PubMed

Curr Issues Mol Biol. 2024 Nov 10;46(11):12733-12745. doi: 10.3390/cimb46110756.ABSTRACTProlonged exposure to hypoxic conditions can lead to reduced appetite, stunted growth, systemic inflammation, and pulmonary hypertension. Previous studies have indicated a correlation between gut dysbiosis and the development of hypoxia-related hazards. We designed an experiment to investigate the effect of microbiota on mitigating hypoxic damage. Gut microbiota from high-altitude-adapted species (Ochotona curzoniae) were transplanted into Sprague Dawley (SD) rats, which were then housed in a simulated 6000 m altitude environment for 30 days. After the experiment, we conducted analyses on average daily weight gain (ADG), feed conversion ratio (FCR), mean pulmonary artery pressure (mPAP), gut flora, and fecal metabolism. The results demonstrated that the ADG in the transplantation group (2.98 ± 0.17 g) was significantly higher than in the control groups (2.68 ± 0.19 g and 2.26 ± 0.13 g) (p < 0.05). The FCR was reduced in the transplantation group (6.30 ± 0.33 g) compared to the control groups (8.20 ± 1.15 g and 8.83 ± 0.45 g) (p < 0.05). The mPAP was decreased in the transplantation group (38.1 ± 1.13 mmHg) compared to the control groups (43.4 ± 1.30 mmHg and 43.5 ± 1.22 mmHg) (p < 0.05). Multi-omics analysis revealed that Lachnospiraceae, Desulfovibrionaceae, and specific amino acid metabolic pathways play crucial roles in hypoxia and are associated with both inflammation and nutritional metabolism. This study proposes a novel approach to the treatment of hypoxic pulmonary hypertension and holds potential significance for improving high-altitude developmental potential.PMID:39590350 | DOI:10.3390/cimb46110756

Curr Issues Mol Biol. 2024 Oct 23;46(11):11890-11905. doi: 10.3390/cimb46110706.ABSTRACTSweet potato (Ipomoea batatas L.) is one of the most important global food crops. This crop exhibits excellent allelopathic potential against various weeds, but its allelopathic mechanism at the molecular level is unclear. Therefore, metabolomic and transcriptomic analyses were performed to explore the allelopathic effects, metabolic pathway, and associated genes for two major compounds with allelopathic activity, palmitic acid and linoleic acid. The sweet potato variety Ningshu 25 was employed in the current study. The results showed that palmitic acid and linoleic acid had strong allelopathic effects on seed germination, plant growth, antioxidant enzyme activity, and chlorophyll content of two weeds Digitaria sanguinalis and Bidens pilosa. The content of the two targeted metabolites was affected by different environmental conditions and was significantly increased under low temperature (15 °C). Five metabolic pathways involved in the two targeted metabolites of fatty acids were found: fatty acid biosynthesis, fatty acid elongation, fatty acid degradation, biosynthesis of cutin, suberine, and wax, and the linoleic acid metabolism pathway. The synthesis of palmitic acid is significantly enriched in the biosynthesis pathways of fatty acids, cutin, suberine, and wax, and the synthesis of linoleic acid is significantly enriched in the linoleic acid metabolism pathway. Under different environmental conditions, there were three key genes expressed-g4988, g11881, and g19673-located in the biosynthesis pathways of cutin, suberine, and wax; four key genes expressed-g31191, g60956, g49811, and g59542-located in the biosynthesis pathway of fatty acids; and six key expressed genes-g26575, g24787, g23517, g57649, g58562, and g4314-located in biosynthesis pathway of linoleic acid, respectively. Our study advances understanding of the molecular mechanisms behind allelopathic traits in sweet potato and provides a set of candidate genes for use in improving allelopathic potential in sweet potato germplasm resources.PMID:39590300 | DOI:10.3390/cimb46110706

Plant Physiol. 2024 Nov 26:kiae604. doi: 10.1093/plphys/kiae604. Online ahead of print.ABSTRACTTemperature is a critical abiotic factor affecting rice (Oryza sativa L.) yields, and cold stress at the seedling stage can inhibit plant growth or even be fatal. Antioxidants such as anthocyanins accumulate in a variety of plants during cold stress, but the underlying mechanisms are not well understood. Here, we report that rice TRANSPARENT TESTA GLABRA 1 (OsTTG1), a major regulator of anthocyanin biosynthesis in rice, responds to short- and long-term cold stress at both the transcriptional and protein levels. Metabolomic and transcriptomic data indicate that OsTTG1 activates the expression of anthocyanidin synthase (OsANS) genes under cold stress. Our data also suggest that OsTTG1 forms a MYB-bHLH-WD (MBW) complex with Basic helix-loop-helix 148 (OsbHLH148) and Myb-related S3 (OsMYBS3), and this complex activates the expression of Dehydration-responsive element-binding protein 1 (OsDREB1) and OsANS genes. Together, our findings reveal the mechanisms by which OsTTG1 coordinates both anthocyanin biosynthesis and the expression of cold-responsive genes in colored rice, providing genetic resources for future cold resistance breeding in rice.PMID:39589910 | DOI:10.1093/plphys/kiae604

