PubMed

J Dairy Sci. 2023 Jun 7:S0022-0302(23)00327-2. doi: 10.3168/jds.2022-22282. Online ahead of print.ABSTRACTThe extent to which a nutrition-related disorder such as ketosis alters the ruminal microbiota or whether microbiota composition is related to ketosis and potential associations with host metabolism is unknown. We aimed to evaluate variations occurring in the ruminal microbiota of ketotic and nonketotic cows in the early postpartum period, and how those changes may affect the risk of developing the disease. Data on milk yield, dry matter intake (DMI), body condition score, and blood β-hydroxybutyrate (BHB) concentrations at 21 d postpartum were used to select 27 cows, which were assigned (n = 9 per group) to a clinical ketotic (CK, 4.10 ± 0.72 mmol BHB/L, DMI 11.61 ± 0.49 kg/d, ruminal pH 7.55 ± 0.07), subclinical ketotic (SK, 1.36 ± 0.12 mmol BHB/L, DMI 15.24 ± 0.34 kg/d, ruminal pH 7.58 ± 0.08), or control (NK, 0.88 ± 0.14 mmol BHB/L, DMI 16.74 ± 0.67/d, ruminal pH 7.61 ± 0.03) group. Cows averaged 3.6 ± 0.5 lactations and a body condition score of 3.11 ± 0.34 at the time of sampling. After blood serum collection for metabolomics analysis (1H nuclear magnetic resonance spectra), 150 mL of ruminal digesta was collected from each cow using an esophageal tube, paired-end (2 × 300 bp) sequencing of isolated DNA from ruminal digesta was performed via Illumina MiSeq, and sequencing data were analyzed using QIIME2 (v 2020.6) to measure the ruminal microbiota composition and relative abundance. Spearman correlation coefficients were used to evaluate relationships between relative abundance of bacterial genera and concentrations of serum metabolites. There were more than 200 genera, with approximately 30 being significant between NK and CK cows. Succinivibrionaceae UCG 1 taxa decreased in CK compared with NK cows. Christensenellaceae (Spearman correlation coefficient = 0.6), Ruminococcaceae (Spearman correlation coefficient = 0.6), Lachnospiraceae (Spearman correlation coefficient = 0.5), and Prevotellaceae (Spearman correlation coefficient = 0.6) genera were more abundant in the CK group and were highly positively correlated with plasma BHB. Metagenomic analysis indicated a high abundance of predicted functions related to metabolism (37.7%), genetic information processing (33.4%), and Brite hierarchies (16.3%) in the CK group. The 2 most important metabolic pathways for butyrate and propionate production were enriched in CK cows, suggesting increased production of acetyl coenzyme A and butyrate and decreased production of propionate. Overall, the combined data suggested that microbial populations may be related to ketosis by affecting short-chain fatty acid metabolism and BHB accumulation even in cows with adequate feed intake in the early postpartum period.PMID:37296048 | DOI:10.3168/jds.2022-22282

Drug Metab Dispos. 2023 Jun 9:DMD-MR-2022-001069. doi: 10.1124/dmd.122.001069. Online ahead of print.ABSTRACTMass spectrometric imaging (MSI) is a non-targeted, tag-free, high-throughput, and highly responsive analytical approach. The highly accurate molecular visualization detection technology enables to provide qualitative and quantitative analyses of biological tissues or cells scanned by mass spectrometry in situ, extracting known and unknown multiple compounds, and simultaneously assessing relative contents of targeting molecules by monitoring their molecular ions, and pinpointing the spatial locations of those molecules distributed. Five mass spectrometric imaging techniques and their characteristics are introduced in the review, including matrix-assisted laser desorption ionization (MALDI) mass spectrometry, secondary ion mass spectrometry (SIMS), desorption electrospray ionization (DESI) mass spectrometry, laser ablation electrospray ionization (LAESI) mass spectrometry, and laser ablation inductively coupled plasma (LA-ICP) mass spectrometry. The mass spectrometry-based techniques provide the possibility for spatial metabolomics with the capability of high throughput and precision detection. The approaches have been widely employed to spatially image not only metabolome of endogenous amino acids, peptides, proteins, neurotransmitters, and lipids, but also the disposition of exogenous chemicals, such as pharmaceutical agents, environmental pollutants, toxicants, natural products, and heavy metals. The techniques also provide us with spatial distribution imaging of analytes in single cells, tissue microregions, organs, and whole animals. Significance Statement The review article includes an overview of five commonly used mass spectrometers for spatial imaging and describes the advantages and disadvantages of each. Examples of the technology applications cover drug disposition, diseases, and omics. Technical aspects of relative and absolute quantification by mass spectrometric imaging and challenges for future new applications are discussed as well. The reviewed knowledge anticipates to benefit the development of new drugs and to better understand biochemical processes related to physiology and diseases.PMID:37295949 | DOI:10.1124/dmd.122.001069

