PubMed

Nat Microbiol. 2024 Aug 29. doi: 10.1038/s41564-024-01799-3. Online ahead of print.ABSTRACTFungal fermentation of food and agricultural by-products holds promise for improving food sustainability and security. However, the molecular basis of fungal waste-to-food upcycling remains poorly understood. Here we use a multi-omics approach to characterize oncom, a fermented food traditionally produced from soymilk by-products in Java, Indonesia. Metagenomic sequencing of samples from small-scale producers in Western Java indicated that the fungus Neurospora intermedia dominates oncom. Further transcriptomic, metabolomic and phylogenomic analysis revealed that oncom-derived N. intermedia utilizes pectin and cellulose degradation during fermentation and belongs to a genetically distinct subpopulation associated with human-generated by-products. Finally, we found that N. intermedia grew on diverse by-products such as fruit and vegetable pomace and plant-based milk waste, did not encode mycotoxins, and could create foods that were positively perceived by consumers outside Indonesia. These results showcase the traditional significance and future potential of fungal fermentation for creating delicious and nutritious foods from readily available by-products.PMID:39209985 | DOI:10.1038/s41564-024-01799-3

Nat Commun. 2024 Aug 29;15(1):7511. doi: 10.1038/s41467-024-51754-3.ABSTRACTThe formation of new ribosomes is tightly coordinated with cell growth and proliferation. In eukaryotes, the correct assembly of all ribosomal proteins and RNAs follows an intricate scheme of maturation and rearrangement steps across three cellular compartments: the nucleolus, nucleoplasm, and cytoplasm. We demonstrate that usnic acid, a lichen secondary metabolite, inhibits the maturation of the large ribosomal subunit in yeast. We combine biochemical characterization of pre-ribosomal particles with a quantitative single-particle cryo-EM approach to monitor changes in nucleolar particle populations upon drug treatment. Usnic acid rapidly blocks the transition from nucleolar state B to C of Nsa1-associated pre-ribosomes, depleting key maturation factors such as Dbp10 and hindering pre-rRNA processing. This primary nucleolar block rapidly rebounds on earlier stages of the pathway which highlights the regulatory linkages between different steps. In summary, we provide an in-depth characterization of the effect of usnic acid on ribosome biogenesis, which may have implications for its reported anti-cancer activities.PMID:39209816 | DOI:10.1038/s41467-024-51754-3

BMJ Open Gastroenterol. 2024 Aug 29;11(1):e001470. doi: 10.1136/bmjgast-2024-001470.ABSTRACTOBJECTIVE: Gut microbes and microbe-dependent metabolites (eg, tryptophan-kynurenine-serotonin pathway metabolites) have been linked to systemic inflammation, but the microbiota-metabolite-inflammation axis remains uncharacterised in children. Here we investigated whether gut microbiota features and circulating metabolites (both microbe-dependent and non-microbe-dependent metabolites) associated with circulating inflammation markers in children.METHODS: We studied children from the prospective Gen3G birth cohort who had data on untargeted plasma metabolome (n=321 children; Metabolon platform), gut microbiota (n=147; 16S rRNA sequencing), and inflammation markers (plasminogen activator inhibitor-1 (PAI-1), monocyte chemoattractant protein-1, and tumour necrosis factor-α) measured at 5-7 years. We examined associations of microbial taxa and metabolites-examining microbe-dependent and non-microbe-dependent metabolites separately-with each inflammatory marker and with an overall inflammation score (InfSc), adjusting for key confounders and correcting for multiple comparisons. We also compared the proportion of significantly associated microbe-dependent versus non-microbe-dependent metabolites, identified a priori (Human Microbial Metabolome Database), with each inflammation marker.RESULTS: Of 335 taxa tested, 149 were associated (qFDR<0.05) with at least one inflammatory marker; 10 of these were robust to pseudocount choice. Several bacterial taxa involved in tryptophan metabolism were associated with inflammation, including kynurenine-degrading Ruminococcus, which was inversely associated with all inflammation markers. Of 1037 metabolites tested, 315 were previously identified as microbe dependent and were more frequently associated with PAI-1 and the InfSc than non-microbe dependent metabolites. In total, 87 metabolites were associated (qFDR<0.05) with at least one inflammation marker, including kynurenine (positively), serotonin (positively), and tryptophan (inversely).CONCLUSION: A distinct set of gut microbes and microbe-dependent metabolites, including those involved in the tryptophan-kynurenine-serotonin pathway, may be implicated in inflammatory pathways in childhood.PMID:39209769 | DOI:10.1136/bmjgast-2024-001470

