PubMed

bioRxiv. 2023 Aug 23:2023.08.22.554286. doi: 10.1101/2023.08.22.554286. Preprint.ABSTRACTEnvironmental exposures such as cigarette smoking influence health outcomes through intermediate molecular phenotypes, such as the methylome, transcriptome, and metabolome. Mediation analysis is a useful tool for investigating the role of potentially high-dimensional intermediate phenotypes in the relationship between environmental exposures and health outcomes. However, little work has been done on mediation analysis when the media-tors are high-dimensional and the outcome is a survival endpoint, and none of it has provided a robust measure of total mediation effect. To this end, we propose an estimation procedure for M ediation A nalysis of S urvival outcome and H igh-dimensional omics mediators (MASH) based on a second-moment-based measure of total mediation effect for survival data analogous to the R 2 measure in a linear model. In addition, we propose a three-step mediator selection procedure to mitigate potential bias induced by non-mediators. Extensive simulations showed good performance of MASH in estimating the total mediation effect and identifying true mediators. By applying MASH to the metabolomics data of 1919 subjects in the Framingham Heart Study, we identified five metabolites as mediators of the effect of cigarette smoking on coronary heart disease risk (total mediation effect, 51.1%) and two metabolites as mediators between smoking and risk of cancer (total mediation effect, 50.7%). Application of MASH to a diffuse large B-cell lymphoma genomics data set identified copy-number variations for eight genes as mediators between the baseline International Prognostic Index score and overall survival.PMID:37662296 | PMC:PMC10473652 | DOI:10.1101/2023.08.22.554286

bioRxiv. 2023 Aug 22:2023.08.21.554149. doi: 10.1101/2023.08.21.554149. Preprint.ABSTRACTThe liver is critical for functions that support metabolism, immunity, digestion, detoxification, and vitamin storage. Aging is associated with severity and poor prognosis of various liver diseases such as nonalcoholic fatty liver disease (NAFLD). Previous studies have used multi-omic approaches to study liver diseases or to examine the effects of aging on the liver. However, to date, no studies have used an integrated omics approach to investigate aging-associated molecular changes in the livers of healthy female nonhuman primates. The goal of this study was to identify molecular changes associated with healthy aging in the livers of female baboons ( Papio sp., n=35) by integrating multiple omics data types (transcriptomics, proteomics, metabolomics) from samples across the adult age span. To integrate omics data, we performed unbiased weighted gene co-expression network analysis (WGCNA), and the results revealed 3 modules containing 3,149 genes and 33 proteins were positively correlated with age, and 2 modules containing 37 genes and 216 proteins were negatively correlated with age. Pathway enrichment analysis showed that unfolded protein response (UPR) and endoplasmic reticulum (ER) stress were positively associated with age, whereas xenobiotic metabolism and melatonin and serotonin degradation pathways were negatively associated with age. The findings of our study suggest that UPR and a reduction in reactive oxygen species generated from serotonin degradation could protect the liver from oxidative stress during the aging process in healthy female baboons.PMID:37662261 | PMC:PMC10473634 | DOI:10.1101/2023.08.21.554149

medRxiv. 2023 Aug 25:2023.08.24.23294581. doi: 10.1101/2023.08.24.23294581. Preprint.ABSTRACTBACKGROUND: We investigated systemic biochemical changes in Alzheimer's disease (AD) by investigating the relationship between circulating plasma metabolites and both clinical and biomarker-assisted diagnosis of AD.METHODS: We used an untargeted approach with liquid chromatography coupled to high-resolution mass spectrometry to measure exogenous and endogenous small molecule metabolites in plasma from 150 individuals clinically diagnosed with AD and 567 age-matched elderly without dementia of Caribbean Hispanic ancestry. Plasma biomarkers of AD were also measured including P-tau181, Aβ40, Aβ42, total tau, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). Association of individual and co-expressed modules of metabolites were tested with the clinical diagnosis of AD, as well as biologically-defined AD pathological process based on P-tau181 and other biomarker levels.RESULTS: Over 4000 metabolomic features were measured with high accuracy. First principal component (PC) of lysophosphatidylcholines (lysoPC) that bind to or interact with docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and arachidonic acid (AHA) was associated with decreased risk of AD (OR=0.91 [0.89-0.96], p=2e-04). Restricted to individuals without an APOE ε 4 allele (OR=0.89 [0.84-0.94], p= 8.7e-05), the association remained. Among individuals carrying at least one APOE ε 4 allele, PC4 of lysoPCs moderately increased risk of AD (OR=1.37 [1.16-1.6], p=1e-04). Essential amino acids including tyrosine metabolism pathways were enriched among metabolites associated with P-tau181 levels and heparan and keratan sulfate degradation pathways were associated with Aβ42/Aβ40 ratio reflecting different pathways enriched in early and middle stages of disease.CONCLUSIONS: Our findings indicate that unbiased metabolic profiling can identify critical metabolites and pathways associated with β-amyloid and phosphotau pathology. We also observed an APOE ε 4 dependent association of lysoPCs with AD and that biologically-based diagnostic criteria may aid in the identification of unique pathogenic mechanisms.PMID:37662203 | PMC:PMC10473810 | DOI:10.1101/2023.08.24.23294581