Environ Toxicol Pharmacol. 2023 Jun 7:104172. doi: 10.1016/j.etap.2023.104172. Online ahead of print.ABSTRACTChronic Cd exposure induces an inflammatory response that contributes to liver damage. In the present study, C57BL/6J mice (8 weeks) were administered CdCl2 (0.6mg/L) orally for 6 months, and the underlying mechanism of chronic Cd-induced hepatotoxicity was explored through the application of transcriptomics and metabolomics. Chronic Cd exposure induced focal necrosis and inflammatory cell infiltration in the livers of mice. Importantly, hepatic IL-1β, IL-6, IL-9, IL-10, IL-17 and GM-CSF levels were significantly increased following chronic Cd exposure. Ingenuity Pathway Analysis of the transcriptomics profiles combined with RTqPCR was used to identify and optimize a crucial inflammatory response network in chronic Cd hepatotoxicity. Furthermore, an integrative analysis combining inflammatory response genes with differential metabolites revealed that 1-stearoyl-2-arachidonoyl-sn-glycerol and 4-hydroxybutanoic acid lactone levels were significantly correlated with all inflammatory response genes. Overall, our findings in this study help decipher the underlying mechanisms and key molecular events of chronic Cd hepatotoxicity.PMID:37295737 | DOI:10.1016/j.etap.2023.104172

Plant Sci. 2023 Jun 7:111762. doi: 10.1016/j.plantsci.2023.111762. Online ahead of print.ABSTRACTTranscription factor (TF) modulation is a promising strategy for plant flavonoid improvement. Here, we observed evident decreases in some major flavones and flavonols and the expression of some key related genes in a 'Newhall' navel orange mutant (MT) relative to the wild type (WT). A consistently downregulated ERF TF CsERF003 in MT could increase the contents of major flavonoids and the precursor phenylalanine when transiently overexpressed in citrus fruit. Overexpression of CsERF003 in 'Micro-Tom' tomato (OE) resulted in a darker and redder fruit color than wild type 'Micro-Tom' (WTm). Two major flavonoids, naringeninchalcone and kaempferolrutinoside, were averagely induced by 7.99- and 36.83-fold in OEs, respectively, while little change was observed in other polyphenols, such as caffeic acid, ferulic acid, and gallic acid. Key genes involved in the initiation of phenylpropanoid (PAL, 4CH, and 4CL) and flavonoid (CHS and CHI) biosynthesis were up-regulated, while most genes participating in the biosynthesis of other polyphenols, such as HCT and CCR, were down-regulated in OEs. Therefore, it could be concluded that carbon flux floods into the phenylpropanoid biosynthetic pathway and is then specifically directed for flavonoid biosynthesis. CsERF003 may be a potentially promising gene for fruit quality improvement and engineering of natural flavonoid components.PMID:37295731 | DOI:10.1016/j.plantsci.2023.111762

Environ Res. 2023 Jun 7:116357. doi: 10.1016/j.envres.2023.116357. Online ahead of print.ABSTRACTPesticide and fertilizer usage is at the center of agricultural production to meet the demands of an ever-increasing global population. However, rising levels of chemicals impose a serious threat to the health of humans, animals, plants, and even the entire biosphere because of their toxic effects. Biostimulants offer the opportunity to reduce the agricultural chemical footprint owing their multilevel, beneficial properties helping to make agriculture more sustainable and resilient. When applied to plants or to the soil an increased absorption and distribution of nutrients, tolerance to environmental stress, and improved quality of plant products explain the mechanisms by which these probiotics are useful. In recent years, the use of plant biostimulants has received widespread attention across the globe as an ecologically acceptable alternative to sustainable agricultural production. As a result, their worldwide market continues to grow, and further research will be conducted to broaden the range of the products now available. Through this review, we present a current understanding of biostimulants, their mode of action and their involvement in modulating abiotic stress responses, including omics research, which may provide a comprehensive assessment of the crop's response by correlating molecular changes to physiological pathways activated under stress conditions aggravated by climate change.PMID:37295582 | DOI:10.1016/j.envres.2023.116357