BMJ Open Gastroenterol. 2024 Aug 28;11(1):e001417. doi: 10.1136/bmjgast-2024-001417.ABSTRACTBACKGROUND AND AIMS: Gallstone disease affects ≥40 million people in the USA and accounts for health costs of ≥$4 billion a year. Risk factors such as obesity and metabolic syndrome are well established. However, data are limited on relevant metabolomic alterations that could offer mechanistic and predictive insights into gallstone disease. This study prospectively identifies and externally validates circulating prediagnostic metabolites associated with incident gallstone disease.METHODS: Female participants in Nurses' Health Study (NHS) and Nurses' Health Study II (NHS II) who were free of known gallstones (N=9960) were prospectively followed up after baseline metabolomic profiling with liquid chromatography-tandem mass spectrometry. Multivariable logistic regression and enrichment analysis were used to identify metabolites and metabolite groups associated with incident gallstone disease at PFDR<0.05. Findings were validated in 1866 female participants in the Women's Health Initiative and a comparative analysis was performed with 2178 male participants in the Health Professionals Follow-up Study.RESULTS: After multivariate adjustment for lifestyle and putative risk factors, we identified and externally validated 17 metabolites associated with incident gallstone disease in women-nine triacylglycerols (TAGs) and diacylglycerols (DAGs) were positively associated, while eight plasmalogens and cholesterol ester (CE) were negatively associated. Enrichment analysis in male and female cohorts revealed positive class associations with DAGs, TAGs (≤56 carbon atoms and ≤3 double bonds) and de novo TAG biosynthesis pathways, as well as inverse associations with CEs.CONCLUSIONS: This study highlights several metabolites (TAGs, DAGs, plasmalogens and CE) that could be implicated in the aetiopathogenesis of gallstone disease and serve as clinically relevant markers.PMID:39209332 | DOI:10.1136/bmjgast-2024-001417

J Ethnopharmacol. 2024 Aug 27:118759. doi: 10.1016/j.jep.2024.118759. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Hypercholesterolemia (HLC) was a key risk factor for cardiovascular disease (CVD) characterized by elevated cholesterol levels, particularly LDL. While traditional Chinese medicine preparations Compound Danshen Pills(CDP) has been clinically used for hypercholesterolemia and coronary heart disease, its specific therapeutic effect on HLC remains understudied, necessitating further investigation into its mechanisms.AIM OF THE STUDY: The aim of this study was to explore the potential of CDP in treating HLC and elucidate its underlying mechanisms and active components.MATERIALS AND METHODS: A hypercholesterolemic lipemia rat model induced by a high-fat diet was employed. Network pharmacology combined with UHPLC-Q exactive orbitrap HRMS technique was used to predict the active components, targets and mechanisms of CDP for HLC. Histological analysis and serum biochemical assays were used to assess the therapeutic effect of CDP and its main active ingredient Sa B on hypercholesterolemic lipemia rat model. Immunofluorescence assays and western blotting were used to verify the mechanism of CDP and Sa B in the treatment of HLC. Metabolomics approach was used to demonstrate that CDP and Sa B affected the metabolic profile of HLC.RESULTS: Our findings demonstrated that both CDP and its main active ingredient Sa B significantly ameliorated hypercholesterolemic lipemic lesions, reducing levels of TC, LDL, AST, ALT, and ALP. Histological analysis revealed a decrease in lipid droplet accumulation and collagen fiber deposition in the liver, as well as reduced collagen fiber deposition in the aorta. Network pharmacology predicted potential targets such as PPARα and CYP27A1. Immunofluorescence assays and western blotting confirmed that CDP and Sa B upregulated the expression of Adipor1, PPARα and CYP27A1. Metabolomics analyses further indicated improvements in ABC transporters metabolic pathways, with differential metabolites such as riboflavin, taurine, and choline showed regression in levels after CDP treatment and riboflavin, L-Threonine, Thiamine, L-Leucine, and Adenosine showed improved expression after Sa B treatment.CONCLUSION: CDP and Sa B have been shown to alleviate high-fat diet-induced hypercholesterolemia by activating the PPAR pathway and improving hepatic lipid metabolism. Our study demonstrated, for the first time, the complex mechanism of CDP, Sa B in the treatment of hypercholesterolemia at the protein and metabolic levels and provided a new reference that could elucidate the pharmacological effects of traditional Chinese medicine on hypercholesterolemia from multiple perspectives.PMID:39209003 | DOI:10.1016/j.jep.2024.118759

