PubMed

Int J Legal Med. 2023 Jul 4. doi: 10.1007/s00414-023-03050-w. Online ahead of print.ABSTRACTINTRODUCTION: Due to its peculiar anatomy and physiology, the pericardial fluid is a biological matrix of particular interest in the forensic field. Despite this, the available literature has mainly focused on post-mortem biochemistry and forensic toxicology, while to the best of authors' knowledge post-mortem metabolomics has never been applied. Similarly, estimation of the time since death or post-mortem interval based on pericardial fluids has still rarely been attempted.OBJECTIVES: We applied a metabolomic approach based on 1H nuclear magnetic resonance spectroscopy to ascertain the feasibility of monitoring post-mortem metabolite changes on human pericardial fluids with the aim of building a multivariate regression model for post-mortem interval estimation.METHODS: Pericardial fluid samples were collected in 24 consecutive judicial autopsies, in a time frame ranging from 16 to 170 h after death. The only exclusion criterion was the quantitative and/or qualitative alteration of the sample. Two different extraction protocols were applied for low molecular weight metabolites selection, namely ultrafiltration and liquid-liquid extraction. Our metabolomic approach was based on the use of 1H nuclear magnetic resonance and multivariate statistical data analysis.RESULTS: The pericardial fluid samples treated with the two experimental protocols did not show significant differences in the distribution of the metabolites detected. A post-mortem interval estimation model based on 18 pericardial fluid samples was validated with an independent set of 6 samples, giving a prediction error of 33-34 h depending on the experimental protocol used. By narrowing the window to post-mortem intervals below 100 h, the prediction power of the model was significantly improved with an error of 13-15 h depending on the extraction protocol. Choline, glycine, ethanolamine, and hypoxanthine were the most relevant metabolites in the prediction model.CONCLUSION: The present study, although preliminary, shows that PF samples collected from a real forensic scenario represent a biofluid of interest for post-mortem metabolomics, with particular regard to the estimation of the time since death.PMID:37402012 | DOI:10.1007/s00414-023-03050-w

EMBO Rep. 2023 Jul 4:e57499. doi: 10.15252/embr.202357499. Online ahead of print.ABSTRACTAbnormal tau protein impairs mitochondrial function, including transport, dynamics, and bioenergetics. Mitochondria interact with the endoplasmic reticulum (ER) via mitochondria-associated ER membranes (MAMs), which coordinate and modulate many cellular functions, including mitochondrial cholesterol metabolism. Here, we show that abnormal tau loosens the association between the ER and mitochondria in vivo and in vitro. Especially, ER-mitochondria interactions via vesicle-associated membrane protein-associated protein (VAPB)-protein tyrosine phosphatase-interacting protein 51 (PTPIP51) are decreased in the presence of abnormal tau. Disruption of MAMs in cells with abnormal tau alters the levels of mitochondrial cholesterol and pregnenolone, indicating that conversion of cholesterol into pregnenolone is impaired. Opposite effects are observed in the absence of tau. Besides, targeted metabolomics reveals overall alterations in cholesterol-related metabolites by tau. The inhibition of GSK3β decreases abnormal tau hyperphosphorylation and increases VAPB-PTPIP51 interactions, restoring mitochondrial cholesterol and pregnenolone levels. This study is the first to highlight a link between tau-induced impairments in the ER-mitochondria interaction and cholesterol metabolism.PMID:37401859 | DOI:10.15252/embr.202357499