Front Plant Sci. 2023 Aug 16;14:1222082. doi: 10.3389/fpls.2023.1222082. eCollection 2023.NO ABSTRACTPMID:37662174 | PMC:PMC10469298 | DOI:10.3389/fpls.2023.1222082

Front Plant Sci. 2023 Aug 16;14:1238624. doi: 10.3389/fpls.2023.1238624. eCollection 2023.ABSTRACTAnthocyanins exist widely in various plant tissues and organs, and they play an important role in plant reproduction, disease resistance, stress resistance, and protection of human vision. Most fruit anthocyanins can be induced to accumulate by light. Here, we shaded the "Hong Deng" sweet cherry and performed an integrated analysis of its transcriptome and metabolome to explore the role of light in anthocyanin accumulation. The total anthocyanin content of the fruit and two of its anthocyanin components were significantly reduced after the shading. Transcriptome and metabolomics analysis revealed that PAL, 4CL, HCT, ANS and other structural genes of the anthocyanin pathway and cyanidin 3-O-glucoside, cyanidin 3-O-rutinoside, and other metabolites were significantly affected by shading. Weighted total gene network analysis and correlation analysis showed that the upstream and middle structural genes 4CL2, 4CL3, and HCT2 of anthocyanin biosynthesis may be the key genes affecting the anthocyanin content variations in fruits after light shading. Their expression levels may be regulated by transcription factors such as LBD, ERF4, NAC2, NAC3, FKF1, LHY, RVE1, and RVE2. This study revealed for the first time the possible role of LBD, FKF1, and other transcription factors in the light-induced anthocyanin accumulation of sweet cherry, thereby laying a preliminary foundation for further research on the role of light in anthocyanin accumulation of deep red fruit varieties and the genetic breeding of sweet cherry.PMID:37662172 | PMC:PMC10469515 | DOI:10.3389/fpls.2023.1238624

Front Plant Sci. 2023 Aug 18;14:1232367. doi: 10.3389/fpls.2023.1232367. eCollection 2023.ABSTRACTThe pathogenicity of intracellular plant pathogenic bacteria is associated with the action of pathogenicity factors/effectors, but their physiological roles for most phytoplasma species, including 'Candidiatus Phytoplasma solani' are unknown. Six putative pathogenicity factors/effectors from six different strains of 'Ca. P. solani' were selected by bioinformatic analysis. The way in which they manipulate the host cellular machinery was elucidated by analyzing Nicotiana benthamiana leaves after Agrobacterium-mediated transient transformation with the pathogenicity factor/effector constructs using confocal microscopy, pull-down, and co-immunoprecipitation, and enzyme assays. Candidate pathogenicity factors/effectors were shown to modulate plant carbohydrate metabolism and the ascorbate-glutathione cycle and to induce autophagosomes. PoStoSP06, PoStoSP13, and PoStoSP28 were localized in the nucleus and cytosol. The most active effector in the processes studied was PoStoSP06. PoStoSP18 was associated with an increase in phosphoglucomutase activity, whereas PoStoSP28, previously annotated as an antigenic membrane protein StAMP, specifically interacted with phosphoglucomutase. PoStoSP04 induced only the ascorbate-glutathione cycle along with other pathogenicity factors/effectors. Candidate pathogenicity factors/effectors were involved in reprogramming host carbohydrate metabolism in favor of phytoplasma own growth and infection. They were specifically associated with three distinct metabolic pathways leading to fructose-6-phosphate as an input substrate for glycolysis. The possible significance of autophagosome induction by PoStoSP28 is discussed.PMID:37662165 | PMC:PMC10471893 | DOI:10.3389/fpls.2023.1232367