Proc Natl Acad Sci U S A. 2024 Dec 3;121(49):e2416882121. doi: 10.1073/pnas.2416882121. Epub 2024 Nov 26.ABSTRACTAdenocarcinomas from multiple tissues can converge to treatment-resistant small cell neuroendocrine (SCN) cancers composed of ASCL1, POU2F3, NEUROD1, and YAP1 subtypes. We investigated how mitochondrial metabolism influences SCN cancer (SCNC) progression. Extensive bioinformatics analyses encompassing thousands of patient tumors and human cancer cell lines uncovered enhanced expression of proliferator-activatedreceptor gamma coactivator 1-alpha (PGC-1α), a potent regulator of mitochondrial oxidative phosphorylation (OXPHOS), across several SCNCs. PGC-1α correlated tightly with increased expression of the lineage marker Achaete-scute homolog 1, (ASCL1) through a positive feedback mechanism. Analyses using a human prostate tissue-based SCN transformation system showed that the ASCL1 subtype has heightened PGC-1α expression and OXPHOS activity. PGC-1α inhibition diminished OXPHOS, reduced SCNC cell proliferation, and blocked SCN prostate tumor formation. Conversely, PGC-1α overexpression enhanced OXPHOS, validated by small-animal Positron Emission Tomography mitochondrial imaging, tripled the SCN prostate tumor formation rate, and promoted commitment to the ASCL1 lineage. These results establish PGC-1α as a driver of SCNC progression and subtype determination, highlighting metabolic vulnerabilities in SCNCs across different tissues.PMID:39589879 | DOI:10.1073/pnas.2416882121

Arch Dermatol Res. 2024 Nov 26;317(1):47. doi: 10.1007/s00403-024-03539-3.ABSTRACTThis study leverages the most up-to-date lipidomic data to provide fresh perspectives on the treatment and prevention of atopic dermatitis. The analysis utilized genome-wide association study (GWAS) data on 179 circulating plasma lipids and AD GWAS data. The primary analysis method employed was the inverse variance weighting (IVW) method, and several sensitivity analyses were conducted to ensure the reliability of the results. Additionally, summary-data-based MR (SMR) and colocalization analysis were utilized to investigate the underlying biological pathways of AD. After rigorous analyses, the IVW method utilized in TSMR analysis pinpointed six plasma lipids with potentially reduced AD risk when elevated. Subsequently, MVMR analysis revealed that there is no independent causal effect of different lipids within the same subtype on AD. Bidirectional MR analysis did not indicate reverse causality, and SMR analysis suggested FADS1 and FADS2 as potential drug targets for AD treatment. This MR study demonstrated a causal relationship between specific plasma lipid levels and AD risk at the genetic level, which can be used for clinical screening of AD plasma lipid biomarkers and provides a novel perspective on potential therapeutic strategies.PMID:39589539 | DOI:10.1007/s00403-024-03539-3

J Agric Food Chem. 2024 Nov 26. doi: 10.1021/acs.jafc.4c07381. Online ahead of print.ABSTRACTPrevious studies demonstrated that sufferers with halitosis can be significantly improved with Lacticaseibacillus paracasei ET-22 (ET-22) postbiotics intervention. The objectives of this investigation were to identify the primary components responsible for inhibiting oral malodor. This study demonstrated that cell-free supernatants (CFSs) were more effective in inhibiting production of volatile sulfur compounds (VSCs). Untargeted metabolomics identified CFSs as primarily consisting of organic acids, lipids, peptides, and nucleotides. Among the potential active components, phenyllactic acid (PLA) and peptide GP(Hyp)GAG significantly inhibited microbial-induced VSCs production, with VSC concentrations reduced by 42.7% and 44.6%, respectively. Given the correlation between biofilms and halitosis, microstructural changes in biofilms were examined. PLA suppressed the biomass of the biofilm by 41.7%, while the biofilm thickness was reduced from 202.3 to 70.0 μm. GP(Hyp)GAG intervention reduced the abundance of Fusobacterium nucleatum and Streptococcus mutans within the biofilm, and the expression of biofilm-forming genes FadA and Gtfb were also suppressed by 41.8% and 59.4%. Additionally, the VSC production capacities were reduced due to the decrease in VSC producing bacteria (F. nucleatum, Prevotella intermedia, and Solobacterium moorei) and down-regulation of Cdl and Mgl genes. Collectively, the current study proved that PLA and GP(Hyp)GAG may be the main contributors to halitosis inhibition by ET-22 postbiotics.PMID:39589428 | DOI:10.1021/acs.jafc.4c07381