Acta Physiol (Oxf). 2023 Jul 4:e14018. doi: 10.1111/apha.14018. Online ahead of print.ABSTRACTAIM: Under hypobaric hypoxia (HH), the heart triggers various defense mechanisms including metabolic remodeling against lack of oxygen. Mitofusin 2 (MFN2), located at the mitochondrial outer membrane, is closely involved in the regulation of mitochondrial fusion and cell metabolism. To date, however, the role of MFN2 in cardiac response to HH has not been explored.METHODS: Loss- and gain-of-function approaches were used to investigate the role of MFN2 in cardiac response to HH. In vitro, the function of MFN2 in the contraction of primary neonatal rat cardiomyocytes under hypoxia was examined. Non-targeted metabolomics and mitochondrial respiration analyses, as well as functional experiments were performed to explore underlying molecular mechanisms.RESULTS: Our data demonstrated that, following 4 weeks of HH, cardiac-specific MFN2 knockout (MFN2 cKO) mice exhibited significantly better cardiac function than control mice. Moreover, restoring the expression of MFN2 clearly inhibited the cardiac response to HH in MFN2 cKO mice. Importantly, MFN2 knockout significantly improved cardiac metabolic reprogramming during HH, resulting in reduced capacity for fatty acid oxidation (FAO) and oxidative phosphorylation, and increased glycolysis and ATP production. In vitro data showed that down-regulation of MFN2 promoted cardiomyocyte contractility under hypoxia. Interestingly, increased FAO through palmitate treatment decreased contractility of cardiomyocyte with MFN2 knockdown under hypoxia. Furthermore, treatment with mdivi-1, an inhibitor of mitochondrial fission, disrupted HH-induced metabolic reprogramming and subsequently promoted cardiac dysfunction in MFN2-knockout hearts.CONCLUSION: Our findings provide the first evidence that down-regulation of MFN2 preserves cardiac function in chronic HH by promoting cardiac metabolic reprogramming.PMID:37401731 | DOI:10.1111/apha.14018

Food Funct. 2023 Jul 4. doi: 10.1039/d3fo01831h. Online ahead of print.ABSTRACTHigh-fat diet (HFD) increases the risk of developing malignant tumors. Ionizing radiation (IR) is used as an adjuvant treatment in oncology. In this study, we investigated the effects of an 8-week 35% fat HFD on the tolerance to IR and the modulatory effect of melatonin (MLT). The results of lethal dose irradiation survival experiments revealed that the 8-week HFD altered the radiation tolerance of female mice and increased their radiosensitivity, whereas it had no comparable effects on males. Pre-treatment with MLT was, however, found to attenuate the radiation-induced hematopoietic damage in mice, promote intestinal structural repair after whole abdominal irradiation (WAI), and enhance the regeneration of Lgr5+ intestinal stem cells. 16S rRNA high-throughput sequencing and untargeted metabolome analyses revealed that HFD consumption and WAI sex-specifically altered the composition of intestinal microbiota and fecal metabolites and that MLT supplementation differentially modulated the composition of the intestinal microflora in mice. However, in both males and females, different bacteria were associated with the modulation of the metabolite 5-methoxytryptamine. Collectively, the findings indicate that MLT ameliorates the radiation-induced damage and sex-specifically shapes the composition of the gut microbiota and metabolites, protecting mice from the adverse side effects associated with HFD and IR.PMID:37401725 | DOI:10.1039/d3fo01831h

Int Neurourol J. 2023 Jun;27(2):88-98. doi: 10.5213/inj.2346068.034. Epub 2023 Jun 30.ABSTRACTPURPOSE: The main treatment options of neurogenic bladder remains catheterization and long-term oral medications. Metabolic interventions have shown good therapeutic results in many diseases. To date, no studies have characterized the metabolites of the detrusor muscle during neurogenic bladder. Using metabolomics, new muscle metabolomic signatures were identified to reveal the temporal metabolic profile of muscle during disease progression.METHODS: We used 42 Sprague-Dawley rats (200±20 g, males) for T10 segmental spinal cord injury modeling and collected detrusor tissue and performed nontargeted metabolomics after sham surgery, 30-minute, 6-hour, 12-hour, 24-hour, 5-day, and 2-week postmodelling, to identify the dysregulated metabolic pathways and key metabolites.RESULTS: By comparing mzCloud, mzVault, MassList, we identified a total of 1,271 metabolites and enriched a total of 12 metabolism-related pathways with significant differences (P<0.05) based on Kyoto Encyclopedia of Genes and Genomes analysis. Metabolites in several differential metabolic pathways such as ascorbate and aldarate metabolism, Steroid hormone biosynthesis, and carbon metabolism are altered in a regular manner before and after ridge shock.CONCLUSION: Our study is the first time-based metabolomic study of rat forced urinary muscle after traumatic spinal cord injury, and we identified multiple differential metabolic pathways during injury that may improve long-term management strategies for neurogenic bladder and reduce costs in long-term treatment.PMID:37401019 | DOI:10.5213/inj.2346068.034