Physiol Genomics. 2023 Sep 4. doi: 10.1152/physiolgenomics.00163.2022. Online ahead of print.ABSTRACTSubmaximal exercise capacity is an indicator of cardiorespiratory fitness with clinical and public health implications. Submaximal exercise capacity and its response to exercise programs are characterized by heritability levels of about 40%. Using power output at a heart rate of 150 beats per minute (PWC150) as an indicator of submaximal exercise capacity in subjects of the HERITAGE Family Study, we have undertaken multi-omics and in silico explorations of the underlying biology of PWC150 and its response to 20 weeks of endurance training. Our goal was to illuminate the biological processes and identify panels of genes associated with human variability in intrinsic PWC150 (iPWC150) and its trainability (dPWC150). Our bioinformatics approach was based on a combination of genome-wide association, skeletal muscle gene expression, and plasma proteomics and metabolomics studies. Genes, proteins, and metabolites showing significant associations with iPWC150 or dPWC150 were further queried for enrichment of biological pathways. We compared genotype-phenotype associations of emerging candidate genes with reported functional consequences of gene knockouts in mouse models. We investigated the associations between DNA variants and multiple muscle and cardiovascular phenotypes measured in HERITAGE subjects. Two panels of prioritized genes of biological relevance to iPWC150 (13 genes) and dPWC150 (6 genes) were identified, supporting the hypothesis that genes and pathways associated with iPWC150 are different from those underlying dPWC150. Finally, the functions of these genes and pathways suggested that human variation in submaximal exercise capacity is mainly driven by skeletal muscle morphology and metabolism and red blood cell oxygen carrying capacity.PMID:37661925 | DOI:10.1152/physiolgenomics.00163.2022

Am J Clin Nutr. 2023 Sep;118(3):591-604. doi: 10.1016/j.ajcnut.2023.07.002. Epub 2023 Aug 8.ABSTRACTBACKGROUND: The capacity of an individual to respond to changes in food intake so that postprandial metabolic perturbations are resolved, and metabolism returns to its pre-prandial state, is called phenotypic flexibility. This ability may be a more important indicator of current health status than metabolic markers in a fasting state.AIM: In this parallel randomized controlled trial study, an energy-restricted healthy diet and 2 dietary challenges were used to assess the effect of weight loss on phenotypic flexibility.METHODS: Seventy-two volunteers with overweight and obesity underwent a 12-wk dietary intervention. The participants were randomized to a weight loss group (WLG) with 20% less energy intake or a weight-maintenance group (WMG). At weeks 1 and 12, participants were assessed for body composition by MRI. Concurrently, markers of metabolism and insulin sensitivity were obtained from the analysis of plasma metabolome during 2 different dietary challenges-an oral glucose tolerance test (OGTT) and a mixed-meal tolerance test.RESULTS: Intended weight loss was achieved in the WLG (-5.6 kg, P < 0.0001) and induced a significant reduction in total and regional adipose tissue as well as ectopic fat in the liver. Amino acid-based markers of insulin action and resistance such as leucine and glutamate were reduced in the postprandial phase of the OGTT in the WLG by 11.5% and 28%, respectively, after body weight reduction. Weight loss correlated with the magnitude of changes in metabolic responses to dietary challenges. Large interindividual variation in metabolic responses to weight loss was observed.CONCLUSION: Application of dietary challenges increased sensitivity to detect metabolic response to weight loss intervention. Large interindividual variation was observed across a wide range of measurements allowing the identification of distinct responses to the weight loss intervention and mechanistic insight into the metabolic response to weight loss.PMID:37661105 | DOI:10.1016/j.ajcnut.2023.07.002

