PubMed

Front Immunol. 2023 Aug 17;14:1170223. doi: 10.3389/fimmu.2023.1170223. eCollection 2023.ABSTRACTINTRODUCTION: Tumor-associated macrophage 2 (TAM2) abundantly infiltrates pancreatic ductal adenocarcinoma (PAAD), and its interaction with malignant cells is involved in the regulation of tumor metabolism. In this study, we explored the metabolic heterogeneity involved in TAM2 by constructing TAM2-associated metabolic subtypes in PAAD.MATERIALS AND METHODS: PAAD samples were classified into molecular subtypes with different metabolic characteristics based on a multi-omics analysis strategy. 20 PAAD tissues and 10 normal pancreatic tissues were collected for proteomic and metabolomic analyses. RNA sequencing data from the TCGA-PAAD cohort were used for transcriptomic analyses. Immunohistochemistry was used to assess TAM2 infiltration in PAAD tissues.RESULTS: The results of transcriptomics and immunohistochemistry showed that TAM2 infiltration levels were upregulated in PAAD and were associated with poor patient prognosis. The results of proteomics and metabolomics indicated that multiple metabolic processes were aberrantly regulated in PAAD and that this dysregulation was linked to the level of TAM2 infiltration. WGCNA confirmed pyruvate and glycolysis/gluconeogenesis as co-expressed metabolic pathways of TAM2 in PAAD. Based on transcriptomic data, we classified the PAAD samples into four TAM2-associated metabolic subtypes (quiescent, pyruvate, glycolysis/gluconeogenesis and mixed). Metabolic subtypes were each characterized in terms of clinical prognosis, tumor microenvironment, immune cell infiltration, chemotherapeutic drug sensitivity, and functional mechanisms.CONCLUSION: Our study confirmed that the metabolic remodeling of pyruvate and glycolysis/gluconeogenesis in PAAD was closely related to TAM2. Molecular subtypes based on TAM2-associated metabolic pathways provided new insights into prognosis prediction and therapy for PAAD patients.PMID:37662928 | PMC:PMC10470650 | DOI:10.3389/fimmu.2023.1170223

Front Immunol. 2023 Aug 16;14:1211612. doi: 10.3389/fimmu.2023.1211612. eCollection 2023.ABSTRACTBACKGROUND: COVID-19 could develop severe respiratory symptoms in certain infected patients, especially in the patients with immune disorders. Gut microbiome and plasma metabolome act important immunological modulators in the human body and could contribute to the immune responses impacting the progression of COVID-19. However, the causal relationship between specific intestinal bacteria, metabolites and severe COVID-19 remains not clear.METHODS: Based on two-sample Mendelian randomization (MR) framework, the causal effects of 131 intestinal taxa and 452 plasma metabolites on severe COVID-19 were evaluated. Single nucleotide polymorphisms (SNPs) strongly associated with the abundance of intestinal taxa and the concentration of plasma metabolites had been utilized as the instrument variables to infer whether they were causal factors of severe COVID-19. In addition, mediation analysis was conducted to find the potential association between the taxon and metabolite, and further colocalization analysis had been performed to validate the causal relationships.RESULTS: MR analysis identified 13 taxa and 53 metabolites, which were significantly associated with severe COVID-19 as causal factors. Mediation analysis revealed 11 mediated relationships. Myo-inositol, 2-stearoylglycerophosphocholine, and alpha-glutamyltyrosine, potentially contributed to the association of Howardella and Ruminiclostridium 6 with severe COVID-19, respectively. Butyrivibrio and Ruminococcus gnavus could mediate the association of myo-inositol and N-acetylalanine, respectively. In addition, Ruminococcus torques abundance was colocalized with severe COVID-19 (PP.H4 = 0.77) and the colon expression of permeability related protein RASIP1 (PP.H4 = 0.95).CONCLUSIONS: Our study highlights the potential causal relationships between gut microbiome, plasma metabolome and severe COVID-19, which potentially serve as clinical biomarkers for risk stratification and prognostication and benefit the mechanism mechanistic investigation of severe COVID-19.PMID:37662924 | PMC:PMC10468967 | DOI:10.3389/fimmu.2023.1211612