J Pharm Pharmacol. 2024 Nov 26:rgae116. doi: 10.1093/jpp/rgae116. Online ahead of print.ABSTRACTBACKGROUND: To explore the blood components of ginger volatile oil (GVO) after gastric perfusion in rats and its different metabolites from blank serum and the network pharmacological analysis and preliminary verification of the main components against breast cancer.METHODS: A total of 20 male rats were randomly allocated to 10 control groups and 10 experimental groups. The administration group was given diluted GVO and the blank group was given the same amount of soybean oil (weigh 12 g of GVO diluted to 100 ml with soybean oil), the serum of rats in the given and blank groups was analyzed by gas chromatography-time-of-flight mass spectrometry, and the differential metabolites were screened and enriched, and the blood components were analyzed by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS).RESULTS: A total of 34 different metabolites were screened, and 31 original components were identified. The content of citral in volatile oil and serum is high, and the pathway of action is also closely related to the results of network pharmacology. Cell experiments showed that both drug-containing serum and citral significantly inhibited the proliferation and lateral transfer ability of breast cancer MCF-7 cells in a concentration and time-dependent manner, flow cytometry was used to measure apoptosis, and the experimental results showed that the proportion of early and late apoptosis was significantly increased in each group compared with the control group, and the proportion of total apoptosis showed a certain concentration-dependent trend.CONCLUSIONS: A combination of serum metabolism, network pharmacology, and experiments was employed; this study offers a significant contribution to the clarification of the material basis and molecular mechanism of GVO- medicated serum against breast cancer.PMID:39589181 | DOI:10.1093/jpp/rgae116

Front Endocrinol (Lausanne). 2024 Nov 11;15:1444282. doi: 10.3389/fendo.2024.1444282. eCollection 2024.ABSTRACTBACKGROUND: Type 2 diabetes mellitus (T2DM) is a global health problem characterized by insulin resistance and hyperglycemia. Early detection and accurate prediction of T2DM is crucial for effective management and prevention. This study explores the integration of machine learning (ML) and explainable artificial intelligence (XAI) approaches based on metabolomics panel data to identify biomarkers and develop predictive models for T2DM.METHODS: Metabolomics data from T2DM (n = 31) and healthy controls (n = 34) were analyzed for biomarker discovery (mostly amino acids, fatty acids, and purines) and T2DM prediction. Feature selection was performed using the least absolute shrinkage and selection operator (LASSO) regression to enhance the model's accuracy and interpretability. Advanced three tree-based ML algorithms (KTBoost: Kernel-Tree Boosting; XGBoost: eXtreme Gradient Boosting; NGBoost: Natural Gradient Boosting) were employed to predict T2DM using these biomarkers. The SHapley Additive exPlanations (SHAP) method was used to explain the effects of metabolomics biomarkers on the prediction of the model.RESULTS: The study identified multiple metabolites associated with T2DM, where LASSO feature selection highlighted important biomarkers. KTBoost [Accuracy: 0.938; CI: (0.880-0.997), Sensitivity: 0.971; CI: (0.847-0.999), Area under the Curve (AUC): 0.965; CI: (0.937-0.994)] demonstrated its effectiveness in using complex metabolomics data for T2DM prediction and achieved better performance than other models. According to KTBoost's SHAP, high levels of phenylactate (pla) and taurine metabolites, as well as low concentrations of cysteine, laspartate, and lcysteate, are strongly associated with the presence of T2DM.CONCLUSION: The integration of metabolomics profiling and XAI offers a promising approach to predicting T2DM. The use of tree-based algorithms, in particular KTBoost, provides a robust framework for analyzing complex datasets and improves the prediction accuracy of T2DM onset. Future research should focus on validating these biomarkers and models in larger, more diverse populations to solidify their clinical utility.PMID:39588339 | PMC:PMC11586166 | DOI:10.3389/fendo.2024.1444282