Gut Microbes. 2023 Jan-Dec;15(1):2229945. doi: 10.1080/19490976.2023.2229945.ABSTRACTInflammatory bowel disease (IBD) is a multifactorial disease with increasing incidence in the U.S. suggesting that environmental factors, including diet, are involved. It has been suggested that excessive consumption of linoleic acid (LA, C18:2 omega-6), which must be obtained from the diet, may promote the development of IBD in humans. To demonstrate a causal link between LA and IBD, we show that a high fat diet (HFD) based on soybean oil (SO), which is comprised of ~55% LA, increases susceptibility to colitis in several models, including IBD-susceptible IL10 knockout mice. This effect was not observed with low-LA HFDs derived from genetically modified soybean oil or olive oil. The conventional SO HFD causes classical IBD symptoms including immune dysfunction, increased intestinal epithelial barrier permeability, and disruption of the balance of isoforms from the IBD susceptibility gene Hepatocyte Nuclear Factor 4α (HNF4α). The SO HFD causes gut dysbiosis, including increased abundance of an endogenous adherent invasive Escherichia coli (AIEC), which can use LA as a carbon source. Metabolomic analysis shows that in the mouse gut, even in the absence of bacteria, the presence of soybean oil increases levels of LA, oxylipins and prostaglandins. Many compounds in the endocannabinoid system, which are protective against IBD, are decreased by SO both in vivo and in vitro. These results indicate that a high LA diet increases susceptibility to colitis via microbial and host-initiated pathways involving alterations in the balance of bioactive metabolites of omega-6 and omega-3 polyunsaturated fatty acids, as well as HNF4α isoforms.PMID:37400966 | DOI:10.1080/19490976.2023.2229945

BMJ Open. 2023 Jul 3;13(7):e070431. doi: 10.1136/bmjopen-2022-070431.ABSTRACTINTRODUCTION: The prevalence of non-alcoholic fatty liver disease (NAFLD) ranges from 25% in the general population to 90% in patients with obesity scheduled for bariatric surgery. NAFLD can progress towards non-alcoholic steatohepatitis (NASH) associated with complications such as cirrhosis, hepatocellular carcinoma and cardiovascular disease. To date, losing weight and lifestyle modifications are the best known treatments for NASH. Bariatric surgery significantly improves NAFLD/NASH in the short term. However, the extent of this improvement is not yet clear and long-term data on the natural course of NAFLD/NASH after bariatric surgery are lacking. The factors involved in NAFLD/NASH regression after bariatric surgery have not been elucidated.METHODS AND ANALYSIS: This is an observational prospective cohort study including patients scheduled for bariatric surgery. Extensive metabolic and cardiovascular analyses will be carried out including measurements of carotid intima media thickness and pulse wave velocity. Genomic, proteomic, lipidomic and metabolomic studies will be done. Microbioma analyses before and 1 year after surgery will be done. Transient elastography measurements will be performed before and at 1, 3 and 5 years after surgery. For those with an elevated preoperative transient elastography measurement by Fibroscan, a laparoscopic liver biopsy will be performed during surgery. Primary outcome measures are the change of steatosis and liver fibrosis 5 years after surgery. Secondary outcome measure is the comparison of the transient elastography measurements with the NAFLD Activity Score from the biopsies.ETHICS AND DISSEMINATION: The protocol has been approved by the Medical Research Ethics Committees United, Nieuwegein, on 1 March 2022 (registration code R21.103/NL79423.100.21). The study results will be submitted for publication in peer-reviewed journals and data will be presented at scientific meetings.TRIAL REGISTRATION NUMBER: NCT05499949.PMID:37400234 | DOI:10.1136/bmjopen-2022-070431