Gene. 2023 Sep 1:147752. doi: 10.1016/j.gene.2023.147752. Online ahead of print.ABSTRACTIsatis indigotica Fortune is a plant species containing lignan compounds of significant economic value. Its root plays a crucial role in treating viruses and exhibits antitumor, anti-inflammatory, antibacterial, and other biological activities. Now, I. indigotica has been included in Isatis tinctoria Linnaeus. In this study, the roots of diploid I. indigotica, tetraploid I. indigotica, and Isatis tinctoria Linnaeus were analyzed using metabolome and transcriptome analysis. The metabolomic analysis detected 48 lignan metabolites, including Lirioresinol A, Vladinol A, Syringaresinol, Arctigenin, Acanthoside B, and Sesamin as characteristic compounds, without significant variations among the remaining metabolites. The transcriptomic analysis identified 41 differentially expressed phenylpropanoid synthase genes, which were further analyzed for variations in lignan transcriptome profiles across different samples. RT-qPCR analysis also revealed differential genes expression related to lignan biosynthesis pathway among the three sample groups. The analysis of transcription factors showed that the AP2-EREBP family (Iin24319), MYB family (Iin24843), and WRKY family (Iin08158) displayed expression patterns similar to Iin14549. Phylogenetic analyses also indicate that Iin14549 may play a role in lignan synthesis. These transcription factor families exhibited high expression in tetraploid I. indigotica, moderate expression in diploid I. indigotica, and low expression in I. tinctoria. The findings of this study can serve as a reference for improving the quality of I. indigotica and developing germplasms with high lignan content. Additionally, these results lay a foundation for the functional characterization of UGTs in lignan biosynthesis pathway.PMID:37661029 | DOI:10.1016/j.gene.2023.147752

J Nutr. 2023 Sep 1:S0022-3166(23)72560-1. doi: 10.1016/j.tjnut.2023.08.032. Online ahead of print.ABSTRACTBACKGROUND: Maternal vitamin B12 (B12) deficiency plays a vital role in fetal programming, as corroborated by previous studies on murine models and longitudinal human cohorts.OBJECTIVE: This study assessed the effects of diet-induced maternal B12 deficiency on F1 offspring in terms of cardiometabolic health and normalization of these effects by maternal peri-conceptional B12 supplementation.METHODS: A diet-induced maternal B12 deficient Wistar rat model was generated where female rats were either fed a control AIN-76A diet (with 0.01 g/Kg B12) or same diet with B12 removed. Females from B12 deficient group were mated with males on control diet. A subset of B12 deficient females was repleted with B12 on day 1 of conception. The offspring in F1 generation were assessed for changes in body composition, plasma biochemical and molecular changes in the liver. A multi-omics approach was used to get a mechanistic insight into the changes in the offspring liver.RESULTS: We show that a 36% reduction in plasma B12 levels during pregnancy in F0 females can lead to continued B12 deficiency (60-70% compared to control) in the F1 offspring and program them for cardio-metabolic adversities. These adversities like high triglycerides and low HDL were seen only among F1 males but not females. DNA methylome analysis in the liver of F1 3-month-old offspring highlights sexual dimorphism in the alteration of methylation status of genes critical to signaling processes. Proteomics and targeted metabolomics analysis confirm that this sex-specific alterations occur through modulations in PPAR signaling and steroid hormone biosynthesis pathway. Repletion of deficient mothers with B12 at conception normalizes most of the molecular and biochemical changes.CONCLUSIONS: Maternal B12 deficiency has a programming effect on the next generation and increases the risk for cardio-metabolic syndrome in a sex-specific manner. Normalization of the molecular risk markers on B12 supplementation indicates a causal role.PMID:37660953 | DOI:10.1016/j.tjnut.2023.08.032