Free Radic Biol Med. 2023 Jun 7:S0891-5849(23)00430-6. doi: 10.1016/j.freeradbiomed.2023.05.014. Online ahead of print.ABSTRACTMyocardial ischemia-reperfusion (IR) injury may result in cardiomyocyte dysfunction. Mitochondria play a critical role in cardiomyocyte recovery after IR injury. The mitochondrial uncoupling protein 3 (UCP3) has been proposed to reduce mitochondrial reactive oxygen species (ROS) production and to facilitate fatty acid oxidation. As both mechanisms might be protective following IR injury, we investigated functional, mitochondrial structural, and metabolic cardiac remodeling in wild-type mice and in mice lacking UCP3 (UCP3-KO) after IR. Results showed that infarct size in isolated perfused hearts subjected to IR ex vivo was larger in adult and old UCP3-KO mice than in equivalent wild-type mice, and was accompanied by higher levels of creatine kinase in the effluent and by more pronounced mitochondrial structural changes. The greater myocardial damage in UCP3-KO hearts was confirmed in vivo after coronary artery occlusion followed by reperfusion. S1QEL, a suppressor of superoxide generation from site IQ in complex I, limited infarct size in UCP3-KO hearts, pointing to exacerbated superoxide production as a possible cause of the damage. Metabolomics analysis of isolated perfused hearts confirmed the reported accumulation of succinate, xanthine and hypoxanthine during ischemia, and a shift to anaerobic glucose utilization, which all recovered upon reoxygenation. The metabolic response to ischemia and IR was similar in UCP3-KO and wild-type hearts, being lipid and energy metabolism the most affected pathways. Fatty acid oxidation and complex I (but not complex II) activity were equally impaired after IR. Overall, our results indicate that UCP3 deficiency promotes enhanced superoxide generation and mitochondrial structural changes that increase the vulnerability of the myocardium to IR injury.PMID:37295539 | DOI:10.1016/j.freeradbiomed.2023.05.014

Adv Mater. 2023 Jun 9:e2301338. doi: 10.1002/adma.202301338. Online ahead of print.ABSTRACTPolycyclic aromatic compounds with an open-shell singlet diradical ground state, namely singlet diradicals, have recently gained attention in the fields of organic electronics, photovoltaics, and spintronics owing to their unique electronic structures and properties. Notably, singlet diradicals exhibit tunable redox amphoterism, which makes them excellent redox-active materials for biomedical applications. However, the safety and therapeutic efficacy of singlet diradicals in biological systems have not yet been explored. Herein, we present a newly designed singlet diradical nanomaterial, diphenyl-substituted biolympicenylidene (BO-Ph), exhibiting low cytotoxicity in vitro, non-significant acute nephrotoxicity in vivo, and the ability to induce metabolic reprogramming in kidney organoids. Integrated transcriptome and metabolome analyses reveal that the metabolism of BO-Ph stimulates glutathione synthesis and fatty acid degradation, increases the levels of intermediates in the tricarboxylic acid and carnitine cycles, and eventually boosts oxidative phosphorylation under redox homeostasis. Benefits of BO-Ph-induced metabolic reprogramming in kidney organoids include enhanced cellular antioxidant capacity and promoted mitochondrial function. The results of this study can facilitate the application of singlet diradical materials in the treatment of clinical conditions induced by mitochondrial abnormalities in kidney. This article is protected by copyright. All rights reserved.PMID:37295411 | DOI:10.1002/adma.202301338

Sci Adv. 2023 Jun 9;9(23):eade9933. doi: 10.1126/sciadv.ade9933. Epub 2023 Jun 9.ABSTRACTIn recent years, ambient ionization mass spectrometry (AIMS) including laser ablation rapid evaporation IMS, has enabled direct biofluid metabolome analysis. AIMS procedures are, however, still hampered by both analytical, i.e., matrix effects, and practical, i.e., sample transport stability, drawbacks that impede metabolome coverage. In this study, we aimed at developing biofluid-specific metabolome sampling membranes (MetaSAMPs) that offer a directly applicable and stabilizing substrate for AIMS. Customized rectal, salivary, and urinary MetaSAMPs consisting of electrospun (nano)fibrous membranes of blended hydrophilic (polyvinylpyrrolidone and polyacrylonitrile) and lipophilic (polystyrene) polymers supported metabolite absorption, adsorption, and desorption. Moreover, MetaSAMP demonstrated superior metabolome coverage and transport stability compared to crude biofluid analysis and was successfully validated in two pediatric cohorts (MetaBEAse, n = 234 and OPERA, n = 101). By integrating anthropometric and (patho)physiological with MetaSAMP-AIMS metabolome data, we obtained substantial weight-driven predictions and clinical correlations. In conclusion, MetaSAMP holds great clinical application potential for on-the-spot metabolic health stratification.PMID:37294759 | DOI:10.1126/sciadv.ade9933