Sci Total Environ. 2023 Jul 1:165260. doi: 10.1016/j.scitotenv.2023.165260. Online ahead of print.ABSTRACTPFAS contamination of urban waters is widespread but understanding the biological impact of its accumulation is limited to humans and common ecotoxicological model organisms. Here, we combine PFAS exposure and bioaccumulation patterns with whole organism responses and omics-based ecosurveillance methods to investigate the potential impacts of PFAS on a wetland top predator, the tiger snake (Notechis scutatus). Tiger snakes (18 male and 17 female) were collected from four wetlands with varying PFAS chemical profiles and concentrations in Perth, Western Australia. Tiger snake livers were tested for 28 known PFAS compounds, and Σ28PFAS in liver tissues ranged between 322 ± 193 μg/kg at the most contaminated site to 1.31 ± 0.86 μg/kg at the least contaminated site. The dominant PFAS compound detected in liver tissues was PFOS. Lower body condition was associated with higher liver PFAS, and male snakes showed signs of high bioaccumulation whereas females showed signs of maternal offloading. Biochemical profiles of snake muscle, fat (adipose tissue), and gonads were analysed using a combination of liquid chromatography triple quadrupole (QqQ) and quadrupole time-of-flight (QToF) mass spectrometry methodologies. Elevated PFAS was associated with enriched energy production and maintenance pathways in the muscle, and had weak associations with energy-related lipids in the fat tissue, and lipids associated with cellular genesis and spermatogenesis in the gonads. These data demonstrate the bioavailability of urban wetland PFAS in higher-order reptilian predators and suggest a negative impact on snake health and metabolic processes. This research contributes to our understanding of the impact of PFAS residue on wildlife health which can be used for improved risk management and regulation. Thus, expanding the use of omics-based ecosurveillance tools for informing mechanistic toxicology.PMID:37400030 | DOI:10.1016/j.scitotenv.2023.165260

Int J Biol Macromol. 2023 Jul 1:125661. doi: 10.1016/j.ijbiomac.2023.125661. Online ahead of print.ABSTRACTParamylon (β-1,3-glucan) produced by Euglena gracilis displays antioxidant, antitumor, and hypolipidaemic functions. The biological properties of paramylon production by E. gracilis can be understood by elucidating the metabolic changes within the algae. In this study, the carbon sources in AF-6 medium were replaced with glucose, sodium acetate, glycerol, or ethanol, and the paramylon yield was measured. Adding 0.1260 g/L glucose to the culture medium resulted in the highest paramylon yield of 70.48 %. The changes in metabolic pathways in E. gracilis grown on glucose were assessed via non-targeted metabolomics analysis using ultra-high-performance liquid chromatography coupled to high-resolution quadrupole-Orbitrap mass spectrometry. We found that glucose, as a carbon source, regulated some differentially expressed metabolites, including l-glutamic acid, γ-aminobutyric acid (GABA), and l-aspartic acid. Pathway analysis using the Kyoto Encyclopedia of Genes and Genomes further showed that glucose regulated the carbon and nitrogen balance through the GABA shunt, which enhanced photosynthesis, regulated the flux of carbon and nitrogen into the tricarboxylic acid cycle, promoted glucose uptake, and increased the accumulation of paramylon. This study provides new insights into E. gracilis metabolism during paramylon synthesis.PMID:37399871 | DOI:10.1016/j.ijbiomac.2023.125661

Environ Int. 2023 Jun 28;178:108073. doi: 10.1016/j.envint.2023.108073. Online ahead of print.ABSTRACTWearing masks is used as an effective way to prevent the spread of viruses. However, the effect of wearing masks on skin health requires further assessment. In this study, a non-invasive D-squame sampling method coupled with an untargeted metabolomics analysis by liquid chromatography high-resolution mass spectrometry was developed to identify the changes in the skin metabolome caused by wearing masks. D-squame method was found to have advantages over the commonly used sterile gauze method, especially for the lipids and lipid-like molecules. A total of 356 skin metabolites were putatively identified from the stratum corneum of 10 volunteers, and 17 differential metabolites were significantly downregulated after wearing surgical masks or N95 respirators. The downregulation of metabolites such as phosphatidylethanolamine and sphingomyelin might be related to hypoxia or increased skin moisture caused by wearing masks. Changes in skin metabolomics indicated a potential risk of skin barrier disruption and skin inflammation. Intermittent removal of the masks can effectively alleviate changes in the skin metabolome.PMID:37399768 | DOI:10.1016/j.envint.2023.108073