Am J Clin Nutr. 2023 Sep 1:S0002-9165(23)66116-7. doi: 10.1016/j.ajcnut.2023.08.018. Online ahead of print.ABSTRACTBACKGROUND: Whether red meat consumption is associated with higher inflammation, or confounded by increased adiposity, remains unclear. Plasma metabolites both capture the effects of diet after food is processed, digested, and absorbed, and correlate with markers of inflammation, so can help clarify diet-health relationships.OBJECTIVE: To identify whether any metabolites associated with red meat intake are also associated with inflammation.DESIGN: A cross-sectional analysis of observational data from older adults (52.84% female, mean age 63±0.3 years), participating in the Multi-Ethnic Study of Atherosclerosis (MESA). Dietary intake was assessed by food frequency questionnaire, alongside C-reactive protein (CRP), interleukin-2, interleukin-6, fibrinogen, homocysteine, and tumor necrosis factor alpha, and untargeted proton nuclear magnetic resonance 1H NMR metabolomic features. Associations between these variables were examined using linear regression models, adjusted for demographic factors lifestyle behaviors, and BMI.RESULTS: Neither processed not unprocessed forms of red meat were associated with any markers of inflammation (all P>.01). However, again in analyses which adjust for BMI, unprocessed red meat was inversely associated with inversely associated with spectral features representing the metabolite glutamine (sentinel hit: β=-0.09 ± 0.02, P=2.0*10-5), an amino acid which was also inversely associated with CRP level (β=-0.11 ± 0.01, P=3.3*10-10).CONCLUSIONS: Our analyses were unable to support a relationship between either processed or unprocessed red meat and inflammation, over and above any confounding by BMI. Glutamine, a plasma correlate of lower unprocessed red meat intake, was associated with lower CRP levels. The differences in diet-inflammation associations vs. diet metabolite-inflammation associations warrants further investigation to understand the extent that these arise from (1) a reduction in measurement error with metabolite measures; (2) the extent that factors other than unprocessed red meat intake contribute to glutamine levels; (3) the ability of plasma metabolites to capture individual differences in how food intake is metabolized.PMID:37660929 | DOI:10.1016/j.ajcnut.2023.08.018

Sci Total Environ. 2023 Sep 1:166697. doi: 10.1016/j.scitotenv.2023.166697. Online ahead of print.ABSTRACTThe drifting process of U. prolifera were simulated in a large-volume flowing water system with conditions similar to the field in the Yellow Sea. Biomass and chl-a content per unit of U. prolifera were monitored in the flowing water system by simulating nutrients and temperature variations of seawaters from starting place to terminus of U. prolifera in the South Yellow Sea. According to the variations of nutrients during the drifting process, the floating process can be divided into three stages. Differentially expressed genes and differential metabolites in the three stages of U. prolifera drifting process were identified, which are mainly related to glycometabolism, nitrogen metabolism, and selenium compound metabolism. The process from Stage I to Stage II are mainly related to the translation and molecular function of biological processes, and the main differential metabolites are primary metabolites, whereas, from Stage II to Stage III, secondary metabolites start to increase, indicating that U. prolifera resisted environmental stress by increasing lipids and producing secondary metabolites. It will provide some guidance for the comprehensive interpretation of the biological basis and ecological mechanisms of the large-scale U. prolifera green tides in the Yellow Sea.PMID:37660825 | DOI:10.1016/j.scitotenv.2023.166697

Sci Total Environ. 2023 Sep 1:166765. doi: 10.1016/j.scitotenv.2023.166765. Online ahead of print.ABSTRACTSilver nanoparticles (AgNPs) are widely present in aquatic and soil environment, raising significant concerns about their impacts on creatures in ecosystem. While the toxicity of AgNPs on microorganisms has been reported, their effects on biogeochemical processes and specific functional microorganisms remain relatively unexplored. In this study, a 28-day microcosmic experiment was conducted to investigate the dose-dependent effects of AgNPs (10 mg and 100 mg Ag kg-1 soil) on nitrogen transformation and functional microorganisms in agricultural soils. The molecular mechanisms were uncovered by examining change in functional microorganisms and metabolic pathways. To enable comparison, the toxicity of positive control with an equivalent Ag+ dose from CH3COOAg was also included. The results indicated that both AgNPs and CH3COOAg enhanced nitrogen fixation and nitrification, corresponding to increased relative abundances of associated functional genes. However, they inhibited denitrification via downregulating nirS, nirK, and nosZ genes as well as reducing nitrate and nitrite reductase activities. In contrast to high dose of AgNPs, low levels increased bacterial diversity. AgNPs and CH3COOAg altered the activities of associated metabolic pathways, resulting in the enrichment of specific taxa that demonstrated tolerance to Ag. At genus level, AgNPs increased the relative abundances of nitrogen-fixing Microvirga and Bacillus by 0.02 %-629.39 % and 14.44 %-30.10 %, respectively, compared with control group (CK). The abundances of denitrifying bacteria, such as Rhodoplanes, Pseudomonas, and Micromonospora, decreased by 19.03 % to 32.55 %, 24.73 % to 50.05 %, and 15.66 % to 76.06 %, respectively, compared to CK. CH3COOAg reduced bacterial network complexity, diminished the symbiosis mode compared to AgNPs. The prediction of genes involved in metabolic pathways related to membrane transporter and cell motility showed sensitive to AgNPs exposure in the soil. Further studies involving metabolomics are necessary to reveal the essential effects of AgNPs and CH3COOAg on biogeochemical cycle of elements in agricultural soil.PMID:37660816 | DOI:10.1016/j.scitotenv.2023.166765