J Med Microbiol. 2023 Jun;72(6). doi: 10.1099/jmm.0.001708.ABSTRACTOrganic acids (short chain fatty acids, amino acids, etc.) are common metabolic byproducts of commensal bacteria of the gut and oral cavity in addition to microbiota associated with chronic infections of the airways, skin, and soft tissues. A ubiquitous characteristic of these body sites in which mucus-rich secretions often accumulate in excess, is the presence of mucins; high molecular weight (HMW), glycosylated proteins that decorate the surfaces of non-keratinized epithelia. Owing to their size, mucins complicate quantification of microbial-derived metabolites as these large glycoproteins preclude use of 1D and 2D gel approaches and can obstruct analytical chromatography columns. Standard approaches for quantification of organic acids in mucin-rich samples typically rely on laborious extractions or outsourcing to laboratories specializing in targeted metabolomics. Here we report a high-throughput sample preparation process that reduces mucin abundance and an accompanying isocratic reverse phase high performance liquid chromatography (HPLC) method that enables quantification of microbial-derived organic acids. This approach allows for accurate quantification of compounds of interest (0.01 mM - 100 mM) with minimal sample preparation, a moderate HPLC method run time, and preservation of both guard and analytical column integrity. This approach paves the way for further analyses of microbial-derived metabolites in complex clinical samples.PMID:37294285 | DOI:10.1099/jmm.0.001708

J Agric Food Chem. 2023 Jun 9. doi: 10.1021/acs.jafc.3c02642. Online ahead of print.ABSTRACTChondroitin sulfate (CS) is a special bioactive substance with lipid metabolism regulation functions; its molecular mechanisms, however, need further study. This study aimed to study the role of gut microbiota and liver metabolome in the anti-obesity effects of CS. The results demonstrated that CS significantly reduced body weight gain and alleviated insulin resistance and dyslipidemia induced by high-fat diet treatment. Moreover, CS interestingly increased the content of Firmicutes in intestinal microbiota. Further studies showed that there were 11 different metabolites involved in metabolic pathways, including the unsaturated fatty acid biosynthesis pathway, primary bile acid biosynthesis, and taurine and hypotaurine metabolism. In addition, Spearman's correlation analysis indicated that the anti-obesity effect of CS is closely related to liver metabolic regulation. Overall, these results provide a possible molecular mechanism by which CS reduces body weight and lipid accumulation.PMID:37294270 | DOI:10.1021/acs.jafc.3c02642

J Exp Bot. 2023 Jun 9:erad223. doi: 10.1093/jxb/erad223. Online ahead of print.ABSTRACTAnthocyanin-less (white) instead of black/red (coloured) fruits develop in grapevine cultivars without functional VviMYBA1 and VviMYBA2 genes, which conditions the colour of wines that can be produced. To evaluate whether this genetic variation has additional consequences on fruit ripening and composition, we performed microenvironment, transcriptomics and metabolomics comparisons of developing grapes between near-isogenic white- and black-berried somatic variants of Garnacha and Tempranillo cultivars. Berry temperature was up to 3.5ºC lower in white- compared to black-berried Tempranillo. An RNA-seq study combined with targeted and untargeted metabolomics revealed that ripening fruits of white-berried variants were characterized by the upregulation of photosynthesis and other light-responsive genes and their higher accumulation of specific terpene aroma precursors, fatty acid-derived aldehyde volatiles and phenylpropanoid precursor amino acids. MYBA1-MYBA2 function proved essential for flavonol trihydroxylation in black-berried somatic variants, which were also characterized by enhanced pathogen defence gene expression in berry skin and increased accumulation of C6-derived alcohol and ester volatiles and GABA. Collectively, our results indicate that anthocyanin depletion entails side effects on grape composition by altering the berry internal microenvironment and the partition of the phenylpropanoid pathway. These findings show how fruit colour can condition other fruit features, such as flavour potential and stress homeostasis.PMID:37294268 | DOI:10.1093/jxb/erad223