ISME Commun. 2023 Jul 3;3(1):67. doi: 10.1038/s43705-023-00275-z.ABSTRACTWhile biodegradable polymers have received increased attention due to the recent marine plastic problem, few studies have compared microbiomes and their degradation processes among biodegradable polymers. In this study, we set up prompt evaluation systems for polymer degradation, allowing us to collect 418 microbiome and 125 metabolome samples to clarify the microbiome and metabolome differences according to degradation progress and polymer material (polycaprolactone [PCL], polybutylene succinate-co-adipate [PBSA], polybutylene succinate [PBS], polybutylene adipate-co-terephthalate [PBAT], and poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) [PHBH]). The microbial community compositions were converged to each polymer material, and the largest differences were observed between PHBH and other polymers. Such gaps were probably formed primarily by the presence of specific hydrolase genes (i.e., 3HB depolymerase, lipase, and cutinase) in the microorganisms. Time-series sampling suggested several steps for microbial succession: (1) initial microbes decrease abruptly after incubation starts; (2) microbes, including polymer degraders, increase soon after the start of incubation and show an intermediate peak; (3) microbes, including biofilm constructers, increase their abundance gradually. Metagenome prediction showed functional changes, where free-swimming microbes with flagella adhered stochastically onto the polymer, and certain microbes started to construct a biofilm. Our large-dataset-based results provide robust interpretations for biodegradable polymer degradation.PMID:37400632 | DOI:10.1038/s43705-023-00275-z

Fish Physiol Biochem. 2023 Jul 3. doi: 10.1007/s10695-023-01216-2. Online ahead of print.ABSTRACTThe aim of this study was to investigate the survival rate, biochemical indices, and metabolome changes of the large yellow croaker after 48 h of live transportation. Two hundred and forty large yellow croakers (body weight: 23.4 ± 5.3 g, total length: 12.2 ± 0.7 cm) were used in this experiment. The transport buckets were filled with fresh seawater and the parameters of the water were a temperature of 16 ± 0.5 °C and a dissolved oxygen content of 6.0-7.2 mg/L. Large yellow crokers were first divided to 0, 10, 20, and 30 mg/L MS-222 groups to observe the 12 h survival rate. The survival rate of 10 mg/L MS-222 group (T1) was the 95%, highest of all, and was further analyzed. The results of liver biochemical indices indicated inhibition of gluconeogenesis and pentose phosphate pathway metabolism. In addition, metabolomics analysis identified significantly differentially expressed metabolites between T1 group and 0 mg/L MS-222 control (C) groups. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) results revealed that the pathways of amino acid metabolism, especially the lysine, aspartate, and homoserine in the liver were significantly affected. In conclusion, the combination of metabolomics and liver biochemical assays provided a characterization of the response mechanism of L. crocea exposed to live transportation.PMID:37400602 | DOI:10.1007/s10695-023-01216-2