Chemosphere. 2023 Sep 1:140048. doi: 10.1016/j.chemosphere.2023.140048. Online ahead of print.ABSTRACTPolychlorinated biphenyls (PCBs) are a class of contaminants of great concern, linked to the development of many chronic diseases. Adverse effects of PCBs have been documented in humans after accidental and massive exposure. However, little is known about the effect of chronic exposure to low-dose PCBs mixtures, and studies regarding scattered lifetime exposures to non-dioxin-like (NDL)-PCBs are especially missing. In this work, serum samples from pigs chronically exposed through their diet during 22 days to Aroclor 1260 (i.e. a commercially available mixture of NDL-PCBs) underwent a metabolomics analysis using gas chromatography-high resolution mass spectrometry (GC-HRMS), with the objective to investigate the effect of exposure to low doses of NDL-PCBs (few ng/kg body weight (b.w.) per day). The study showed that the serum profiles of 84 metabolites are significantly altered by the administration of Aroclor 1260, of which 40 could be identified at least at level 2. The aggregate interpretation of the results of this study, together with the outcome of a previous one involving LC-HRMS profiling, provided a substantial and concise overview of the effect of low dose exposure to NDL-PCBs, reflecting the hepatotoxic and neurotoxic effects already reported in literature at higher and longer exposures. These results are intended to contribute to the debate on the current toxicological reference values for these substances.PMID:37660801 | DOI:10.1016/j.chemosphere.2023.140048

Prog Neuropsychopharmacol Biol Psychiatry. 2023 Sep 1:110858. doi: 10.1016/j.pnpbp.2023.110858. Online ahead of print.ABSTRACTRestricted and repetitive behaviors (RRBs) are one of the characteristics of various neuropsychiatric disorders with complex and diverse molecular mechanisms. Repetitive self-grooming behavior is one of the manifestations of RRBs in humans and rodents. Research on the neural mechanism of repetitive self-grooming behavior is expected to reveal the underlying logic of the occurrence of RRBs. Pax2 is an important member of the paired-box transcription factor family. It is expressed in different regions of the developing central nervous system. Our previous study showed that Pax2 heterozygous gene knockout mice (Pax2+/- KO mice) exhibit significantly increased self-grooming, which suggests that the Pax2 gene is involved in the control of self-grooming behavior, but the molecular mechanism is still unclear. In this study, we further constructed the Pax2 neuron-specific deletion mice (Nestin-Pax2 mice). Targeted metabolomics and transcriptomics techniques was used to analyze. The results showed that there is an excitatory/inhibitory imbalance of the neurotransmitter system and the Arc gene was significantly up-regulated in the prefrontal cortex (PFC) of Nestin-Pax2 mice. This study suggests that the potential regulatory mechanism of the increased repetitive self-grooming behavior in Pax2 gene deletion mice is that the deletion of the Pax2 gene affects the expression of Arc in the PFC, leading to impaired synaptic plasticity and excitatory/inhibitory imbalance, and participating in the occurrence of repetitive self-grooming behavior.PMID:37660748 | DOI:10.1016/j.pnpbp.2023.110858