Front Microbiomes. 2023;2:1153691. doi: 10.3389/frmbi.2023.1153691. Epub 2023 May 5.ABSTRACTObesity and associated changes to the gut microbiome worsen airway inflammation and hyperresponsiveness in asthma. Obesogenic host-microbial metabolomes have altered production of metabolites that may influence lung function and inflammatory responses in asthma. To understand the interplay of the gut microbiome, metabolism, and host inflammation in obesity-associated asthma, we used a multi-omics approach to profile the gut-lung axis in the setting of allergic airway disease and diet-induced obesity. We evaluated an immunomodulator, nitro-oleic acid (NO2-OA), as a host- and microbial-targeted treatment intervention for obesity-associated allergic asthma. Allergic airway disease was induced using house dust mite and cholera toxin adjuvant in C57BL6/J mice with diet-induced obesity to model obesity-associated asthma. Lung function was measured by flexiVent following a week of NO2-OA treatment and allergen challenge. 16S rRNA gene (from DNA, taxa presence) and 16S rRNA (from RNA, taxa activity) sequencing, metabolomics, and host gene expression were paired with a Treatment-Measured-Response model as a data integration framework for identifying latent/hidden relationships with linear regression among variables identified from high-dimensional meta-omics datasets. Targeting both the host and gut microbiota, NO2-OA attenuated airway inflammation, improved lung elastance, and modified the gut microbiome. Meta-omics data integration and modeling determined that gut-associated inflammation, metabolites, and functionally active gut microbiota were linked to lung function outcomes. Using Treatment-Measured-Response modeling and meta-omics profiling of the gut-lung axis, we uncovered a previously hidden network of interactions between gut levels of amino acid metabolites involved in elastin and collagen synthesis, gut microbiota, NO2-OA, and lung elastance. Further targeted metabolomics analyses revealed that obese mice with allergic airway disease had higher levels of proline and hydroxyproline in the lungs. NO2-OA treatment reduced proline biosynthesis by downregulation of pyrroline-5-carboxylate reductase 1 (PYCR1) expression. These findings are relevant to human disease: adults with mild-moderate asthma and BMI ≥ 25 had higher plasma hydroxyproline levels. Our results suggest that changes to structural proteins in the lung airways and parenchyma may contribute to heightened lung elastance and serve as a potential therapeutic target for obese allergic asthma.PMID:37293566 | PMC:PMC10249466 | DOI:10.3389/frmbi.2023.1153691

Front Mol Biosci. 2023 May 24;10:1192088. doi: 10.3389/fmolb.2023.1192088. eCollection 2023.ABSTRACTBamboo species have traditionally been used as building material and potential source of bioactive substances, as they produce a wide variety of phenolic compounds, including flavonoids and cinnamic acid derivatives that are considered biologically active. However, the effects of growth conditions such as location, altitude, climate, and soil on the metabolome of these species still need to be fully understood. This study aimed to evaluate variations in chemical composition induced by altitudinal gradient (0-3000 m) by utilizing an untargeted metabolomics approach and mapping chemical space using molecular networking analysis. We analyzed 111 samples from 12 bamboo species collected from different altitudinal ranges using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). We used multivariate and univariate statistical analyses to identify the metabolites that showed significant differences in the altitude environments. Additionally, we used the Global Natural Products Social Molecular Networking (GNPS) web platform to perform chemical mapping by comparing the metabolome among the studied species and the reference spectra from its database. The results showed 89 differential metabolites between the altitudinal ranges investigated, wherein high altitude environments significantly increased the profile of flavonoids. While, low altitude environments significantly boosted the profile of cinnamic acid derivatives, particularly caffeoylquinic acids (CQAs). MolNetEnhancer networks confirmed the same differential molecular families already found, revealing metabolic diversity. Overall, this study provides the first report of variations induced by altitude in the chemical profile of bamboo species. The findings may possess fascinating active biological properties, thus offering an alternative use for bamboo.PMID:37293555 | PMC:PMC10246775 | DOI:10.3389/fmolb.2023.1192088

