PubMed

J Breath Res. 2023 May 19. doi: 10.1088/1752-7163/acd715. Online ahead of print.ABSTRACTProlonged exposure to hyperbaric hyperoxia can lead to pulmonary oxygen toxicity (PO2tox). PO2tox is a mission limiting factor for special operations forces divers using closed-circuit rebreathing apparatus and a potential side effect for patients undergoing hyperbaric oxygen (HBO) treatment. In this study, we aim to determine if there is a specific breath profile of compounds in exhaled breath condensate (EBC) that is indicative of the early stages of pulmonary hyperoxic stress/PO2tox. 
Using a double-blind, randomized "sham" controlled, cross-over design 14 U.S. Navy trained diver volunteers breathed two different gas mixtures at an ambient pressure of 2 ATA (33 fsw, 10 msw) for 6.5 hours. One test gas consisted of 100% O2 (HBO) and the other was a gas mixture containing 30.6% O2 with the balance N2 (Nitrox). The high O2 stress dive (HBO) and low O2 stress dive (nitrox) were separated by at least seven days and were conducted dry and at rest inside a hyperbaric chamber. EBC samples were taken immediately before and after each dive and subsequently underwent a targeted and untargeted metabolomics analysis using liquid chromatography coupled to mass spectrometry (LC-MS). 
Following the HBO dive, 10 out of 14 subjects reported symptoms of the early stages of PO2tox and one subject terminated the dive early due to severe symptoms of PO2tox. No symptoms of PO2tox were reported following the nitrox dive. A Partial Least-Squares Discriminant Analysis of the normalized (relative to pre-dive) untargeted data gave good classification abilities between the HBO and nitrox EBC with an AUC of 0.99 (± 2%) and sensitivity and specificity of 0.93 (± 10%) and 0.94 (± 10%), respectively. The resulting classifications identified specific biomarkers that included human metabolites and lipids and their derivatives from different metabolic pathways that may explain metabolomic changes resulting from prolonged HBO exposure.
&#xD.PMID:37207635 | DOI:10.1088/1752-7163/acd715

Biochem Biophys Res Commun. 2023 May 4;667:34-42. doi: 10.1016/j.bbrc.2023.05.018. Online ahead of print.ABSTRACTIslet regeneration is a complex process involving multiple metabolic adaptions, but the specific characterization of the islet metabolome in relation to cell proliferation has not been established. This study aimed to investigate the metabolomic changes of regenerative islets from partial pancreatectomy (Ppx) mice and speculate underlying mechanisms. Islet samples were collected from C57/BL6 mice undergoing 70-80% Ppx or sham surgery, followed by analyses of glucose homeostasis, islet morphology, and untargeted metabolomics profiles using liquid chromatography-tandem mass spectrometry (LC-MS/MS). There is no difference in blood glucose and body weight between sham and Ppx mice. After surgery, the Ppx mice showed impaired glucose tolerance, increased Ki67 positive beta cells, and elevated beta-cell mass. LC-MS/MS analysis identified fourteen differentially changed metabolites in islets of Ppx mice, including long-chain fatty acids (e.g., docosahexaenoic acid) and amino acid derivatives (e.g., creatine). Pathway analysis based on the KEGG database revealed five significantly enriched signaling pathways including cAMP signaling pathway. Further immunostaining assay on pancreatic tissue sections showed the levels of p-CREB, a transcription factor downstream of cAMP, elevated in islets from Ppx mice. In conclusion, our results demonstrate that islet regeneration involves metabolic alterations in long-chain fatty acids and amino acid derivatives, as well as the activation of the cAMP signaling pathway.PMID:37207562 | DOI:10.1016/j.bbrc.2023.05.018