J Stroke Cerebrovasc Dis. 2024 Aug 27:107887. doi: 10.1016/j.jstrokecerebrovasdis.2024.107887. Online ahead of print.ABSTRACTOBJECTIVES: To evaluate the relationship among the gut microbiome, serum metabolites and the Intracranial atherosclerosis stenosis.MATERIALS AND METHODS: Integrated analysis of 16S rDNA sequencing of fecal samples and untargeted serum metabolomics was applied to identify alterations in the gut microbiome and serum metabolome in 29 Intracranial atherosclerosis stenosis patients and 29 healthy control individuals.RESULTS: Compared to healthy control individuals, the abundances of forty-five genera and one hundred seventy-seven metabolites were significantly altered in Intracranial atherosclerosis stenosis patients. At the species level, the Intracranial atherosclerosis stenosis group exhibited higher abundances of Bacteroidetes and lower abundances of Megaphaera and Muribacoccaceae. Microbial functional prediction analysis revealed enhanced activity of bacterial chemotaxis and oxidative phosphorylation within the Intracranial atherosclerosis stenosis group. In terms of metabolomic findings, the levels of dulcitol were significantly increased in the Intracranial atherosclerosis stenosis group. The levels of specific metabolites within the phosphatidylcholine and lysophosphatidylcholine families, such as PC (14:0e/24:4) and LPC 20:5, were increased, while the levels of certain other specific metabolites were decreased. Dysregulation of certain pathways, such as unsaturated fatty acid metabolism, arginine and proline metabolism may be involved in the development of Intracranial atherosclerosis stenosis. Correlation analysis of the gut microbiome and metabolites revealed a positive correlation between Bacteroides and multiple metabolites, such as Acar 12:3 and PC (8:0/22:6).CONCLUSIONS: Our analysis revealed that Bacteroides is a key bacterial genus in gut dysbiosis and may be related to the development of Intracranial atherosclerosis stenosis.PMID:39208915 | DOI:10.1016/j.jstrokecerebrovasdis.2024.107887

Int J Biol Macromol. 2024 Aug 27:135144. doi: 10.1016/j.ijbiomac.2024.135144. Online ahead of print.ABSTRACTSoybean hull polysaccharides (SHPS) enhance the physicochemical properties of plant-based yogurt. However, their effects on the nutritional profile and biochemical mechanisms remain unclear. This study aimed to assess the impact of SHPS addition on the nonvolatile components of plant-based yogurt and its underlying mechanisms through widely targeted metabolomics analysis. The results demonstrated that the addition of SHPS (0.2 %-1.0 % w/v) enhanced the levels of free amino acids, sugars, and organic acids, with the addition of 0.6 % w/v being particularly effective in improving yogurt quality. Widely targeted metabolomics analysis revealed 278 differential metabolites between yogurt supplemented with 0.6 % SHPS (SPY) and the control sample. SHPS increased the content of various metabolites, including amino acids and derivatives, saccharides, organic acids, and flavonoids, among others. Key metabolic pathways affected by SHPS included pantothenate and CoA biosynthesis; valine, leucine, and isoleucine biosynthesis; and benzoate degradation. As the primary component of SHPS, galacturonic acid affected the metabolic products in yogurt by participating in the pentose and glucuronate interconversions and ascorbate and aldarate metabolism pathways. These findings elucidate the role of SHPS in modulating the nutritional composition of plant-based yogurt, offering valuable insights into its functional mechanisms in food processing.PMID:39208892 | DOI:10.1016/j.ijbiomac.2024.135144