Front Mol Biosci. 2023 May 24;10:1156310. doi: 10.3389/fmolb.2023.1156310. eCollection 2023.ABSTRACTIn order to provide new insights into the physiological responses of lenok (Brachymystax lenok: Salmonidae) to acute and severe heat stress (25°C, 48 h), dynamic changes in redox state and metabolic responses are studied combined biochemical index and non-targeted metabolome. Nicotinamide adenine dinucleotide (NAD+) consumption causes significant increases in ratio of reduced NADH to NAD+ and ratio of reduced nicotinamide adenine dinucleotide phosphate (NADPH) to NADP+, which induced the redox imbalance in heat stressed lenok. Lowered reduced glutathione/oxidized glutathione (GSH/GSSG) ratios suggested that more oxidized conditions occurred in heat-stressed lenok, leading to membrane lipid oxidation. The first few hours of heat stress promoted the activity of enzymes involved in anaerobic glycolysis (hexokinase, pyruvate kinase, lactic dehydrogenase) and glutamicpyruvic transaminase and glutamic oxaloacetic transaminase, which might lead to consumption of many carbohydrates and amino acid catabolism. These enzyme activities decreased with time in a possible compensatory strategy to manage anabolic and catabolic metabolism, maintaining the redox homeostasis. After 48 h of recovery, NAD+, carbohydrate levels and enzyme activities had returned to control levels, whereas many amino acids were consumed for repair and new synthesis. GSH remained at levels lower than controls, and the more oxidized conditions had not recovered, aggravating oxidative damage. Glutamic acid, glutamine, lysine and arginine may play important roles in survival of heat-stressed lenok.PMID:37293553 | PMC:PMC10244579 | DOI:10.3389/fmolb.2023.1156310

bioRxiv. 2023 May 22:2023.05.20.541585. doi: 10.1101/2023.05.20.541585. Preprint.ABSTRACTAIMS: Mitochondria play a vital role in cellular metabolism and energetics and support normal cardiac function. Disrupted mitochondrial function and homeostasis cause a variety of heart diseases. Fam210a (family with sequence similarity 210 member A), a novel mitochondrial gene, is identified as a hub gene in mouse cardiac remodeling by multi-omics studies. Human FAM210A mutations are associated with sarcopenia. However, the physiological role and molecular function of FAM210A remain elusive in the heart. We aim to determine the biological role and molecular mechanism of FAM210A in regulating mitochondrial function and cardiac health in vivo .METHODS AND RESULTS: Tamoxifen-induced αMHC MCM -driven conditional knockout of Fam210a in the mouse cardiomyocytes induced progressive dilated cardiomyopathy and heart failure, ultimately causing mortality. Fam210a deficient cardiomyocytes exhibit severe mitochondrial morphological disruption and functional decline accompanied by myofilament disarray at the late stage of cardiomyopathy. Furthermore, we observed increased mitochondrial reactive oxygen species production, disturbed mitochondrial membrane potential, and reduced respiratory activity in cardiomyocytes at the early stage before contractile dysfunction and heart failure. Multi-omics analyses indicate that FAM210A deficiency persistently activates integrated stress response (ISR), resulting in transcriptomic, translatomic, proteomic, and metabolomic reprogramming, ultimately leading to pathogenic progression of heart failure. Mechanistically, mitochondrial polysome profiling analysis shows that FAM210A loss of function compromises mitochondrial mRNA translation and leads to reduced mitochondrial encoded proteins, followed by disrupted proteostasis. We observed decreased FAM210A protein expression in human ischemic heart failure and mouse myocardial infarction tissue samples. To further corroborate FAM210A function in the heart, AAV9-mediated overexpression of FAM210A promotes mitochondrial-encoded protein expression, improves cardiac mitochondrial function, and partially rescues murine hearts from cardiac remodeling and damage in ischemia-induced heart failure.CONCLUSION: These results suggest that FAM210A is a mitochondrial translation regulator to maintain mitochondrial homeostasis and normal cardiomyocyte contractile function. This study also offers a new therapeutic target for treating ischemic heart disease.TRANSLATIONAL PERSPECTIVE: Mitochondrial homeostasis is critical for maintaining healthy cardiac function. Disruption of mitochondrial function causes severe cardiomyopathy and heart failure. In the present study, we show that FAM210A is a mitochondrial translation regulator required for maintaining cardiac mitochondrial homeostasis in vivo . Cardiomyocyte-specific FAM210A deficiency leads to mitochondrial dysfunction and spontaneous cardiomyopathy. Moreover, our results indicate that FAM210A is downregulated in human and mouse ischemic heart failure samples and overexpression of FAM210A protects hearts from myocardial infarction induced heart failure, suggesting that FAM210A mediated mitochondrial translation regulatory pathway can be a potential therapeutic target for ischemic heart disease.PMID:37293097 | PMC:PMC10245825 | DOI:10.1101/2023.05.20.541585