Front Endocrinol (Lausanne). 2024 Nov 11;15:1440984. doi: 10.3389/fendo.2024.1440984. eCollection 2024.ABSTRACTAIMS: Our study, employing a multi-omics approach, aimed to delineate the distinct gut microbiota and metabolic characteristics in individuals under 30 with unclassified diabetes, thus shedding light on the underlying pathophysiological mechanisms.METHODS: This age- and sex-matched case-control study involved 18 patients with unclassified diabetes, 18 patients with classic type 1 diabetes, 13 patients with type 2 diabetes, and 18 healthy individuals. Metagenomics facilitated the profiling of the gut microbiota, while untargeted liquid chromatography-mass spectrometry was used to quantify the serum lipids and metabolites.RESULTS: Our findings revealed a unique gut microbiota composition in unclassified diabetes patients, marked by a depletion of Butyrivibrio proteoclasticus and Clostridium and an increase in Ruminococcus torques and Lachnospiraceae bacterium 8_1_57FAA. Comparative analysis identified the combined marker panel of five bacterial species, seven serum biomarkers, and three clinical parameters could differentiate patients with UDM from HCs with an AUC of 0.94 (95% CI 0.85-1). Notably, the gut microbiota structure of patients with unclassified diabetes resembled that of type 2 diabetes patients, especially regarding disrupted lipid and branched-chain amino acid metabolism.CONCLUSIONS: Despite sharing certain metabolic features with type 2 diabetes, unclassified diabetes presents unique features. The distinct microbiota and metabolites in unclassified diabetes patients suggest a significant role in modulating glucose, lipid, and amino acid metabolism, potentially influencing disease progression. Further longitudinal studies are essential to explore therapeutic strategies targeting the gut microbiota and metabolites to modify the disease trajectory.PMID:39588334 | PMC:PMC11586653 | DOI:10.3389/fendo.2024.1440984

Front Vet Sci. 2024 Nov 11;11:1449141. doi: 10.3389/fvets.2024.1449141. eCollection 2024.ABSTRACTLocally produced fish hydrolysate and oil from the agrifood sector comprises a sustainable solution both to the problem of fish waste disposal and to the petfood sector with potential benefits for the animal's health. This study evaluated the effects of the dietary replacement of mainly imported shrimp hydrolysate (5%) and salmon oil (3%; control diet) with locally produced fish hydrolysate (5%) and oil (3.2%) obtained from fish waste (experimental diet) on systemic inflammation markers, adipokines levels, cardiac function and fecal microbiota of adult dogs. Samples and measurements were taken from a feeding trial conducted according to a crossover design with two diets (control and experimental diets), six adult Beagle dogs per diet and two periods of 6 weeks each. The experimental diet, with higher docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids contents, decreased plasmatic triglycerides and the activity of angiotensin converting enzyme, also tending to decrease total cholesterol. No effects of diet were observed on serum levels of the pro-inflammatory cytokines interleukin (IL)-1β, IL-8, and IL-12/IL-23 p40, and of the serum levels of the anti-inflammatory adipokine adiponectin. Blood pressure, heart rate and echocardiographic measurements were similar between diets with the only exception of left atrial to aorta diameter ratio that was higher in dogs fed the experimental diet, but without clinical relevance. Diet did not significantly affect fecal immunoglobulin A concentration. Regarding fecal microbiome, Megasphaera was the most abundant genus, followed by Bifidobacterium, Fusobacterium, and Prevotella, being the relative abundances of Fusobacterium and Ileibacterium genera positively affected by the experimental diet. Overall, results from the performed short term trial suggest that shrimp hydrolysate and salmon oil can be replaced by protein hydrolysate and oil from fish by-products without affecting systemic inflammatory markers, cardiac structure and function, but potentially benefiting bacterial genera associated with healthy microbiome. Considering the high DHA and EPA contents and the antioxidant properties of fish oil and hydrolysate, it would be worthwhile in the future to assess their long-term effects on inflammatory markers and their role in spontaneous canine cardiac diseases and to perform metabolomic and metagenomics analysis to elucidate the relevance of microbiota changes in the gut.PMID:39588199 | PMC:PMC11586376 | DOI:10.3389/fvets.2024.1449141