Adv Sci (Weinh). 2023 Jul 3:e2300569. doi: 10.1002/advs.202300569. Online ahead of print.ABSTRACTHarmful algal blooms (HABs), which are promoted by eutrophication and intensified by global warming, occur worldwide. Allelochemicals, which are natural chemicals derived from plants or microbes, are emerging weapons to eliminate these blooms. However, the cost and technical challenges have limited the discovery of novel antialgal allelochemicals. Herein, the decomposition of agricultural straws is manipulated by white-rot fungi and achieved elevated antialgal efficiency. The transcriptomic analysis reveals that nutrient limitation activated fungal decomposition. By using a comparative nontarget metabolomics approach, a new type of allelochemical sphingosines (including sphinganine, phytosphingosine, sphingosine, and N-acetylsphingosine) is identified. These novel natural algaecides exhibit superior antialgal capability, with as high as an order of magnitude lower effective concentration on blooming species than other prevalent allelochemicals. The co-expression relationship between transcriptomic and metabolomic results indicate that sphinganine is strongly correlated with the differentially expressed lignocellulose degradation unigenes. The algal growth suppression is triggered by the activation of programmed cell death, malfunction of algal photosystem and antioxidant system, the disruption on CO2 assimilation and light absorption. The sphingosines reported here are a new category of allelochemicals in addition to the well-known antialgal natural chemicals, which are potential species-specific agents for HABs control identified by multi-omics methodology.PMID:37400420 | DOI:10.1002/advs.202300569

Proc Natl Acad Sci U S A. 2023 Jul 11;120(28):e2301007120. doi: 10.1073/pnas.2301007120. Epub 2023 Jul 3.ABSTRACTWood-decaying fungi are the major decomposers of plant litter. Heavy sequencing efforts on genomes of wood-decaying fungi have recently been made due to the interest in their lignocellulolytic enzymes; however, most parts of their proteomes remain uncharted. We hypothesized that wood-decaying fungi would possess promiscuous enzymes for detoxifying antifungal phytochemicals remaining in the dead plant bodies, which can be useful biocatalysts. We designed a computational mass spectrometry-based untargeted metabolomics pipeline for the phenotyping of biotransformation and applied it to 264 fungal cultures supplemented with antifungal plant phenolics. The analysis identified the occurrence of diverse reactivities by the tested fungal species. Among those, we focused on O-xylosylation of multiple phenolics by one of the species tested, Lentinus brumalis. By integrating the metabolic phenotyping results with publicly available genome sequences and transcriptome analysis, a UDP-glycosyltransferase designated UGT66A1 was identified and validated as an enzyme catalyzing O-xylosylation with broad substrate specificity. We anticipate that our analytical workflow will accelerate the further characterization of fungal enzymes as promising biocatalysts.PMID:37399371 | DOI:10.1073/pnas.2301007120

J Agric Food Chem. 2023 Jul 3. doi: 10.1021/acs.jafc.3c02015. Online ahead of print.ABSTRACTCarambola is a tropical fruit that is highly sought after by consumers due to its unique flavor, star shape, and nutritional value. Enhancing the flavor quality of this fruit can increase the consumer acceptance and market demand. However, flavor is an intrinsic characteristic of fruits. Its decoding requires in-depth knowledge based on recognizing key biological pathways relevant to flavor formation and development. In this study, the volatile and non-volatile metabolites contributing to the flavor variation of five carambola cultivars were investigated by a novel strategy combining GC-MS/O-based volatilomics with LC-MS-based metabolomics. Several significant flavor-related pathways, involving biosynthesis or metabolism of amino acids, terpenoids, fatty acids, sugar and organic acid, and flavonoids were identified based on the enrichment analysis of important volatile and non-volatile metabolites. The results indicated that there were metabolites in the flavor-related pathways being up- or downregulated, leading to the differences in flavor traits of different carambola cultivars. This study could provide a valuable reference for breeders and researchers of interest in the mechanisms underlying the regulation of flavor, which would ultimately lead to the creation of carambola cultivars with more attractive flavor profiles and pleasurable consuming experiences.PMID:37399281 | DOI:10.1021/acs.jafc.3c02015