bioRxiv. 2023 May 24:2023.05.23.541633. doi: 10.1101/2023.05.23.541633. Preprint.ABSTRACTBioactive metabolites produced by symbiotic microbiota causally impact host health and disease, nonetheless, incomplete functional annotation of genes as well as complexities and dynamic nature of microbiota make understanding species-level contribution in production and actions difficult. Alpha-galactosylceramides produced by Bacteroides fragilis (BfaGC) are one of the first modulators of colonic immune development, but biosynthetic pathways and the significance of the single species in the symbiont community still remained elusive. To address these questions at the microbiota level, we have investigated the lipidomic profiles of prominent gut symbionts and the metagenome-level landscape of responsible gene signatures in the human gut. We first elucidated the chemical diversity of sphingolipid biosynthesis pathways of major bacterial species. In addition to commonly shared ceramide backbone synthases showing two distinct intermediates, alpha-galactosyltransferase (agcT), the necessary and sufficient component for BfaGC production and host colonic type I natural killer T (NKT) cell regulation by B. fragilis, was characterized by forward-genetics based targeted metabolomic screenings. Phylogenetic analysis of agcT in human gut symbionts revealed that only a few ceramide producers have agcT and hence can produce aGCs, on the other hand, structurally conserved homologues of agcT are widely distributed among species lacking ceramides. Among them, alpha-glucosyl-diacylglycerol(aGlcDAG)-producing glycosyltransferases with conserved GT4-GT1 domains are one of the most prominent homologs in gut microbiota, represented by Enterococcus bgsB . Of interest, aGlcDAGs produced by bgsB can antagonize BfaGC-mediated activation of NKT cells, showing the opposite, lipid structure-specific actions to regulate host immune responses. Further metagenomic analysis of multiple human cohorts uncovered that the agcT gene signature is almost exclusively contributed by B. fragilis , regardless of age, geographical and health status, where the bgsB signature is contributed by >100 species, of which abundance of individual microbes is highly variable. Our results collectively showcase the diversities of gut microbiota producing biologically relevant metabolites in multiple layers-biosynthetic pathways, host immunomodulatory functions and microbiome-level landscapes in the host.PMID:37293019 | PMC:PMC10245877 | DOI:10.1101/2023.05.23.541633

bioRxiv. 2023 May 22:2023.05.20.541602. doi: 10.1101/2023.05.20.541602. Preprint.ABSTRACTThe Sorting and Assembly Machinery (SAM) Complex functions in the assembly of β-barrel in the mitochondrial membrane. The SAM complex is made up of three subunits, Sam35, Sam37, and Sam50. While both Sam35 and Sam37 are peripheral membrane proteins that are not required for survival, Sam50 interacts with the MICOS complex to connect the inner and outer mitochondrial membranes and forms the mitochondrial intermembrane space bridging (MIB) complex. Specifically, Sam50 stabilizes the MIB complex for protein transport, respiratory chain complex assembly, and cristae integrity regulation. To structurally form and sustain the cristae, the MICOS complex assembles at the cristae junction and binds directly to Sam50. However, the role of Sam50 in overall mitochondrial structure and metabolism in skeletal muscle remains unclear. Here, we use SBF-SEM and Amira software perform 3D renderings of mitochondria and autophagosomes in human myotubes. Beyond this, Gas Chromatography-Mass Spectrometry-based metabolomics was utilized to interrogate differential changes of the metabolites in wild-type (WT) and Sam50 deficient myotubes. Ablation of Sam50 , revealed increases in ß-Alanine, propanoate, and phenylalanine, and tyrosine metabolism. Additionally, we observed that mitochondrial fragmentation and autophagosome formation was increased in Sam50 -deficient myotubes compared to control myotubes. Beyond this, the metabolomic analysis revealed an increase in amino acid metabolism and fatty acid metabolism. XF24 Seahorse Analyzer shows that oxidative capacity is further impaired upon ablation of Sam50 in both murine and human myotubes. Together, these data suggest Sam50 is critical for establishing and maintaining mitochondria, mitochondrial cristae structure, and mitochondrial metabolism.PMID:37292887 | PMC:PMC10245823 | DOI:10.1101/2023.05.20.541602