Front Microbiol. 2024 Nov 11;15:1490064. doi: 10.3389/fmicb.2024.1490064. eCollection 2024.ABSTRACTINTRODUCTION: L-arginine is an α-amino acid and a semi-essential nutrient of significant biological interest. It plays a role in influencing various aspects of animal meat traits, gut microbiota composition, and physiological metabolism.METHODS: This study aimed to investigate the combined effects of L-arginine supplementation on gut microbiota composition and the metabolism of the longissimus dorsi muscle in fattening pigs. Eighteen Yorkshire commercial pigs were divided into two groups: a control group that received no supplements and a treatment group that was given 1% L-arginine for 52 days. The diversity and composition of microorganisms in the feces of the control (NC) and L-arginine (Arg) groups were analyzed by sequencing the 16S rRNA V3 -V4 region of the bacterial genome.RESULTS: The findings indicated that L-arginine supplementation increased both the abundance and diversity of gut microbiota, particularly affecting the Firmicutes and Bacteroidetes phyla. KEGG enrichment analysis revealed significant changes in several metabolism-related pathways, including amino acid, carbohydrate, and lipid metabolism. Metabolomic analysis identified 85 differential metabolites between the arginine and control groups, with phospholipids ranking among the top 20. Additionally, functional predictions indicated an increased abundance in the glycerophospholipid metabolism pathway. Correlation analysis linked changes in gut microbiota to phospholipid levels, which subsequently influenced post-slaughter meat color and drip loss.DISCUSSION: These results suggest that L-arginine supplementation positively impacts gut microbiota composition and the metabolic profile of the longissimus dorsi muscle in fattening pigs, with potential implications for meat quality.PMID:39588104 | PMC:PMC11586382 | DOI:10.3389/fmicb.2024.1490064

Adv Sci (Weinh). 2024 Nov 26:e2411559. doi: 10.1002/advs.202411559. Online ahead of print.ABSTRACTHigh-magnitude cyclic stretch from arterial blood pressure significantly contributes to the excessive proliferation and migration of vascular smooth muscle cells (VSMCs), leading to neointima formation in vein grafts. However, the molecular mechanisms remain unclear. This study highlights the critical role of cytosolic Phospholipase A2 (cPLA2)/ Yin Yang 1 (YY1)/ carnitine palmitoyltransferase 1b (CPT1B) signaling in coordinating VSMC mechanical activation by inhibiting fatty acid β-oxidation. Metabolomic analysis showed that a 15%-1 Hz arterial cyclic stretch, compared to a 5%-1 Hz venous stretch, increased long-chain fatty acids in VSMCs. cPLA2, identified as a mechanoresponsive molecule, produces excessive arachidonic acid (ArAc) under the 15%-1 Hz stretch, inhibiting CPT1B expression, a key enzyme in fatty acid β-oxidation. ArAc promotes transcription factor YY1 degradation, downregulating CPT1B. Inadequate fatty acid oxidation caused by knockdown of CPT1B or YY1, or etomoxir treatment, increased nuclear membrane tension, orchestrating the activation of cPLA2. Overexpressing CPT1B or inhibiting cPLA2 reduced VSMC proliferation and migration in vein grafts, decreasing neointimal hyperplasia. This study uncovers a novel mechanism in lipid metabolic reprogramming in vein grafts, suggesting a new therapeutic target for vein graft hyperplasia.PMID:39587975 | DOI:10.1002/advs.202411559

J Nanobiotechnology. 2024 Nov 26;22(1):732. doi: 10.1186/s12951-024-02976-6.ABSTRACTBACKGROUND: Recent years, exosomes have been increasing used to treat diseases, but there is little research on how exosomes affect the metabolism of the body after entering. Therefore, in this study, we discussed the changes of metabolic spectrum and determined the differentially expressed metabolites in the serum of cynomolgus monkeys after injecting exosomes. Six cynomolgus monkeys were divided into control group and exosomes group. After intravenous injection of exosomes, the peripheral blood serum of cynomolgus monkeys was collected at baseline, day 1, day 7 and day 14 respectively. An ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry-based non-targeted metabolomics platform was used to detect the metabolites. The metabolic spectra of two groups of cynomolgus monkeys were identified and compared, and the time series changes of metabolites in exosomes were described.RESULTS: The results showed that there was significant difference in metabolic spectrum between the two groups. 45, 114, 49, 39 differentially expressed metabolites were identified in baseline, day 1, day 7, and day 14, respectively. 6-hydroxydopamine, a metabolite related to the regulation of nerve function, was also found. Tryptophan metabolism, choline metabolism in cancer, porphyrin and chlorophyll metabolism were involved in day 1. Sphingolipid metabolism and histidine metabolism were involved in day 7. Three pathways, including choline metabolism, sphingolipid metabolism and biotin metabolism in cancer were involved in day 14. Through time series analysis, it was found that the level of propionylcarnitine and biliverdin increased on day 1 after inoculation with exosomes, while the level of hippuric acid decreased. These changes of immune-related metabolites suggested that exosomes might participate in the immunoregulation reaction after entering the body of cynomolgus monkeys.CONCLUSIONS: In our current study, we found that exosomes injected intravenously affect the changes of metabolites and metabolic pathways in cynomolgus monkeys. Intravenous injection of exosomes may affect the metabolite 6-hydroxydopamine, sphingolipid metabolic pathway, and choline metabolic in cancer pathway, which is of some significance for the treatment of Parkinson's disease. In addition, exosomes may also affect the immune-related metabolites in vivo, such as propionylcarnitine, biliverdin, hippuric acid metabolites, as well as tryptophan metabolism pathway, sphingolipid metabolism pathway involved in immune regulation, which is of great significance for the future study of immune-regulatory mechanisms of exosomes.PMID:39587650 | DOI:10.1186/s12951-024-02976-6