Plant Physiol Biochem. 2023 May 12;200:107742. doi: 10.1016/j.plaphy.2023.107742. Online ahead of print.ABSTRACTAnthocyanins and selenium (Se) play critical roles in antioxidant, anticancer, antibacterial, and antiviral treatments. Previous studies indicate that colored-grain wheat accumulates more Se than regular wheat, and Se synergistically promotes anthocyanin synthesis. However, the mechanism through which Se regulates anthocyanin synthesis remains unclear. We studied anthocyanin accumulation during the grain-filling stage of colored-grain wheat development by employing transcriptomics and metabolomics. We show that Se biofortification increased the concentrations of Se, anthocyanin, chlorophyll a and b, and carotenoids in colored-grain wheat. Genes related to biosynthesis of anthocyanins, phenylpropanoids biosynthesis, and flavonoids biosynthesis were significantly upregulated after Se treatment, which led to the accumulation of anthocyanin metabolites in colored-grain wheat. Genetic alterations in the expression profiles of several genes and transcription factors were observed, which slowed down lignin and proanthocyanidin biosynthesis and accelerated anthocyanin synthesis. Our results deepen the understanding of anthocyanin metabolism in Se-treated colored-grain wheat, which will likely promote harvest of these varieties.PMID:37207492 | DOI:10.1016/j.plaphy.2023.107742

Aquat Toxicol. 2023 May 17;260:106569. doi: 10.1016/j.aquatox.2023.106569. Online ahead of print.ABSTRACTCarbonate alkalinity (CA) is one of the environmental factors affecting the survival and growth of aquatic animals. However, the toxic effects of CA stress on Pacific white shrimp Litopenaeus vannamei at the molecular level are completely unclear. In this study, we investigated the changes of the survival and growth, and hepatopancreas histology of L. vannamei under different levels of CA stress, and integrated transcriptomics and metabolomics to explore major functional changes in the hepatopancreas and identify biomarkers. After CA exposure for 14 days, the survival and growth of the shrimp were reduced, and the hepatopancreas showed obvious histological damage. A total of 253 genes were differentially expressed in the three CA stress groups, and immune-related genes such as pattern recognition receptors, phenoloxidase system and detoxification metabolism were affected; substance transport-related regulators and transporters were mostly downregulated. Furthermore, the metabolic pattern of the shrimp was also altered by CA stress, especially amino acids, arachidonic acid and B-vitamin metabolites. The integration analysis of differential metabolites and genes further showed that the functions of ABC transporters, protein digestion and absorption, and amino acid biosynthesis and metabolism were highly altered by CA stress. The results of this study revealed that CA stress caused immune, substance transport, and amino acid metabolic variations in L. vannamei, and identified several potential biomarkers related to stress response.PMID:37207485 | DOI:10.1016/j.aquatox.2023.106569

J Neuroimmunol. 2023 May 11;379:578105. doi: 10.1016/j.jneuroim.2023.578105. Online ahead of print.ABSTRACTTo prioritize circulating metabolites that likely play causal roles in the pathogenesis of multiple sclerosis (MS). Two-sample Mendelian randomization analysis was performed to estimate the causal effects of 571 circulating metabolites on the risk of MS. Genetic instruments for circulating metabolites were obtained from three previous genome-wide association studies (GWAS) of the blood metabolome (N = 7824; 24,925; and 115,078; respectively), while genetic associations with MS were from a large GWAS by the International Multiple Sclerosis Genetics Consortium (14,802 cases and 26,703 control). The primary analysis was performed with the multiplicative random-effect inverse variance-weighted method, while multiple sensitivity analyses were conducted with the weighted median, weighted mode, MR-Egger, and MR-PRESSO. A total of 29 metabolites had suggestive evidence of causal associations with MS. Genetically instrumented levels of serine (OR = 1.56, 95% CI = 1.25-1.95), lysine (OR = 1.18, 95% CI = 1.01-1.38), acetone (OR = 2.45, 95% CI = 1.02-5.90), and acetoacetate (OR = 2.47, 95% CI = 1.14-5.34) were associated with a higher MS risk. Total cholesterol and phospholipids in large very-low-density lipoprotein were associated with a lower MS risk (OR = 0.83, 95% CI = 0.69-1.00; OR = 0.80, 95% CI = 0.68-0.95), but risk-increasing associations (OR = 1.20, 95% CI = 1.04-1.40; OR = 1.13, 95% CI = 1.00-1.28) were observed for the same two lipids in very large high-density lipoprotein. Our metabolome-wide Mendelian randomization study prioritized a list of circulating metabolites, such as serine, lysine, acetone, acetoacetate, and lipids, that likely have causal associations with MS.PMID:37207441 | DOI:10.1016/j.jneuroim.2023.578105