Heliyon. 2023 Aug 25;9(9):e19487. doi: 10.1016/j.heliyon.2023.e19487. eCollection 2023 Sep.ABSTRACTOver the past half century, limited use of synthetic fertilizers, pesticides, and conservation of the environment and natural resources have become the interdependent goals of sustainable agriculture. These practices support agriculture sustainability with less environmental and climatic impacts. Therefore, there is an upsurge in the need to introduce compatible booster methods for maximizing net production. The best straightforward strategy is to explore and utilize plant-associated beneficial microorganisms and their products. Bioinoculants are bioformulations consisting of selected microbial strains on a suitable carrier used in the enhancement of crop production. Fungal endophytes used as bioinoculants confer various benefits to the host, such as protection against pathogens by eliciting immune response, mineralization of essential nutrients, and promoting plant growth. Besides, they also produce various bioactive metabolites, phytohormones, and volatile organic compounds. To design various bioformulations, transdisciplinary approaches like genomics, transcriptomics, metabolomics, proteomics, and microbiome modulation strategies like gene editing and metabolic reconstruction have been explored. These studies will refine the existing knowledge on the diversity, phylogeny and beneficial traits of the microbes. This will also help in synthesizing microbial consortia by evaluating the role of structural and functional elements of communities in a controlled manner. The present review summarizes the beneficial aspects associated with fungal endophytes for capitalizing agricultural outputs, enlists various multi-omics techniques for understanding and modulating the mechanism involved in endophytism and the generation of new bioformulations for providing novel solutions for the enhancement of crop production.PMID:37662754 | PMC:PMC10472071 | DOI:10.1016/j.heliyon.2023.e19487

Heliyon. 2023 Aug 24;9(9):e19355. doi: 10.1016/j.heliyon.2023.e19355. eCollection 2023 Sep.ABSTRACTLike astronauts, animals need to undergo training and screening before entering space. At present, pre-launch training for mice mainly focuses on adaptation to habitat system. Training for the weightless environment of space in mice has not received much attention. Three-dimensional (3D) clinostat is a method to simulate the effects of microgravity on Earth. However, few studies have used a 3D clinostat apparatus to simulate the effects of microgravity on animal models. Therefore, we conducted a study to evaluate the feasibility and effects of long-term treatment with three-dimensional clinostat in C57BL/6 J mice. Thirty 8-week-old male C57BL/6 J mice were randomly assigned to three groups: mice in individually ventilated cages (MC group, n = 6), mice in survival boxes (SB group, n = 12), and mice in survival boxes receiving 3D clinostat treatment (CS group, n = 12). The mice showed good tolerance after 12 weeks of alternate day training. To evaluate the biological effects of simulated microgravity, the changes in serum metabolites were monitored using untargeted metabolomics, whereas bone loss was assessed using microcomputed tomography of the left femur. Compared with the metabolome of the SB group, the metabolome of the CS group showed significant differences during the first three weeks and the last three weeks. The KEGG pathways in the late stages were mainly related to the nervous system, indicating the influence of long-term microgravity on the central nervous system. Besides, a marked reduction in the trabecular number (P < 0.05) and an increasing trend of trabecular spacing (P < 0.1) were observed to occur in a time-dependent manner in the CS group compared with the SB group. These results showed that mice tolerated well in a 3D clinostat and may provide a new strategy in pre-launch training for mice and conducting relevant ground-based modeling experiments.PMID:37662714 | PMC:PMC10472007 | DOI:10.1016/j.heliyon.2023.e19355