Biol Direct. 2024 Nov 26;19(1):121. doi: 10.1186/s13062-024-00526-6.ABSTRACTBACKGROUND: Preeclampsia (PE) is a severe pregnancy complication characterized by complex molecular interactions. Understanding these interactions is crucial for developing effective therapeutic strategies.METHODS: This study applies a pharmacometabolomics approach to explore the roles of miR-155 and PKG1 in PE, focusing on the regulatory influence of the NF-κB signaling pathway. Blood metabolomic profiles were analyzed, and bioinformatics tools, IHC staining, Western blot (WB) analysis, and immunofluorescence (IF) localization were employed to determine the expression and function of miR-155 and PKG1. Cell invasion, migration, proliferation, and apoptosis assays were conducted to assess miR-155's modulation of PKG1. Additionally, RT-qPCR and WB analysis elucidated NF-κB-mediated regulation mechanisms.RESULTS: Our findings indicate significant metabolic alterations associated with miR-155 modulation of PKG1, with NF-κB acting as a critical upstream regulator. The study demonstrates that miR-155 affects cellular functions such as invasion, migration, proliferation, and apoptosis through PKG1 modulation. Furthermore, the NF-κB signaling pathway regulates miR-155 expression, contributing to the pathological processes of PE.CONCLUSION: This study provides a proof of concept for using pharmacometabolomics to understand the molecular mechanisms of PE, suggesting new therapeutic targets and advancing personalized medicine approaches. These insights highlight the potential of pharmacometabolomics to complement genomic and transcriptional data in disease characterization and treatment strategies, offering new avenues for therapeutic intervention in PE.PMID:39587640 | DOI:10.1186/s13062-024-00526-6

J Exp Clin Cancer Res. 2024 Nov 26;43(1):310. doi: 10.1186/s13046-024-03232-3.ABSTRACTBACKGROUND: Approximately half of all human cancers harbour mutations in the p53 gene, leading to the generation of neomorphic p53 mutant proteins. These mutants can exert gain-of-function (GOF) effects, potentially promoting tumour progression. However, the clinical significance of p53 GOF mutations, as well as the selectivity of individual variants, remains controversial and unclear.METHODS: To elucidate the metabolic regulations and molecular underpinnings associated with the specific p53R270H and p53R172H mutant variants (the mouse equivalents of human p53R273H and p53R175H, respectively), we employed a comprehensive approach. This included integrating global metabolomic analysis with epigenomic and transcriptomic profiling in mouse pancreatic cancer cells. Additionally, we assessed metabolic parameters such as oxygen consumption rate and conducted analyses of proliferation and cell-cell competition to validate the biological impact of metabolic changes on pancreatic ductal adenocarcinoma (PDAC) phenotype. Our findings were further corroborated through analysis of clinical datasets from human cancer cohorts.RESULTS: Our investigation revealed that the p53R270H variant, but not p53R172H, sustains mitochondrial function and energy production while also influencing cellular antioxidant capacity. Conversely, p53R172H, while not affecting mitochondrial metabolism, attenuates the activation of pro-tumorigenic metabolic pathways such as the urea cycle. Thus, the two variants selectively control different metabolic pathways in pancreatic cancer cells. Mechanistically, p53R270H induces alterations in the expression of genes associated with oxidative stress and reduction in mitochondrial respiration. In contrast, p53R172H specifically impacts the expression levels of enzymes involved in the urea metabolism. However, our analysis of cell proliferation and cell competition suggested that the expression of either p53R270H or p53R172H does not influence confer any selective advantage to this cellular model in vitro. Furthermore, assessment of mitochondrial priming indicated that the p53R270H-driven mitochondrial effect does not alter cytochrome c release or the apoptotic propensity of pancreatic cancer cells.CONCLUSIONS: Our study elucidates the mutant-specific impact of p53R270H and p53R172H on metabolism of PDAC cancer cells, highlighting the need to shift from viewing p53 mutant variants as a homogeneous group of entities to a systematic assessment of each specific p53 mutant protein. Moreover, our finding underscores the importance of further exploring the significance of p53 mutant proteins using models that more accurately reflect tumor ecology.PMID:39587609 | DOI:10.1186/s13046-024-03232-3