Curr Opin Chem Biol. 2023 May 17;75:102324. doi: 10.1016/j.cbpa.2023.102324. Online ahead of print.ABSTRACTWith the rapid progress in metabolomics and sequencing technologies, more data on the metabolome of single microbes and their communities become available, revealing the potential of microorganisms to metabolize a broad range of chemical compounds. The analysis of microbial metabolomics datasets remains challenging since it inherits the technical challenges of metabolomics analysis, such as compound identification and annotation, while harboring challenges in data interpretation, such as distinguishing metabolite sources in mixed samples. This review outlines the recent advances in computational methods to analyze primary microbial metabolism: knowledge-based approaches that take advantage of metabolic and molecular networks and data-driven approaches that employ machine/deep learning algorithms in combination with large-scale datasets. These methods aim at improving metabolite identification and disentangling reciprocal interactions between microbes and metabolites. We also discuss the perspective of combining these approaches and further developments required to advance the investigation of primary metabolism in mixed microbial samples.PMID:37207402 | DOI:10.1016/j.cbpa.2023.102324

Adv Mater. 2023 May 19:e2301623. doi: 10.1002/adma.202301623. Online ahead of print.ABSTRACTDrug combination provides an efficient pathway to combat drug resistance in bacteria and bacterial biofilms. However, the facile methodology to construct the drug combinations and their applications in nanocomposites is still lacking. Here we report the two-tailed antimicrobial amphiphiles (T2 A2 ) composed of nitric oxide (NO)-donor (diethylenetriamine NONOate, DN) and various natural aldehydes. T2 A2 self-assemble into nanoparticles due to their amphiphilic nature, with remarkably low critical aggregation concentration. The representative cinnamaldehyde (Cin)-derived T2 A2 (Cin-T2 A2 ) assemblies demonstrate excellent bactericidal efficacy, notably higher than free Cin and free DN. Cin-T2 A2 assemblies kill multidrug-resistant staphylococci and eradicate their biofilms via multiple mechanisms, as proved by mechanism studies, molecular dynamics simulations, proteomics, and metabolomics. Furthermore, Cin-T2 A2 assemblies rapidly eradicate bacteria and alleviate inflammation in the subsequent murine infection models. Together, our Cin-T2 A2 assemblies may provide an efficient, non-antibiotic alternative in combating the ever-increasing threat of drug-resistant bacteria and their biofilms. This article is protected by copyright. All rights reserved.PMID:37207289 | DOI:10.1002/adma.202301623

iScience. 2023 Apr 25;26(5):106744. doi: 10.1016/j.isci.2023.106744. eCollection 2023 May 19.ABSTRACTEmerging studies demonstrate that inflammation plays a crucial role in the pathogenesis of bipolar disorder (BD), but the underlying mechanism remains largely unclear. Given the complexity of BD pathogenesis, we performed high-throughput multi-omic profiling (metabolomics, lipidomics, and transcriptomics) of the BD zebrafish brain to comprehensively unravel the molecular mechanism. Our research proved that in BD zebrafish, JNK-mediated neuroinflammation altered metabolic pathways involved in neurotransmission. On one hand, disturbed metabolism of tryptophan and tyrosine limited the participation of the monoamine neurotransmitters serotonin and dopamine in synaptic vesicle recycling. On the other hand, dysregulated metabolism of the membrane lipids sphingomyelin and glycerophospholipids altered the synaptic membrane structure and neurotransmitter receptors (chrnα7, htr1b, drd5b, and gabra1) activity. Our findings revealed that disturbance of serotonergic and dopaminergic synaptic transmission mediated by the JNK inflammatory cascade was the key pathogenic mechanism in a zebrafish model of BD, provides critical biological insights into the pathogenesis of BD.PMID:37207274 | PMC:PMC10189518 | DOI:10.1016/j.isci.2023.106744