Am J Physiol Regul Integr Comp Physiol. 2023 Jul 3. doi: 10.1152/ajpregu.00016.2023. Online ahead of print.ABSTRACTINTRODUCTION: Diet is considered a culprit for symptoms in irritable bowel syndrome (IBS), although mechanistic understanding of underlying causes is lacking. Metabolomics, i.e. the analysis of metabolites in biological samples may offer a diet-responsive fingerprint for IBS. Our aim was to explore alterations in the plasma metabolome after interventions with fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) or gluten versus control in IBS, and to relate such alterations to symptoms.METHODS: People with IBS (n=110) were included in a double-blind, randomized, crossover study with one-week provocations of FODMAPs, gluten or placebo. Symptoms were evaluated with the IBS severity scoring system (IBS-SSS). Untargeted metabolomics was performed on plasma samples using LC-qTOF-MS. Discovery of metabolite alterations by treatment was performed using random forest followed by linear mixed modelling. Associations were studied using Spearman correlation.RESULTS: The metabolome was affected by FODMAP (classification rate (CR) 0.88, p<0.0001), but less by gluten intake CR 0.72, p=0.01). FODMAP lowered bile acids, whereas phenolic-derived metabolites and 3-indolepropionic acid (IPA) were higher compared to placebo. IPA and some unidentified metabolites correlated weakly to abdominal pain and quality of life. Gluten affected lipid metabolism weakly, but with no interpretable relationship to IBS.CONCLUSIONS: FODMAP affected gut microbial-derived metabolites relating to positive health outcomes. IPA and unknown metabolites correlated weakly to IBS severity. Minor symptom worsening by FODMAP intake must be weighed against general positive health aspects of FODMAP. The gluten intervention affected lipid metabolism weakly with no interpretable association to IBS severity.REGISTRATION: www.CLINICALTRIALS: gov as NCT03653689.PMID:37399002 | DOI:10.1152/ajpregu.00016.2023

Front Physiol. 2023 Jun 14;14:1197224. doi: 10.3389/fphys.2023.1197224. eCollection 2023.ABSTRACTObjective: The purpose of this study was to employ metabolomics for the analysis of urine metabolites in swimmers, with the aim of establishing models for assessing their athletic status and competitive potential. Furthermore, the study sought to compare the identification efficacy of multi-component (urine and blood) model versus single-component (urine or blood) models, in order to determine the optimal approach for evaluating training and competitive status. Methods: A total of 187 Chinese professional swimmers, comprising 103 elite and 84 sub-elite level athletes, were selected as subjects for this study. Urine samples were obtained from each participant and subjected to nuclear magnetic resonance (NMR) metabolomics analysis. Significant urine metabolites were screened through multivariable logistic regression analysis, and an identification model was established. Based on the previously established model of blood metabolites, this study compared the discriminative and predictive performance of three models: either urine or blood metabolites model and urine + blood metabolites model. Results: Among 39 urine metabolites, 10 were found to be significantly associated with the athletic status of swimmers (p < 0.05). Of these, levels of 2-KC, cis-aconitate, formate, and LAC were higher in elite swimmers compared to sub-elite athletes, while levels of 3-HIV, creatinine, 3-HIB, hippurate, pseudouridine, and trigonelline were lower in elite swimmers. Notably, 2-KC and 3-HIB exhibited the most substantial differences. An identification model was developed to estimate physical performance and athletic level of swimmers while adjusting for different covariates and including 2-KC and 3-HIB. The urine metabolites model showed an area under the curve (AUC) of 0.852 (95% CI: 0.793-0.912) for discrimination. Among the three identification models tested, the combination of urine and blood metabolites showed the highest performance than either urine or blood metabolites, with an AUC of 0.925 (95% CI: 0.888-0.963). Conclusion: The two urine metabolites, 2-KC and 3-HIV, can serve as significant urine metabolic markers to establish a discrimination model for identifying the athletic status and competitive potential of Chinese elite swimmers. Combining two screened urine metabolites with four metabolites reported exhibiting significant differences in blood resulted in improved predictive performance compared to using urine metabolites alone. These findings indicate that combining blood and urine metabolites has a greater potential for identifying and predicting the athletic status and competitive potential of Chinese professional swimmers.PMID:37398904 | PMC:PMC10307620 | DOI:10.3389/fphys.2023.1197224