BMC Pregnancy Childbirth. 2024 Nov 25;24(1):783. doi: 10.1186/s12884-024-06974-2.ABSTRACTBACKGROUND: Preterm birth (PTB) is a serious health problem. PTB complications is the main cause of death in infants under five years of age worldwide. The ability to accurately predict risk for PTB during early pregnancy would allow early monitoring and interventions to provide personalized care, and hence improve outcomes for the mother and infant.OBJECTIVE: This study aims to predict the risks of early preterm (< 35 weeks of gestation) or very early preterm (≤ 26 weeks of gestation) deliveries by using high-resolution maternal urinary metabolomic profiling in early pregnancy.DESIGN: A retrospective cohort study was conducted by two independent preterm and term cohorts using high-density weekly urine sampling. Maternal urine was collected serially at gestational weeks 8 to 24. Global metabolomics approaches were used to profile urine samples with high-resolution mass spectrometry. The significant features associated with preterm outcomes were selected by Gini Importance. Metabolite biomarker identification was performed by liquid chromatography tandem mass spectrometry (LCMS-MS). XGBoost models were developed to predict early or very early preterm delivery risk.SETTING AND PARTICIPANTS: The urine samples included 329 samples from 30 subjects at Stanford University, CA for model development, and 156 samples from 24 subjects at the University of Alabama, Birmingham, AL for validation.RESULTS: 12 metabolites associated with PTB were selected and identified for modelling among 7,913 metabolic features in serial-collected urine samples of pregnant women. The model to predict early PTB was developed using a set of 12 metabolites that resulted in the area under the receiver operating characteristic (AUROCs) of 0.995 (95% CI: [0.992, 0.995]) and 0.964 (95% CI: [0.937, 0.964]), and sensitivities of 100% and 97.4% during development and validation testing, respectively. Using the same metabolites, the very early PTB prediction model achieved AUROCs of 0.950 (95% CI: [0.878, 0.950]) and 0.830 (95% CI: [0.687, 0.826]), and sensitivities of 95.0% and 60.0% during development and validation, respectively.CONCLUSION: Models for predicting risk of early or very early preterm deliveries were developed and tested using metabolic profiling during the 1st and 2nd trimesters of pregnancy. With patient validation studies, risk prediction models may be used to identify at-risk pregnancies prompting alterations in clinical care, and to gain biological insights of preterm birth.PMID:39587571 | DOI:10.1186/s12884-024-06974-2

Sci Rep. 2024 Nov 25;14(1):29140. doi: 10.1038/s41598-024-80862-9.ABSTRACTThe present preliminary study aimed to provide a targeted lipidomic analysis of Hashimoto (HT) and non-HT patients with well-controlled hypothyroidism as well as in healthy adults, and is the first to demonstrate the association of several components of the human lipidome with hypothyroidism in relation to the total plasma selenium content. All the patients and age-, sex-, and BMI-matched healthy controls met the very strict qualification criteria. Se levels were analyzed by ICP-MS, and lipidome studies were conducted using TQ-LC/MS. The 40 acylcarnitines, 90 glycerophospholipids, and 15 sphingomyelins were identified and quantified. PCaaC26:0 and PCaaC40:1 were negatively correlated with Se concentrations. Other lipids that were negatively correlated with Se concentrations but did not present significant differences between the three groups in the Kruskal-Wallis ANOVA test were PCaaC32:0, PCaeC30:0, PCaeC36:5, SMC18:0, and SM C18:1. In the multiple linear regression analyses, Se levels showed negative relationship, whereas different phosphatidylcholines: PCaaC24:0, PCaaC26:0, PCaeC30:1, PCaeC34:0, PCaeC36:4, PCaeC42:0 were positively associated with the presence of (H). Different lipidome components were identified in healthy and hypothyroid patients regardless of the cause of that condition. Studies on larger populations are needed to determine cause-and-effect relations and the potential mechanisms underlying these associations.PMID:39587337 | DOI:10.1038/s41598-024-80862-9