Life Metab. 2023 Apr;2(2):load014. doi: 10.1093/lifemeta/load014. Epub 2023 Apr 4.ABSTRACTWeight loss from an overweight state is associated with a disproportionate decrease in whole-body energy expenditure that may contribute to the heightened risk for weight regain. Evidence suggests that this energetic mismatch originates from lean tissue. Although this phenomenon is well documented, the mechanisms have remained elusive. We hypothesized that increased mitochondrial energy efficiency in skeletal muscle is associated with reduced expenditure under weight loss. Wildtype (WT) male C57BL6/N mice were fed with high fat diet for 10 weeks, followed by a subset of mice that were maintained on the obesogenic diet (OB) or switched to standard chow to promote weight loss (WL) for additional 6 weeks. Mitochondrial energy efficiency was evaluated using high-resolution respirometry and fluorometry. Mass spectrometric analyses were employed to describe the mitochondrial proteome and lipidome. Weight loss promoted ~50% increase in the efficiency of oxidative phosphorylation (ATP produced per O2 consumed, or P/O) in skeletal muscle. However, weight loss did not appear to induce significant changes in mitochondrial proteome, nor any changes in respiratory supercomplex formation. Instead, it accelerated the remodeling of mitochondrial cardiolipin (CL) acyl-chains to increase tetralinoleoyl CL (TLCL) content, a species of lipids thought to be functionally critical for the respiratory enzymes. We further show that lowering TLCL by deleting the CL transacylase tafazzin was sufficient to reduce skeletal muscle P/O and protect mice from diet-induced weight gain. These findings implicate skeletal muscle mitochondrial efficiency as a novel mechanism by which weight loss reduces energy expenditure in obesity.PMID:37206438 | PMC:PMC10195096 | DOI:10.1093/lifemeta/load014

Front Physiol. 2023 May 3;14:1211911. doi: 10.3389/fphys.2023.1211911. eCollection 2023.NO ABSTRACTPMID:37206364 | PMC:PMC10189146 | DOI:10.3389/fphys.2023.1211911

Front Microbiol. 2023 May 3;14:1160821. doi: 10.3389/fmicb.2023.1160821. eCollection 2023.ABSTRACTOBJECTIVE: Bile reflux plays a key role in the development of gastric intestinal metaplasia (GIM), an independent risk factor of gastric cancer. Here, we aimed to explore the biological mechanism of GIM induced by bile reflux in a rat model.METHODS: Rats were treated with 2% sodium salicylate and allowed to freely drink 20 mmol/L sodium deoxycholate for 12 weeks, and GIM was confirmed by histopathological analysis. Gastric microbiota was profiled according to the 16S rDNA V3-V4 region, gastric transcriptome was sequenced, and serum bile acids (BAs) were analyzed by targeted metabolomics. Spearman's correlation analysis was used in constructing the network among gastric microbiota, serum BAs, and gene profiles. Real-time polymerase chain reaction (RT-PCR) measured the expression levels of nine genes in the gastric transcriptome.RESULTS: In the stomach, deoxycholic acid (DCA) decreased the microbial diversity but promoted the abundances of several bacterial genera, such as Limosilactobacillus, Burkholderia-Caballeronia-Paraburkholderia, and Rikenellaceae RC9 gut group. Gastric transcriptome showed that the genes enriched in gastric acid secretion were significantly downregulated, whereas the genes enriched in fat digestion and absorption were obviously upregulated in GIM rats. The GIM rats had four promoted serum BAs, namely cholic acid (CA), DCA, taurocholic acid, and taurodeoxycholic acid. Further correlation analysis showed that the Rikenellaceae RC9 gut group was significantly positively correlated with DCA and RGD1311575 (capping protein-inhibiting regulator of actin dynamics), and RGD1311575 was positively correlated with Fabp1 (fatty acid-binding protein, liver), a key gene involved in fat digestion and absorption. Finally, the upregulated expression of Dgat1 (diacylglycerol acyltransferase 1) and Fabp1 related to fat digestion and absorption was identified by RT-PCR and IHC.CONCLUSION: DCA-induced GIM enhanced gastric fat digestion and absorption function and impaired gastric acid secretion function. The DCA-Rikenellaceae RC9 gut group-RGD1311575/Fabp1 axis might play a key role in the mechanism of bile reflux-related GIM.PMID:37206332 | PMC:PMC10188980 | DOI:10.3389/fmicb.2023.1160821