Aquat Toxicol. 2023 Aug 19;263:106666. doi: 10.1016/j.aquatox.2023.106666. Online ahead of print.ABSTRACTUnder high-density culture, cannibalism occurs frequently during the molting of the Chinese mitten crabs Eriocheir sinensis, resulting in a large reduction in production. We found that the leakage of molting fluid from sexually immature crabs informs conspecifics that they are in a molting process. This hypothesis was verified through metabolomics analyses combined with behavioral experiments. The GlcNAc-6-P was identified as a molting biomarker from the differential metabolites by non-targeted metabolomics. In addition, we found that the concentration of GlcNAc-6-P in the molting fluid was significantly higher than other molting metabolites at different molting stages, reaching 5.84 μmol L-1, indicating that the molting fluid was the source of GlcNAc-6-P. Moreover, the behavioral experiments showed that crabs were actively approached to high concentrations of GlcNAc-6-P (1 μmol L-1), but had no obvious choice tendency at different concentrations of UTP, 20-HE and low concentrations of GlcNAc-6-P (0.1 μmol L-1, 0.01 μmol L-1) compared with the control groups. In conclusion, that E. sinensis by sensing the concentration change of GlcNAc-6-P can locate the source of GlcNAc-6-P release and actively approach the high concentration GlcNAc-6-P area and attack the molting crab, causing cannibalism. Blocking the reception pathway of molting chemical cues in E. sinensis, thereby preventing the perception of signals originating from conspecifics' molting in the vicinity, could lead to a reduction in cannibalistic behavior and an increase in overall production. Additionally, this method presents a prospective solution for addressing cannibalism in other crustacean species where such behavior is prevalent.PMID:37660581 | DOI:10.1016/j.aquatox.2023.106666

Mol Genet Metab. 2023 Aug 25;140(3):107689. doi: 10.1016/j.ymgme.2023.107689. Online ahead of print.ABSTRACTTriheptanoin (triheptanoylglycerol) has shown value as anaplerotic therapy for patients with long chain fatty acid oxidation disorders but is contraindicated in medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. In search for anaplerotic therapy for patients with MCAD deficiency, fibroblasts from three patients homozygous for the most common mutation, ACADMG985A/G985A, were treated with fatty acids hypothesized not to require MCAD for their metabolism, including heptanoic (C7; the active component of triheptanoin), 2,6-dimethylheptanoic (dMC7), 6-amino-2,4-dimethylheptanoic (AdMC7), or 4,8-dimethylnonanoic (dMC9) acids. Their effectiveness as anaplerotic fatty acids was assessed in live cells by monitoring changes in cellular oxygen consumption rate (OCR) and mitochondrial protein lysine succinylation, which reflects cellular succinyl-CoA levels, using immunofluorescence (IF) staining. Krebs cycle intermediates were also quantitated in these cells using targeted metabolomics. The four fatty acids induced positive changes in OCR parameters, consistent with their oxidative catalysis and utilization. Increases in cellular IF staining of succinylated lysines were observed, indicating that the fatty acids were effective sources of succinyl-CoA in the absence of media glucose, pyruvate, and lipids. The ability of MCAD deficient cells to metabolize C7 was confirmed by the ability of extracts to enzymatically utilize C7-CoA as substrate but not C8-CoA. To evaluate C7 therapeutic potential in vivo, Acadm-/- mice were treated with triheptanoin for seven days. Dose dependent increase in plasma levels of heptanoyl-, valeryl-, and propionylcarnitine indicated efficient metabolism of the medication. The pattern of the acylcarnitine profile paralleled resolution of liver pathology including reversing hepatic steatosis, increasing hepatic glycogen content, and increasing hepatocyte protein succinylation, all indicating improved energy homeostasis in the treated mice. These results provide the impetus to evaluate triheptanoin and the medium branched chain fatty acids as potential therapeutic agents for patients with MCAD deficiency.PMID:37660571 | DOI:10.1016/j.ymgme.2023.107689

