiosis with arbuscular mycorrhizal (AM) fungi to cope with adverse environmental stresses. The development of AM symbiosis is energetically costly and needs to be dynamically controlled by plants to maintain the association at mutual beneficial levels. Multiple components involved in the autoregulation of mycorrhiza (AOM) have been recently identified from several plant species; however, the mechanisms underlying the feedback regulation of AM symbiosis remain largely unknown. Here, we report that AM colonization promotes the flavonol biosynthesis pathway in tomato (Solanum lycopersicum), and an AM-specific UDP-glucosyltransferase SlUGT132, which probably has the flavonol glycosylation activity, negatively regulates AM development. SlUGT132 was predominantly expressed in the arbuscule-containing cells, and its knockout or knockdown mutants showed increased soluble sugar content, root colonization level and arbuscule formation. Conversely, overexpression of SlUGT132 resulted in declined soluble sugar content and mycorrhization degree. Metabolomic assay revealed decreased contents of astragalin, tiliroside and cynaroside in slugt132 mycorrhizal roots, but increased accumulation of these flavonoid glycosides in SlUGT132-overexpressing plant roots. Our results highlight the presence of a novel, SlUGT132-mediated AOM mechanism, which enable plants to flexibly control the accumulation of soluble sugars and flavonoid glycosides in mycorrhizal roots and modulate colonization levels.PMID:39468788 | DOI:10.1111/pce.15241

J Natl Cancer Inst. 2024 Oct 28:djae270. doi: 10.1093/jnci/djae270. Online ahead of print.ABSTRACTBACKGROUND: Metabolomic profiles may influence colorectal cancer (CRC) development. Few studies have performed pre-diagnostic metabolome-wide analyses with CRC risk.METHODS: We conducted a nested case-control study among women (Nurses' Health Study (NHS)) and men (Health Professionals Follow-up Study (HPFS)) who provided blood between 1989 and 1995. Over 22.9 years, 684 (409 NHS, 275 HPFS) incident CRC cases occurred and were matched 1:1 to controls. Liquid chromatography-mass spectrometry (LC-MS) identified 255 plasma metabolites after quality control. Cohort-specific and combined metabolite association analyses were performed using conditional logistic regression. Metabolite set enrichment analysis (MSEA) was used to identify differential abundance in metabolite classes. Weighted Correlation Network Analysis (WGCNA) provided modules of covarying metabolites, which were tested for CRC association.RESULTS: MSEA identified specific acylcarnitines associated with higher CRC risk and triacylglycerols with lower CRC risk among women and men. Further, phosphatidylcholines were associated with a higher risk of CRC among men. In an analysis restricted to CRC cases diagnosed two years after blood draw, myristoleic acid (OR = 1.37; 95%CI = 1.15-1.62; FDR = 0.072) and C60:12 triacylglycerol (OR = 0.75; 95%CI = 0.64-0.88; FDR = 0.072 were associated with CRC risk in women. WGCNA identified amino acids associated with CRC in men, fatty acid esters (carnitines) with distal CRC in men, and triradylcglycerols inversely associated with CRC in women.CONCLUSIONS: We identified pre-diagnostic CRC-associated metabolites with distinct sex-specific profiles. These results provide insight into CRC etiopathogenesis and have implications for risk prediction strategies.PMID:39468739 | DOI:10.1093/jnci/djae270