Front Microbiol. 2023 May 3;14:1164877. doi: 10.3389/fmicb.2023.1164877. eCollection 2023.ABSTRACTMicroorganisms and their hosts communicate with each other by secreting numerous components. This cross-kingdom cell-to-cell signaling involves proteins and small molecules, such as metabolites. These compounds can be secreted across the membrane via numerous transporters and may also be packaged in outer membrane vesicles (OMVs). Among the secreted components, volatile compounds (VOCs) are of particular interest, including butyrate and propionate, which have proven effects on intestinal, immune, and stem cells. Besides short fatty acids, other groups of volatile compounds can be either freely secreted or contained in OMVs. As vesicles might extend their activity far beyond the gastrointestinal tract, study of their cargo, including VOCs, is even more pertinent. This paper is devoted to the VOCs secretome of the Bacteroides genus. Although these bacteria are highly presented in the intestinal microbiota and are known to influence human physiology, their volatile secretome has been studied relatively poorly. The 16 most well-represented Bacteroides species were cultivated; their OMVs were isolated and characterized by NTA and TEM to determine particle morphology and their concentration. In order to analyze the VOCs secretome, we propose a headspace extraction with GC-MS analysis as a new tool for sample preparation and analysis of volatile compounds in culture media and isolated bacterial OMVs. A wide range of released VOCs, both previously characterized and newly described, have been revealed in media after cultivation. We identified more than 60 components of the volatile metabolome in bacterial media, including fatty acids, amino acids, and phenol derivatives, aldehydes and other components. We found active butyrate and indol producers among the analyzed Bacteroides species. For a number of Bacteroides species, OMVs have been isolated and characterized here for the first time as well as volatile compounds analysis in OMVs. We observed a completely different distribution of VOC in vesicles compared to the bacterial media for all analyzed Bacteroides species, including almost complete absence of fatty acids in vesicles. This article provides a comprehensive analysis of the VOCs secreted by Bacteroides species and explores new perspectives in the study of bacterial secretomes in relation the intercellular communication.PMID:37206326 | PMC:PMC10189065 | DOI:10.3389/fmicb.2023.1164877

Front Cardiovasc Med. 2023 May 3;10:1161761. doi: 10.3389/fcvm.2023.1161761. eCollection 2023.ABSTRACTBACKGROUND: The intermediate metabolites associated with the development of atherosclerotic cardiovascular disease (ASCVD) remain largely unknown. Thus, we conducted a large panel of metabolomics profiling to identify the new candidate metabolites that were associated with 10-year ASCVD risk.METHODS: Thirty acylcarnitines and twenty amino acids were measured in the fasting plasma of 1,102 randomly selected individuals using a targeted FIA-MS/MS approach. The 10-year ASCVD risk score was calculated based on 2013 ACC/AHA guidelines. Accordingly, the subjects were stratified into four groups: low-risk (n = 620), borderline-risk (n = 110), intermediate-risk (n = 225), and high-risk (n = 147). 10 factors comprising collinear metabolites were extracted from principal component analysis.RESULTS: C4DC, C8:1, C16OH, citrulline, histidine, alanine, threonine, glycine, glutamine, tryptophan, phenylalanine, glutamic acid, arginine, and aspartic acid were significantly associated with the 10-year ASCVD risk score (p-values ≤ 0.044). The high-risk group had higher odds of factor 1 (12 long-chain acylcarnitines, OR = 1.103), factor 2 (5 medium-chain acylcarnitines, OR = 1.063), factor 3 (methionine, leucine, valine, tryptophan, tyrosine, phenylalanine, OR = 1.074), factor 5 (6 short-chain acylcarnitines, OR = 1.205), factor 6 (5 short-chain acylcarnitines, OR = 1.229), factor 7 (alanine, proline, OR = 1.343), factor 8 (C18:2OH, glutamic acid, aspartic acid, OR = 1.188), and factor 10 (ornithine, citrulline, OR = 1.570) compared to the low-risk ones; the odds of factor 9 (glycine, serine, threonine, OR = 0.741), however, were lower in the high-risk group. "D-glutamine and D-glutamate metabolism", "phenylalanine, tyrosine, and tryptophan biosynthesis", and "valine, leucine, and isoleucine biosynthesis" were metabolic pathways having the highest association with borderline/intermediate/high ASCVD events, respectively.CONCLUSIONS: Abundant metabolites were found to be associated with ASCVD events in this study. Utilization of this metabolic panel could be a promising strategy for early detection and prevention of ASCVD events.PMID:37206107 | PMC:PMC10188945 | DOI:10.3389/fcvm.2023.1161761