medRxiv. 2023 May 24:2023.05.17.23289772. doi: 10.1101/2023.05.17.23289772. Preprint.ABSTRACTPulmonary hypertension (PH) is a severe hemodynamic, progressive condition associated with high morbidity and mortality where early and less invasive diagnostics could crucially improve management. There is a need for biomarkers in PH that are functional, diagnostic, and prognostic. We used a broad metabolomics approach with machine learning analysis and specific free fatty acid (FFA)/lipid-ratios to develop diagnostic and prognostic PH biomarkers. In a training cohort of 74 PH patients, 30 disease controls without PH, and 65 healthy controls, we identified diagnostic and prognostic markers that were validated in an independent cohort of 64 subjects. Markers based on lipophilic metabolites were more robust than those based on hydrophilic metabolites. FFA/lipid-ratios provided excellent diagnostic accuracy for PH with an AUC of up to 0.89 and 0.90 in the training and the validation cohorts, respectively. The ratios provided age-independent prognostic information and a combination of a ratio with established clinical scores increased the hazard ratio (HR) for FPHR4p and COMPERA2 from 2.5 to 4.3 and from 3.3 to 5.6, respectively. Pulmonary arteries (PA) of idiopathic PAH (IPAH) lungs show lipid accumulation and altered expression of lipid homeostasis-related genes that may explain this accumulation. Our functional studies in PA endothelial and smooth muscle cells have shown that increased FFA levels caused excessive proliferation and PA endothelial barrier dysfunction, both hallmarks of pulmonary artery hypertension (PAH). In conclusion, lipidomic changes in PH provide novel diagnostic and prognostic biomarkers and may point to new metabolic therapy targets.PMID:37292870 | PMC:PMC10246148 | DOI:10.1101/2023.05.17.23289772

bioRxiv. 2023 May 26:2023.05.26.542501. doi: 10.1101/2023.05.26.542501. Preprint.ABSTRACTArthropod-borne microbes rely on the metabolic state of a host to cycle between evolutionarily distant species. For instance, arthropod tolerance to infection may be due to redistribution of metabolic resources, often leading to microbial transmission to mammals. Conversely, metabolic alterations aids in pathogen elimination in humans, who do not ordinarily harbor arthropod-borne microbes. To ascertain the effect of metabolism on interspecies relationships, we engineered a system to evaluate glycolysis and oxidative phosphorylation in the tick Ixodes scapularis . Using a metabolic flux assay, we determined that the rickettsial bacterium Anaplasma phagocytophilum and the Lyme disease spirochete Borrelia burgdorferi , which are transstadially transmitted in nature, induced glycolysis in ticks. On the other hand, the endosymbiont Rickettsia buchneri, which is transovarially maintained, had a minimal effect on I. scapularis bioenergetics. Importantly, the metabolite β-aminoisobutyric acid (BAIBA) was elevated during A. phagocytophilum infection of tick cells following an unbiased metabolomics approach. Thus, we manipulated the expression of genes associated with the catabolism and anabolism of BAIBA in I. scapularis and detected impaired feeding on mammals, reduced bacterial acquisition, and decreased tick survival. Collectively, we reveal the importance of metabolism for tick-microbe relationships and unveil a valuable metabolite for I. scapularis fitness.PMID:37292783 | PMC:PMC10245996 | DOI:10.1101/2023.05.26.542501

Front Immunol. 2023 May 24;14:1203015. doi: 10.3389/fimmu.2023.1203015. eCollection 2023.ABSTRACTBACKGROUND: Postpartum depression has a crucial impact on the physical and psychological comfort and the work of postnatal women, the growth and development of infants and mental health in adulthood. Finding a safe and effective anti-postnatal depression drug is currently an important research goal in this field.METHODS: In this study, the forced swimming test (FST) and tail suspension test (TST) were used to evaluated the depressive behaviors of mice, and the changes of metabolites and intestinal microflora in mice with postpartum depression were examined through non-target metabolomics and 16S RNA sequencing respectively.RESULTS: We found that traditional Chinese medicine compound 919 Syrup could alleviate postpartum depression in mice and inhibit the elevated erucamide level in depressive hippocampus. However, mice treated with antibiotics were not sensitive to the anti-postnatal depression effect of 919 Syrup, and the level of 5-aminovaleric acid betaine (5-AVAB) in their hippocampus was significantly decreased. Transplanting fecal microflora treated with 919 Syrup could effectively improve the depressive behaviors of mice, upregulate the level of gut-derived 5-AVAB in the hippocampus, and downregulate the level of erucamide. Erucamide was significantly negatively correlated with increased Bacteroides in intestine after 919 Syrup treatment or fecal transplantation, and significantly positively correlated with Ruminococcaceae UCG-014 which was increased in feces of mice with postpartum depression. The increase of Bacteroides, Lactobacillus, and Ruminiclostridium in intestine after fecal transplantation had a clearly positive correlation with 5-AVAB.CONCLUSION: In brief, 919 Syrup may downregulate the ratio of hippocampal metabolites erucamide to 5-AVAB by regulating intestinal flora to alleviate postpartum depression, laying a scientific foundation for future pathological research and development of therapeutic drugs for postpartum depression.PMID:37292211 | PMC:PMC10244653 | DOI:10.3389/fimmu.2023.1203015