Front Nutr. 2023 Aug 3;10:1197998. doi: 10.3389/fnut.2023.1197998. eCollection 2023.ABSTRACTSanghuangporus vaninii is a profitable traditional and medicinal edible fungus with uncommon therapeutic properties and medicinal value. The accumulation of active ingredients in this fungus that is used in traditional Chinese medicine is affected by its years of growth, and their pharmacological activities are also affected. However, the effects of age on the medicinal value of fruiting bodies of S. vaninii cultivated on cut log substrate remain unclear. In this study, an untargeted liquid chromatography mass spectrometry (LC-MS)-based metabolomics approach was performed to characterize the profiles of metabolites from 1-, 2- and 3-year-old fruiting bodies of S. vaninii. A total of, 156 differentially accumulated metabolites (DAMs) were screened based on the criterion of a variable importance projection greater than 1.0 and p < 0.01, including 75% up regulated and 25% down regulated. The results of enrichment of metabolic pathways showed that the metabolites involved the biosynthesis of plant secondary metabolites, biosynthesis of amino acids, central carbon metabolism in cancer, steroid hormone biosynthesis, linoleic acid metabolism, prolactin signaling pathway, and arginine biosynthesis, and so on. The biosynthesis of plant secondary metabolites pathway was significantly activated. Five metabolites were significantly elevated within the growth of fruiting bodies, including 15-keto-prostaglandin F2a, (4S, 5R)-4,5,6-trihydroxy-2-iminohexanoate, adenylsuccinic acid, piplartine, and chenodeoxycholic acid. 15-keto-prostaglandin F2a is related to the pathway of arachidonic acid metabolism and was significantly increased up to 1,320- and 535-fold in the 2- and 3-year-old fruiting bodies, respectively, compared with those in the 1-year-old group. The presence of these bioactive natural products in S. vaninii is consistent with the traditional use of Sanghuang, which prompted an exploration of its use as a source of natural prostaglandin in the form of foods and nutraceuticals. These findings may provide insight into the functional components of S. vaninii to develop therapeutic strategies.PMID:37662599 | PMC:PMC10472941 | DOI:10.3389/fnut.2023.1197998

bioRxiv. 2023 Aug 23:2023.08.22.554315. doi: 10.1101/2023.08.22.554315. Preprint.ABSTRACTThe gut and local esophageal microbiome progressively shift from healthy commensal bacteria to inflammatory-linked pathogenic bacteria in patients with gastroesophageal reflux disease, Barrett's esophagus and esophageal adenocarcinoma (EAC). However, mechanisms by which microbial communities and metabolites contribute to reflux-driven EAC remain incompletely understood and challenging to target. Herein, we utilized a rat reflux-induced EAC model to investigate targeting the gut microbiome-esophageal metabolome axis with cranberry proanthocyanidins (C-PAC) to inhibit EAC progression. Sprague Dawley rats, with or without reflux-induction received water or C-PAC ad libitum (700 µg/rat/day) for 25 or 40 weeks. C-PAC exerted prebiotic activity abrogating reflux-induced dysbiosis, and mitigating bile acid metabolism and transport, culminating in significant inhibition of EAC through TLR/NF-κB/P53 signaling cascades. At the species level, C-PAC mitigated reflux-induced pathogenic bacteria (Clostridium perfringens, Escherichia coli, and Proteus mirabilis). C-PAC specifically reversed reflux-induced bacterial, inflammatory and immune-implicated proteins and genes including Ccl4, Cd14, Crp, Cxcl1, Il6, Il1β, Lbp, Lcn2, Myd88, Nfkb1, Tlr2 and Tlr4 aligning with changes in human EAC progression, as confirmed through public databases. C-PAC is a safe promising dietary constituent that may be utilized alone or potentially as an adjuvant to current therapies to prevent EAC progression through ameliorating reflux-induced dysbiosis, inflammation and cellular damage.PMID:37662411 | PMC:PMC10473615 | DOI:10.1101/2023.08.22.554315