Heliyon. 2023 Apr 20;9(5):e15602. doi: 10.1016/j.heliyon.2023.e15602. eCollection 2023 May.ABSTRACTShengjiang Xiexin Decoction (SXD) is a widely recognized formula in Traditional Chinese Medicine (TCM) for treating diarrhea and is commonly used in clinical practice. Clostridium difficile infection (CDI) is a type of antibiotic-associated diarrhea with a rising incidence rate that has severe consequences for humans. Recent clinical applications have found significant efficacy in using SXD as an adjunct to CDI treatment. However, the pharmacodynamic substance basis and therapeutic mechanism of SXD remain unclear. This study aimed to systematically analyze the metabolic mechanisms and key pharmacodynamic components of SXD in CDI mice by combining non-targeted metabolomics of Chinese medicine and serum medicinal chemistry. We established a CDI mouse model to observe the therapeutic effect of SXD on CDI. We investigated the mechanism of action and active substance composition of SXD against CDI by analyzing 16S rDNA gut microbiota, untargeted serum metabolomics, and serum pharmacochemistry. We also constructed a multi-scale, multifactorial network for overall visualization and analysis. Our results showed that SXD significantly reduced fecal toxin levels and attenuated colonic injury in CDI model mice. Additionally, SXD partially restored CDI-induced gut microbiota composition. Non-targeted serum metabolomics studies showed that SXD not only regulated Taurine and hypotaurine metabolism but also metabolic energy and amino acid pathways such as Ascorbate and aldarate metabolism, Glycerolipid metabolism, Pentose and glucuronate interconversions, as well as body and other metabolite production in the host. Through the implementation of network analysis methodologies, we have discerned that Panaxadiol, Methoxylutcolin, Ginsenoside-Rf, Suffruticoside A, and 10 other components serve as critical potential pharmacodynamic substance bases of SXD for CDI. This study reveals the metabolic mechanism and active substance components of SXD for the treatment of CDI mice using phenotypic information, gut microbiome, herbal metabolomics, and serum pharmacochemistry. It provides a theoretical basis for SXD quality control studies.PMID:37206044 | PMC:PMC10189181 | DOI:10.1016/j.heliyon.2023.e15602

Oncoimmunology. 2023 May 15;12(1):2212547. doi: 10.1080/2162402X.2023.2212547. eCollection 2023.ABSTRACTIn a recent paper in Science, Chen et al. reported the genetic engineering of S. epidermidis expressing tumor cross-reactive antigens that trigger T cell responses and exhibit anticancer effects after topical administration. Here we discuss direct local effects and indirect systemic effects of exposure to engineered S. epidermidis strains.PMID:37205984 | PMC:PMC10190176 | DOI:10.1080/2162402X.2023.2212547