Anal Chem. 2024 Aug 28. doi: 10.1021/acs.analchem.4c02973. Online ahead of print.ABSTRACTDeep vein thrombosis (DVT) is a serious health issue that often leads to considerable morbidity and mortality. Diagnosis of DVT in a clinical setting, however, presents considerable challenges. The fusion of metabolomics techniques and machine learning methods has led to high diagnostic and prognostic accuracy for various pathological conditions. This study explored the synergistic potential of dual-platform metabolomics (specifically, gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS)) to expand the detection of metabolites and improve the precision of DVT diagnosis. Sixty-one differential metabolites were identified in serum from DVT patients: 22 from GC-MS and 39 from LC-MS. Among these, five key metabolites were highlighted by SHapley Additive exPlanations (SHAP)-guided feature engineering and then used to develop a stacking diagnostic model. Additionally, a user-friendly interface application system was developed to streamline and automate the application of the diagnostic model, enhancing its practicality and accessibility for clinical use. This work showed that the integration of dual-platform metabolomics with a stacking machine learning model enables faster and more accurate diagnosis of DVT in clinical environments.PMID:39197159 | DOI:10.1021/acs.analchem.4c02973

J Agric Food Chem. 2024 Aug 28. doi: 10.1021/acs.jafc.4c05009. Online ahead of print.ABSTRACTDrought dramatically affects plant growth and yield. A previous study indicated that endophytic fungus Phomopsis liquidambaris can improve the drought resistance of peanuts, which is related with the root arbuscular mycorrhizal fungi (AMF) community; however, how root endophytes mediate AMF assembly to affect plant drought resistance remains unclear. Here, we explored the mechanism by which endophytic fungus recruits AMF symbiotic partners via rhizodeposits to improve host drought resistance. The results showed that Ph. liquidambaris enhanced peanut drought resistance by enriching the AMF genus Claroideoglomus of the rhizosphere. Furthermore, metabolomic analysis indicated that Ph. liquidambaris significantly promoted isoformononetin and salicylic acid (SA) synthesis in rhizodeposits, which were correlated with the increase in Claroideoglomus abundance following Ph. liquidambaris inoculation. Coinoculation experiments confirmed that isoformononetin and SA could enrich Claroideoglomus etunicatum in the rhizosphere, thereby improving the drought resistance. This study highlights the crucial role of fungal consortia in plant stress resistance.PMID:39197047 | DOI:10.1021/acs.jafc.4c05009

J Fungi (Basel). 2024 Jul 25;10(8):518. doi: 10.3390/jof10080518.ABSTRACTCandida auris, an emerging non-albicans multidrug-resistant yeast, has become a significant cause of invasive candidiasis in healthcare settings. So far, data on the metabolites of C. auris in different clades are minimal, and no studies have focused on clade V metabolites. Therefore, Gas chromatography-mass spectrometry (GC-MS) was used for the metabolomic profiling of clade I C. auris compared with fluconazole-resistant and susceptible C. auris in clade V strains. GC-MS chromatography revealed 28, 22, and 30 compounds in methanolic extracts of the fluconazole-susceptible and fluconazole-resistant C. auris clade V and C. auris clade I strain, respectively. Some compounds, such as acetamide and metaraminol, were found in fluconazole-susceptible and resistant C. auris clade V and clade I. N-methyl-ethanamine and bis(2-ethylhexyl) phthalate metabolites were found in both fluconazole -susceptible and resistant C. auris clade V, as well as 3-methyl-4-isopropylphenol, 3,5-bis(1,1-dimethyl)-1,2-benzenediol, and diisostyl phthalate metabolites in both fluconazole resistant C. auris clade V and I. Identifying these metabolites contributes to understanding the morphogenesis and pathogenesis of C. auris, highlighting their potential role in antifungal drug resistance and the control of fungal growth. However, further experiments are warranted to fully comprehend the identified metabolites' regulatory responses, and there may be potential challenges in translating these findings into clinical applications.PMID:39194844 | DOI:10.3390/jof10080518