bioRxiv. 2023 Aug 24:2023.08.23.554488. doi: 10.1101/2023.08.23.554488. Preprint.ABSTRACTTechnologies assessing the lipidomics, genomics, epigenomics, transcriptomics, and proteomics of tissue samples at single-cell resolution have deepened our understanding of physiology and pathophysiology at an unprecedented level of detail. However, the study of single-cell spatial metabolomics in undecalcified bones faces several significant challenges, such as the fragility of bone which often requires decalcification or fixation leading to the degradation or removal of lipids and other molecules and. As such, we describe a method for performing mass spectrometry imaging on undecalcified spine that is compatible with other spatial omics measurements. In brief, we use fresh-freeze rat spines and a system of carboxyl methylcellulose embedding, cryofilm, and polytetrafluoroethylene rollers to maintain tissue integrity, while avoiding signal loss from variations in laser focus and artifacts from traditional tissue processing. This reveals various tissue types and lipidomic profiles of spinal regions at 10 μm spatial resolutions using matrix-assisted laser desorption/ionization mass spectrometry imaging. We expect this method to be adapted and applied to the analysis of spinal cord, shedding light on the mechanistic aspects of cellular heterogeneity, development, and disease pathogenesis underlying different bone-related conditions and diseases. This study furthers the methodology for high spatial metabolomics of spines, as well as adds to the collective efforts to achieve a holistic understanding of diseases via single-cell spatial multi-omics.PMID:37662353 | PMC:PMC10473750 | DOI:10.1101/2023.08.23.554488

bioRxiv. 2023 Aug 24:2023.08.23.554369. doi: 10.1101/2023.08.23.554369. Preprint.ABSTRACTCaloric restriction (CR) extends organismal lifespan and health span by improving glucose homeostasis mechanisms. How CR affects organellar structure and function of pancreatic beta cells over the lifetime of the animal remains unknown. Here, we used single nucleus transcriptomics to show that CR increases the expression of genes for beta cell identity, protein processing, and organelle homeostasis. Gene regulatory network analysis link this transcriptional phenotype to transcription factors involved in beta cell identity (Mafa) and homeostasis (Atf6). Imaging metabolomics further demonstrates that CR beta cells are more energetically competent. In fact, high-resolution light and electron microscopy indicates that CR reduces beta cell mitophagy and increases mitochondria mass, increasing mitochondrial ATP generation. Finally, we show that long-term CR delays the onset of beta cell aging and senescence to promote longevity by reducing beta cell turnover. Therefore, CR could be a feasible approach to preserve compromised beta cells during aging and diabetes.PMID:37662336 | PMC:PMC10473730 | DOI:10.1101/2023.08.23.554369

bioRxiv. 2023 Aug 25:2023.08.24.552964. doi: 10.1101/2023.08.24.552964. Preprint.ABSTRACTLung immune tone, i.e. the immune state of the lung, can vary between individuals and over a single individual's lifetime, and its basis and regulation in the context of inflammatory responses to injury is poorly understood. The gut microbiome, through the gut-lung axis, can influence lung injury outcomes but how the diet and microbiota affect lung immune tone is also unclear. We hypothesized that lung immune tone would be influenced by the presence of fiber-fermenting short-chain fatty acid (SCFA)-producing gut bacteria. To test this hypothesis, we conducted a fiber diet intervention study followed by lung injury in mice and profiled gut microbiota using 16S sequencing, metabolomics, and lung immune tone. We also studied germ-free mice to evaluate lung immune tone in the absence of microbiota and performed in vitro mechanistic studies on immune tone and metabolic programming of alveolar macrophages exposed to the SCFA propionate (C3). Mice on high-fiber diet were protected from sterile lung injury compared to mice on a fiber-free diet. This protection strongly correlated with lower lung immune tone, elevated propionate levels and enrichment of specific fecal microbiota taxa; conversely, lower levels of SCFAs and an increase in other fatty acid metabolites and bacterial taxa correlated with increased lung immune tone and increased lung injury in the fiber-free group. In vitro , C3 reduced lung alveolar macrophage immune tone (through suppression of IL-1β and IL-18) and metabolically reprogrammed them (switching from glycolysis to oxidative phosphorylation after LPS challenge). Overall, our findings reveal that the gut-lung axis, through dietary fiber intake and enrichment of SCFA-producing gut bacteria, can regulate innate lung immune tone via IL-1β and IL-18 pathways. These results provide a rationale for the therapeutic development of dietary interventions to preserve or enhance specific aspects of host lung immunity.PMID:37662303 | PMC:PMC10473695 | DOI:10.1101/2023.08.24.552964

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