PLoS Biol. 2023 May 19;21(5):e3002125. doi: 10.1371/journal.pbio.3002125. Online ahead of print.ABSTRACTHuman gut bacteria perform diverse metabolic functions with consequences for host health. The prevalent and disease-linked Actinobacterium Eggerthella lenta performs several unusual chemical transformations, but it does not metabolize sugars and its core growth strategy remains unclear. To obtain a comprehensive view of the metabolic network of E. lenta, we generated several complementary resources: defined culture media, metabolomics profiles of strain isolates, and a curated genome-scale metabolic reconstruction. Stable isotope-resolved metabolomics revealed that E. lenta uses acetate as a key carbon source while catabolizing arginine to generate ATP, traits which could be recapitulated in silico by our updated metabolic model. We compared these in vitro findings with metabolite shifts observed in E. lenta-colonized gnotobiotic mice, identifying shared signatures across environments and highlighting catabolism of the host signaling metabolite agmatine as an alternative energy pathway. Together, our results elucidate a distinctive metabolic niche filled by E. lenta in the gut ecosystem. Our culture media formulations, atlas of metabolomics data, and genome-scale metabolic reconstructions form a freely available collection of resources to support further study of the biology of this prevalent gut bacterium.PMID:37205710 | DOI:10.1371/journal.pbio.3002125

medRxiv. 2023 May 1:2023.04.29.23289299. doi: 10.1101/2023.04.29.23289299. Preprint.ABSTRACTValvular heart disease is associated with a high global burden of disease. Even mild aortic stenosis confers increased morbidity and mortality, prompting interest in understanding normal variation in valvular function at scale. We developed a deep learning model to study velocity-encoded magnetic resonance imaging in 47,223 UK Biobank participants. We calculated eight traits, including peak velocity, mean gradient, aortic valve area, forward stroke volume, mitral and aortic regurgitant volume, greatest average velocity, and ascending aortic diameter. We then computed sex-stratified reference ranges for these phenotypes in up to 31,909 healthy individuals. In healthy individuals, we found an annual decrement of 0.03cm 2 in the aortic valve area. Participants with mitral valve prolapse had a 1 standard deviation [SD] higher mitral regurgitant volume (P=9.6 × 10 -12 ), and those with aortic stenosis had a 4.5 SD-higher mean gradient (P=1.5 × 10 -431 ), validating the derived phenotypes' associations with clinical disease. Greater levels of ApoB, triglycerides, and Lp(a) assayed nearly 10 years prior to imaging were associated with higher gradients across the aortic valve. Metabolomic profiles revealed that increased glycoprotein acetyls were also associated with an increased aortic valve mean gradient (0.92 SD, P=2.1 x 10 -22 ). Finally, velocity-derived phenotypes were risk markers for aortic and mitral valve surgery even at thresholds below what is considered relevant disease currently. Using machine learning to quantify the rich phenotypic data of the UK Biobank, we report the largest assessment of valvular function and cardiovascular disease in the general population.PMID:37205587 | PMC:PMC10187336 | DOI:10.1101/2023.04.29.23289299

bioRxiv. 2023 Mar 30:2023.03.29.534718. doi: 10.1101/2023.03.29.534718. Preprint.ABSTRACTIschemic stroke results in a loss of tissue homeostasis and integrity, the underlying pathobiology of which stems primarily from the depletion of cellular energy stores and perturbation of available metabolites 1 . Hibernation in thirteen-lined ground squirrels (TLGS), Ictidomys tridecemlineatus , provides a natural model of ischemic tolerance as these mammals undergo prolonged periods of critically low cerebral blood flow without evidence of central nervous system (CNS) damage 2 . Studying the complex interplay of genes and metabolites that unfolds during hibernation may provide novel insights into key regulators of cellular homeostasis during brain ischemia. Herein, we interrogated the molecular profiles of TLGS brains at different time points within the hibernation cycle via RNA sequencing coupled with untargeted metabolomics. We demonstrate that hibernation in TLGS leads to major changes in the expression of genes involved in oxidative phosphorylation and this is correlated with an accumulation of the tricarboxylic acid (TCA) cycle intermediates citrate, cis-aconitate, and α-ketoglutarate-αKG. Integration of the gene expression and metabolomics datasets led to the identification of succinate dehydrogenase (SDH) as the critical enzyme during hibernation, uncovering a break in the TCA cycle at that level. Accordingly, the SDH inhibitor dimethyl malonate (DMM) was able to rescue the effects of hypoxia on human neuronal cells in vitro and in mice subjected to permanent ischemic stroke in vivo . Our findings indicate that studying the regulation of the controlled metabolic depression that occurs in hibernating mammals may lead to novel therapeutic approaches capable of increasing ischemic tolerance in the CNS.PMID:37205496 | PMC:PMC10187245 | DOI:10.1101/2023.03.29.534718