Ecotoxicol Environ Saf. 2023 Sep 1;264:115411. doi: 10.1016/j.ecoenv.2023.115411. Online ahead of print.ABSTRACTCadmium (Cd) is a ubiquitous heavy metal with neurotoxicity. Our previous study reported that Cd could inhibit the proliferation of mouse neural stem cells (mNSCs). However, the underlying mechanisms are obscure. In recent years, the rapid growth of multi-omics techniques enables us to explore the cellular responses that occurred after toxicant exposure at the molecular level. In this study, we used a combination of metabolomics and transcriptomics approaches to investigate the effects of exposure to Cd on mNSCs. After treatment with Cd, the metabolites and transcripts in mNSCs changed significantly with 110 differentially expressed metabolites and 2135 differentially expressed genes identified, respectively. The altered metabolites were mainly involved in glycerophospholipid metabolism, arginine and proline metabolism, arginine biosynthesis, glyoxylate and dicarboxylate metabolism. Meanwhile, the transcriptomic data demonstrated perturbed membrane function and signal transduction. Furthermore, integrated analysis of metabolomic and transcriptomic data suggested that glycerophospholipid metabolism might be the major metabolic pathway affected by Cd in mNSCs. More interestingly, the supplementation of lysophosphatidylethanolamine (LPE) attenuated Cd-induced mitochondrial impairment and the inhibition of cell proliferation and differentiation in mNSCs, further supporting our analysis. Overall, the study provides new insights into the mechanisms of Cd-induced neurotoxicity.PMID:37660531 | DOI:10.1016/j.ecoenv.2023.115411

Reprod Biol. 2023 Sep 1;23(4):100811. doi: 10.1016/j.repbio.2023.100811. Online ahead of print.ABSTRACTType 2 diabetes mellitus (T2DM) can cause prostate damage and affect male reproductive function, but the underlying mechanisms are not completely understood. In this study, we used liquid chromatography-mass spectrometry (LC-MS)-based untargeted metabolomics to identify endogenous metabolites in the prostate of a T2DM mouse model. The selected endogenous metabolites were then subjected to bioinformatics analysis and metabolic pathway studies to understand their role in the development of T2DM-induced prostate damage. We used male homozygous BTBR ob/ob mice (n = 12) and BTBR WT mice (n = 11) in this study. We monitored changes in blood glucose, body weight, prostate weight, and prostate index, as well as performed hematoxylin and eosin (H&E) staining and observed that the prostate of the BTBR ob/ob was damaged. We then used ultra-high-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) for metabolomics analysis. The stability of the model was validated using principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA). Using variable importance in projection (VIP) > 1, false discovery rate (FDR) < 0.05, and coefficient of variation (CV) < 30 as criteria, a total of 149 differential metabolites (62 upregulated and 87 downregulated) were identified between the prostates of the two groups of mice. Topological pathway analysis showed that these differential metabolites were mainly involved in sphingolipid (SP) and glycerophospholipid (GP) metabolism. In conclusion, our study not only emphasizes the damage caused by T2DM to the prostate but also provides new insights into the potential mechanisms of T2DM-induced male reproductive dysfunction.PMID:37660522 | DOI:10.1016/j.repbio.2023.100811

World J Microbiol Biotechnol. 2023 Sep 4;39(11):298. doi: 10.1007/s11274-023-03736-8.ABSTRACTSaccharomyces cerevisiae is a health microorganism closely related to human life, especially in food and pharmaceutical industries. S. cerevisiae W303a and CEN.PK2-1C are two commonly used strains for synthetic biology-based natural product production. Yet, the metabolomic and transcriptomic differences between these two strains have not been compared. In this study, metabolomics and transcriptomics were applied to analyze the differential metabolites and differential expression genes (DEGs) between W303a and CEN.PK2-1C cultured in YPD and SD media. The growth rate of W303a in YPD medium was the lowest compared with other groups. When cultured in YPD medium, CEN.PK2-1C produced more phenylalanine than W303a; when cultured in SD medium, W303a produced more phospholipids than CEN.PK2-1C. Transcriptomic analysis revealed that 19 out of 22 genes in glycolysis pathway were expressed at higher levels in CEN.PK2-1C than that in W303a no matter which media were used, and three key genes related to phenylalanine biosynthesis including ARO9, ARO7 and PHA2 were up-regulated in CEN.PK2-1C compared with W303a when cultured in YPD medium, whereas seven DEGs associated with phospholipid biosynthesis were up-regulated in W303a compared with CEN.PK2-1C when cultured in SD medium. The high phenylalanine produced by CEN.PK2-1C and high phospholipids produced by W303a indicated that CEN.PK2-1C may be more suitable for synthesis of natural products with phenylalanine as precursor, whereas W303a may be more appropriate for synthesis of phospholipid metabolites. This finding provides primary information for strain selection between W303a and CEN.PK2-1C for synthetic biology-based natural product production.PMID:37661201 | DOI:10.1007/s11274-023-03736-8