Insects. 2024 Jul 30;15(8):578. doi: 10.3390/insects15080578.ABSTRACTHoney bees (Apis mellifera) provide a useful model for studying aging because of the differences in longevity between the relatively short-lived summer and long-lived winter bees, as well as bees lacking signs of cognitive senescence as they age. Bee brains were dissected from newly emerged, 14-day-, and 28-day- old bees in mid- and late summer, as well as brood nest bees in fall, winter, and spring, before, during, and after overwintering, respectively. Brains were examined with nuclear magnetic resonance (NMR) spectroscopy to analyze their metabolome. Nine variable importance in projection (VIP) variables were identified, primarily amino acids and choline derivatives. Differences in metabolite concentrations were found with different ages of summer bees, mostly between newly emerged and 14-day- old bees, such as a decrease in phenylalanine and an increase in β-alanine, but there were also changes in older adults, such as o-phosphocholine that declined in 28-day- old bees. Differences in brood nest bees were observed, including a decline in tryptophan and an increase in β-alanine. These may provide distinct metabolomic signatures with age and season. Such research holds promise for a better understanding of the complex interplays between bee physiology, development, and aging, which has implications for improving bee health and management.PMID:39194783 | DOI:10.3390/insects15080578

Proc Natl Acad Sci U S A. 2024 Sep 3;121(36):e2406925121. doi: 10.1073/pnas.2406925121. Epub 2024 Aug 28.ABSTRACTEndosymbionts provide essential nutrients for hosts, promoting growth, development, and reproduction. However, the molecular regulation of nutrient transport from endosymbiont to host is not well understood. Here, we used bioinformatic analysis, RNA-Sequencing, luciferase assays, RNA immunoprecipitation, and in situ hybridization to show that a bacteriocyte-distributed MRP4 gene (multidrug resistance-associated protein 4) is negatively regulated by a host (aphid)-specific microRNA (miR-3024). Targeted metabolomics, microbiome analysis, vitamin B6 (VB6) supplements, 3D modeling/molecular docking, in vitro binding assays (voltage clamp recording and microscale thermophoresis), and functional complementation of Escherichia coli were jointly used to show that the miR-3024/MRP4 axis controls endosymbiont (Serratia)-produced VB6 transport to the host. The supplementation of miR-3024 increased the mortality of aphids, but partial rescue was achieved by providing an external source of VB6. The use of miR-3024 as part of a sustainable aphid pest-control strategy was evaluated by safety assessments in nontarget organisms (pollinators, predators, and entomopathogenic fungi) using virus-induced gene silencing assays and the expression of miR-3024 in transgenic tobacco. The supplementation of miR-3024 suppresses MRP4 expression, restricting the number of membrane channels, inhibiting VB6 transport, and ultimately killing the host. Under aphids facing stress conditions, the endosymbiont titer is decreased, and the VB6 production is also down-regulated, while the aphid's autonomous inhibition of miR-3024 enhances the expression of MRP4 and then increases the VB6 transport which finally ensures the VB6 homeostasis. The results confirm that miR-3024 regulates nutrient transport in the endosymbiont-host system and is a suitable target for sustainable pest control.PMID:39196627 | DOI:10.1073/pnas.2406925121