bioRxiv. 2023 May 3:2023.05.02.539172. doi: 10.1101/2023.05.02.539172. Preprint.ABSTRACTExercise modulates vascular plasticity in multiple organ systems; however, the metabolomic transducers underlying exercise and vascular protection in the disturbed flow-prone vasculature remain under-investigated. We simulated exercise-augmented pulsatile shear stress (PSS) to mitigate flow recirculation in the lesser curvature of the aortic arch. When human aortic endothelial cells (HAECs) were subjected to PSS ( τ ave = 50 dyne·cm -2 , ∂τ/∂t = 71 dyne·cm -2 ·s -1 , 1 Hz), untargeted metabolomic analysis revealed that Stearoyl-CoA Desaturase (SCD1) in the endoplasmic reticulum (ER) catalyzed the fatty acid metabolite, oleic acid (OA), to mitigate inflammatory mediators. Following 24 hours of exercise, wild-type C57BL/6J mice developed elevated SCD1-catalyzed lipid metabolites in the plasma, including OA and palmitoleic acid (PA). Exercise over a 2-week period increased endothelial SCD1 in the ER. Exercise further modulated the time-averaged wall shear stress (TAWSS or τ ave) and oscillatory shear index (OSI ave ), upregulated Scd1 and attenuated VCAM1 expression in the disturbed flow-prone aortic arch in Ldlr -/- mice on high-fat diet but not in Ldlr -/- Scd1 EC-/- mice. Scd1 overexpression via recombinant adenovirus also mitigated ER stress. Single cell transcriptomic analysis of the mouse aorta revealed interconnection of Scd1 with mechanosensitive genes, namely Irs2 , Acox1 and Adipor2 that modulate lipid metabolism pathways. Taken together, exercise modulates PSS ( τ ave and OSI ave ) to activate SCD1 as a metabolomic transducer to ameliorate inflammation in the disturbed flow-prone vasculature.PMID:37205360 | PMC:PMC10187200 | DOI:10.1101/2023.05.02.539172

Nanoscale Adv. 2023 Jan 30;5(10):2674-2723. doi: 10.1039/d2na00534d. eCollection 2023 May 16.ABSTRACTNowadays, nanomaterials (NMs) are widely present in daily life due to their significant benefits, as demonstrated by their application in many fields such as biomedicine, engineering, food, cosmetics, sensing, and energy. However, the increasing production of NMs multiplies the chances of their release into the surrounding environment, making human exposure to NMs inevitable. Currently, nanotoxicology is a crucial field, which focuses on studying the toxicity of NMs. The toxicity or effects of nanoparticles (NPs) on the environment and humans can be preliminary assessed in vitro using cell models. However, the conventional cytotoxicity assays, such as the MTT assay, have some drawbacks including the possibility of interference with the studied NPs. Therefore, it is necessary to employ more advanced techniques that provide high throughput analysis and avoid interferences. In this case, metabolomics is one of the most powerful bioanalytical strategies to assess the toxicity of different materials. By measuring the metabolic change upon the introduction of a stimulus, this technique can reveal the molecular information of the toxicity induced by NPs. This provides the opportunity to design novel and efficient nanodrugs and minimizes the risks of NPs used in industry and other fields. Initially, this review summarizes the ways that NPs and cells interact and the NP parameters that play a role in this interaction, and then the assessment of these interactions using conventional assays and the challenges encountered are discussed. Subsequently, in the main part, we introduce the recent studies employing metabolomics for the assessment of these interactions in vitro.PMID:37205285 | PMC:PMC10186990 | DOI:10.1039/d2na00534d