Commun Biol. 2024 Nov 25;7(1):1565. doi: 10.1038/s42003-024-07083-8.ABSTRACTLactic acid bacteria metabolism affects the composition of volatile organic compounds (VOCs) in alfalfa silage, which results in differences of odor and quality. The aim of this study was to reveal the effects of commercial Lactobacillus plantarum (CL), screened Lactobacillus plantarum (LP), and screened Pediococcus pentosaceus (PP) on quality, microbial community, and VOCs of alfalfa silage based on volatile metabolomics and metagenomics. The results showed that the LP and PP groups had higher sensory and quality grades, and the dominant bacteria were Lactiplantibacillus plantarum and Pediococcus pentosaceus. The main VOCs in alfalfa silage were terpenoids (25.29%), esters (17.08%), and heterocyclic compounds (14.43%), and esters such as methyl benzoate, ethyl benzoate, and ethyl salicylate were significantly increased in the LP and PP groups (P < 0.05). Correlation analysis showed that terpenoids, esters, and alcohols with aromatic odors were positively correlated with Lactiplantibacillus plantarum and Pediococcus pentosaceus. Microbial functions in carbohydrate and amino acid metabolism, biosynthesis of secondary metabolites, and degradation of aromatic compounds were significantly enriched. In conclusion, the addition of lactic acid bacteria can increase the aromatic substances in silage and further improve silage odor and quality.PMID:39587335 | DOI:10.1038/s42003-024-07083-8

Sci Rep. 2024 Nov 25;14(1):29180. doi: 10.1038/s41598-024-80701-x.ABSTRACTFeed restriction is a common nutritional practice in rabbit farming; however, decreased feed intake can also signal potential digestive disorders at an early stage. This study endeavors to investigate the impact of feed restriction on selected productive traits and the urinary metabolome of juvenile rabbits across diverse genetic backgrounds. Our objective is to identify potential biomarkers capable of detecting periods of fasting. A total of 48 growing rabbits were used from two genetic types: Prat line (selected for litter size at weaning, n = 24) and Caldes line (selected for post-weaning growth rate, n = 24). At 60 days of age, a digestibility trial was carried out. Changes in productive traits (through bioelectrical impedance analysis, live weight control, average daily gain, energy, and protein retention) were evaluated when the animals were fed ad libitum from 60 to 64 days of age and when the same animals were subjected to feed restriction (50% of maintenance energy requirements) from 70 to 74 days of age, in a split-plot trial. In addition, untargeted urine metabolomics analysis was performed at both periods (ad libitum vs. restricted). Although some differences between genetic lines were observed in the animals' performance traits (average daily gain and retention of energy and protein), no differences in the urine metabolome were found between genetic types. However, feed restriction caused notable changes in the metabolome. When the animals were subjected to feed restriction, they had higher levels of ascorbic acid (P = 0.001) and p-cresol sulphate (P = 0.058) and lower levels of pyrocatechol sulphate/hydroquinone sulphate (P < 0.001), resorcinol sulphate (P = 0.002), enterolactone sulphate (P < 0.001), enterolactone (P < 0.001), kynurenic acid (P = 0.0002), proline betaine (P < 0.001), pipecolic acid betaine (P < 0.001), xanthurenic acid (P < 0.001) and quinaldic acid (P < 0.001) than the same animals when they were fed ad libitum. This study proposes urine ascorbic acid as potential biomarker for fasting events in rabbits. As urine ascorbic acid is the sole metabolite that significantly increases in the restricted group, it offers promising indicator for early detection and targeted management of digestive disorders in rabbits.PMID:39587239 | DOI:10.1038/s41598-024-80701-x

Cell Discov. 2024 Nov 26;10(1):117. doi: 10.1038/s41421-024-00746-0.ABSTRACTAs a critical component of the tumour immune microenvironment (TIME), the resident microbiota promotes tumorigenesis across a variety of cancer types. Here, we integrated multiple types of omics data, including microbiome, transcriptome, and metabolome data, to investigate the functional role of intratumoral bacteria in gastric cancer (GC). The microbiome was used to categorize GC samples into six subtypes, and patients with a high abundance of Streptococcus or Pseudomonas had a markedly worse prognosis. Further assays revealed that Streptococcus anginosus (SA) promoted tumour cell proliferation and metastasis while suppressing the differentiation and infiltration of CD8+ T cells. However, antibiotic treatment significantly suppressed tumorigenesis in SA+ mice in vivo. We further demonstrated that the SA arginine pathway increased the abundance of ornithine, which may be a major contributor to reshaping of the TIME. Our findings demonstrated that SA, a novel risk factor, plays significant roles in the initiation and progression of GC, suggesting that SA might be a promising target for the diagnosis and treatment of GC.PMID:39587089 | DOI:10.1038/s41421-024-00746-0