Int J Syst Evol Microbiol. 2024 Aug;74(8). doi: 10.1099/ijsem.0.006500.ABSTRACTTwo new strains JP48T and JP55 affiliated with the acidobacterial class Terriglobia have been isolated from fen soil sampled in the Fichtelgebirge Mountains near Bayreuth, Germany. Both strains were Gram-stain-negative, non-motile, non-spore-forming rods that divide by binary fission, segregate exopolysaccharide-like material and form capsules. Strains JP48T and JP55 grew at 4-36 °C (optimum at 27 °C), pH 3.6-7.3 (optimum at pH 4.6-5.5) and with NaCl concentrations of 0-3% (optimum at 1.0%; w/v). Strains JP48T and JP55 grew aerobically on a wide range of organic substrates including mono- and oligosaccharides, amino acids and short-chained fatty acids. MK-8 was identified as the major respiratory quinone. The major fatty acids for strains JP48T and JP55 were iso-C15 : 0, C16 : 1 ω7c, C16 : 0 and iso-diabolic acid. Phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, lysophophatidylethanolamine, phosphatidylcholine, unidentified glyco- and glycophospholipids, and unidentified high mass lipid species were the major polar membrane lipids. The G+C content of strains JP48T and JP55 was 57.4 and 57.2 mol%, respectively. The genomes of strains JP48T and JP55 contained nine potential secondary metabolite regions encoding for the compound classes NRPS(-like), T3PKS, terpene, or lanthipeptide class IV. Phylogenetic reconstruction and 16S rRNA gene sequence similarities of 98.3 and 96.9% identified Edaphobacter dinghuensis DHF9T and Edaphobacter lichenicola DSM 104462T as the most closely related type strains to strains JP48T and JP55. Based on their phenotype, phylogeny and chemotaxonomy, we propose the novel species Edaphobacter paludis sp. nov. (type strain JP48T=DSM 109919T=CECT 30269T; additional strain JP55=DSM 109920=CECT 30268) within the class Terriglobia of the phylum Acidobacteriota.PMID:39196616 | DOI:10.1099/ijsem.0.006500

JAMA Dermatol. 2024 Aug 28. doi: 10.1001/jamadermatol.2024.2849. Online ahead of print.ABSTRACTIMPORTANCE: Eicosanoids have a pathophysiological role in atopic dermatitis (AD), but it is unknown whether this is affected by prenatal ω-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA; ie, fish oil) supplementation and genetic variations in the cyclooxygenase-1 (COX1) pathway.OBJECTIVE: To explore the association of n-3 LCPUFA supplementation during pregnancy with risk of childhood AD overall and by maternal COX1 genotype.DESIGN, SETTING, AND PARTICIPANTS: This prespecified secondary analysis of a randomized clinical trial included mother-child pairs from the Danish Copenhagen Prospective Studies on Asthma in Childhood 2010 birth cohort, with prospective follow-up until children were aged 10 years. In the trial, maternal and child COX1 genotypes were determined, and urinary eicosanoids were quantified when the child was 1 year of age. The present study was conducted from January 2019 to December 2021, and data were analyzed from January to September 2023.INTERVENTION: A total of 736 pregnant women at 24 weeks' gestation were randomized 1:1 to 2.4 g of n-3 LCPUFA (fish oil) or placebo (olive oil) per day until 1 week post partum.MAIN OUTCOMES AND MEASURES: Risk of childhood AD until age 10 years overall and by maternal COX1 genotype.RESULTS: At age 10 years, 635 children (91%; 363 [57%] female) completed the clinical follow-up, and these mother-child pairs were included in this study; 321 (51%) were in the intervention group and 314 (49%) in the control group. Pregnancy n-3 LCPUFA supplementation was associated with lower urinary thromboxane A2 metabolites at age 1 year (β, -0.46; 95% CI, -0.80 to -0.13; P = .006), which was also associated with COX1 rs1330344 genotype (β per C allele, 0.47; 95% CI, 0.20-0.73; P = .001). Although neither n-3 LCPUFA supplementation (hazard ratio [HR], 1.00; 95% CI, 0.76-1.33; P = .97) nor maternal COX1 genotype (HR, 0.94; 95% CI, 0.74-1.19; P = .60) was associated with risk of childhood AD until age 10 years, there was evidence of an interaction between these variables (P < .001 for interaction). Among mothers with the TT genotype, risk of AD was reduced in the n-3 LCPUFA group compared with the placebo group (390 mother-child pairs [61%]; HR, 0.70; 95% CI, 0.50-0.98; P = .04); there was no association for mothers with the CT genotype (209 [33%]; HR, 1.29; 95% CI, 0.79-2.10; P = .31), and risk was increased among offspring of mothers with the CC genotype (37 [6%]; HR, 5.77; 95% CI, 1.63-20.47; P = .007). There was a significant interaction between n-3 LCPUFA supplementation and child COX1 genotype and development of AD (P = .002 for interaction).CONCLUSIONS AND RELEVANCE: In this secondary analysis of a randomized clinical trial, the association of prenatal n-3 LCPUFA supplementation with risk of childhood AD varied by maternal COX1 genotype. The findings could be used to inform a personalized prevention strategy of providing supplementation only to pregnant individuals with the TT genotype.TRIAL REGISTRATION: ClinicalTrials.gov: NCT00798226.PMID:39196551 | DOI:10.1001/jamadermatol.2024.2849