Front Immunol. 2023 Jun 15;14:1222662. doi: 10.3389/fimmu.2023.1222662. eCollection 2023.ABSTRACT[This corrects the article DOI: 10.3389/fimmu.2023.1135588.].PMID:37398675 | PMC:PMC10311434 | DOI:10.3389/fimmu.2023.1222662

medRxiv. 2023 Jun 21:2023.06.12.23291054. doi: 10.1101/2023.06.12.23291054. Preprint.ABSTRACTInvestigating the association of lipidome profiles with central Alzheimer's disease (AD) biomarkers, including amyloid/tau/neurodegeneration (A/T/N), can provide a holistic view between the lipidome and AD. We performed cross-sectional and longitudinal association analysis of serum lipidome profiles with AD biomarkers in the Alzheimer's Disease Neuroimaging Initiative cohort (N=1,395). We identified lipid species, classes, and network modules that were significantly associated with cross-sectional and longitudinal changes of A/T/N biomarkers for AD. Notably, we identified the lysoalkylphosphatidylcholine (LPC(O)) as associated with "A/N" biomarkers at baseline at lipid species, class, and module levels. Also, G M3 ganglioside showed significant association with baseline levels and longitudinal changes of the "N" biomarkers at species and class levels. Our study of circulating lipids and central AD biomarkers enabled identification of lipids that play potential roles in the cascade of AD pathogenesis. Our results suggest dysregulation of lipid metabolic pathways as precursors to AD development and progression.PMID:37398438 | PMC:PMC10312871 | DOI:10.1101/2023.06.12.23291054

bioRxiv. 2023 Jun 13:2023.06.13.544113. doi: 10.1101/2023.06.13.544113. Preprint.ABSTRACTThe highly conserved Rnf complex is important for energy conservation and ion transport in many bacteria, yet its potential role in bacterial virulence is poorly understood. Here, we illuminate the Rnf complex function in Fusobacterium nucleatum , a pathobiont of the human oral cavity that promotes many oral and extraoral diseases including periodontitis, preterm birth, and colorectal cancer. We show that the fusobacterial rnf locus, comprised of rnfCDGEAB genes, is functional and that the genetic disruption of the Rnf complex via non-polar, in-frame deletion of rnfC (Δ rnfC ) abrogates not only polymicrobial interaction (or coaggregation) associated with adhesin RadD and biofilm formation, but also hydrogen sulfide production. The defect in coaggregation is not due to reduced cell surface of RadD, but rather an increased level of extracellular lysine, which binds RadD and inhibits coaggregation. Indeed, removal of extracellular lysine via washing Δ rnfC cells restores coaggregation, while addition of lysine inhibits this process. These phenotypes mirror that of a mutant (Δ kamA ) that fails to metabolize extracellular lysine. Strikingly, the Δ rnfC mutant is defective in ATP production, cell growth, cell morphology, and expression of the enzyme MegL that produces hydrogen sulfide from cysteine. Metabolic profiling demonstrated that catabolism of many amino acids, including histidine and lysine, is altered in Δ rnfC cells, leading to reduction in butyrate. Most importantly, we show that the Δ rnfC mutant is severely attenuated in a mouse model of preterm birth. Thus, the Rnf complex plays a critical role in fusobacterial virulence via modulation of many metabolic pathways.IMPORTANCE: Although viewed as an oral commensal, the Gram-negative F. nucleatum is an opportunistic pathogen that can traverse to extra-oral sites, such as placenta and colon, promoting adverse pregnancy outcomes and colorectal cancer, respectively. How this anaerobe sustains the various metabolically changing environments enabling its virulence potential remains unclear. Here, we demonstrate that the Rnf complex is key to F. nucleatum metabolism and virulence as genetic disruption of Rnf causes pleiotropic defects in polymicrobial interaction, biofilm formation, cell growth and morphology, hydrogen sulfide production, and ATP synthesis. Targeted metabolomic profiling demonstrates that the loss of this highly conserved respiratory enzyme significantly diminishes catabolism of numerous amino acids, which negatively impacts fusobacterial virulence as tested in a preterm birth model in mice.PMID:37398403 | PMC:PMC10312631 | DOI:10.1101/2023.06.13.544113