Nat Cardiovasc Res. 2023 Dec;2(12):1327. doi: 10.1038/s44161-023-00389-6.NO ABSTRACTPMID:39196157 | DOI:10.1038/s44161-023-00389-6

Nat Cardiovasc Res. 2023 Mar;2(3):268-289. doi: 10.1038/s44161-023-00223-z. Epub 2023 Mar 9.ABSTRACTDysregulation of estrogen receptor alpha (ERα) has been linked with increased metabolic and cardiovascular disease risk. Here, we generate and characterize cardiomyocyte-specific ERα knockout (ERαHKO) mice to assess the role of ERα in the heart. The most striking phenotype was obesity in female ERαHKO but not male ERαHKO mice. Female ERαHKO mice showed cardiac dysfunction, mild glucose and insulin intolerance and reduced ERα gene expression in skeletal muscle and white adipose tissue. Transcriptomic, proteomic, lipidomic and metabolomic analyses revealed evidence of contractile and/or metabolic dysregulation in heart, skeletal muscle and white adipose tissue. We show that heart-derived extracellular vesicles from female ERαHKO mice contain a distinct proteome associated with lipid and metabolic regulation, and have the capacity to metabolically reprogram the target skeletal myocyte proteome with functional impacts on glycolytic capacity and reserve. This multi-omics study uncovers a cardiac-initiated and sex-specific cardiometabolic phenotype regulated by ERα and provides insights into extracellular vesicle-mediated interorgan communication.PMID:39196021 | DOI:10.1038/s44161-023-00223-z

Nat Cardiovasc Res. 2023 Aug;2(8):746-763. doi: 10.1038/s44161-023-00305-y. Epub 2023 Jul 17.ABSTRACTLipids contribute to hematopoiesis and membrane properties and dynamics; however, little is known about the role of lipids in megakaryopoiesis. Here we show that megakaryocyte progenitors, megakaryocytes and platelets present a unique lipidome progressively enriched in polyunsaturated fatty acid (PUFA)-containing phospholipids. In vitro, inhibition of both exogenous fatty acid functionalization and uptake as well as de novo lipogenesis impaired megakaryocyte differentiation and proplatelet production. In vivo, mice on a high saturated fatty acid diet had significantly lower platelet counts, which was prevented by eating a PUFA-enriched diet. Fatty acid uptake was largely dependent on CD36, and its deletion in mice resulted in low platelets. Moreover, patients with a CD36 loss-of-function mutation exhibited thrombocytopenia and increased bleeding. Our results suggest that fatty acid uptake and regulation is essential for megakaryocyte maturation and platelet production and that changes in dietary fatty acids may be a viable target to modulate platelet counts.PMID:39195958 | DOI:10.1038/s44161-023-00305-y

Nat Cardiovasc Res. 2022 May;1(5):445-461. doi: 10.1038/s44161-022-00057-1. Epub 2022 May 9.ABSTRACTHypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disease with heterogeneous clinical presentations, governed by multiple molecular mechanisms. Metabolic perturbations underlie most cardiovascular diseases; however, the metabolic alterations and their function in HCM are unknown. Here, we describe the metabolome and lipidome of heart and plasma samples from individuals with and without HCM. Correlation analyses showed strong association between metabolic alterations and cardiac function and prognosis of patients with HCM. Using machine learning we identified metabolite panels as potential HCM diagnostic markers or predictors of survival. Clustering based on metabolome and lipidome of heart enabled stratification of patients with HCM into three subgroups with distinct cardiac function and survival. Integration of metabolomics and proteomics data identified metabolic pathways significantly altered in patients with HCM, with the pentose phosphate pathway and oxidative stress being particularly upregulated. Thus, targeting the pentose phosphate pathway and oxidative stress may serve as potential therapeutic strategies for HCM.PMID:39195941 | DOI:10.1038/s44161-022-00057-1

Nat Cardiovasc Res. 2022 Jun;1(6):568-576. doi: 10.1038/s44161-022-00083-z. Epub 2022 Jun 9.ABSTRACTHere we report application of human umbilical cord mesenchymal stem cell (HUCMSC)-derived therapy for pulmonary arterial hypertension (PAH). A 3-year-old female presented with heritable PAH associated with hereditary hemorrhagic telangiectasia and was treated for 6 months with serial intravascular infusions of conditioned media (CM) from allogenic HUCMSCs. The treatment markedly improved clinical and hemodynamic parameters and decreased blood plasma markers of vascular fibrosis, injury and inflammation. A comparative analysis of single-cell RNA sequencing data collected from three HUCMSCs and two human umbilical vein endothelial cell (HUVEC) controls identified eight common cell clusters, all of which indicated regenerative potential specific for HUCMSCs. The properties of HUCMSCs were validated by untargeted label-free quantitation of the cell and CM proteome, suggesting increased activity of regeneration, autophagy and anti-inflammation pathways and mitochondrial function. Prostaglandin analysis demonstrated increased HUCMSC secretion of prostaglandin E2, known for its regenerative capacity. Additional prospective clinical studies are warranted to confirm and further explore the benefits of HUCMSC-derived therapy for PAH.PMID:39195868 | DOI:10.1038/s44161-022-00083-z

Vet Sci. 2024 Aug 6;11(8):356. doi: 10.3390/vetsci11080356.ABSTRACTThis study aimed to evaluate the effects of licorice extract (LE) on growth performance, nutrient apparent digestibility, serum index (biochemistry, hormones, humoral immunity, and antioxidant function), hindgut fecal microbiota, and metabolism in beef cattle. In total, 12 male yellow cattle aged 12 months were divided into two groups (6 cattle per group): the basal diet (CK group) and the basal diet supplemented with 2 g/kg LE (CHM group). The entire experimental phase lasted for 120 days, including a 30-day pre-feeding period. Compared to the CK group, the average daily gain, crude fiber, calcium, and crude protein nutrient digestibility were greater on d 30 than d 60 (p < 0.05) and the feed meat ratio was lower for LE addition (p < 0.01). In terms of serum indexes, the insulin and nitric oxide contents were enhanced on d 30, the alkaline phosphatase level was improved on d 60, and the levels of albumin, immunoglobulin A, and catalase were increased on d 90 (p < 0.05). In contrast, the cholesterol content was lower on d 60 for LE addition compared with the CK group (p < 0.05). The higher enrichment of [Eubacterium]-oxidoreducens-group, p-2534-18b5-gut-group, and Ileibacterium were observed in the CHM group (p < 0.05), while the relative abundances of Gallibacterium and Breznakia in the CHM group were lower compared with the CK group (p < 0.05). In addition, the differential metabolites related to healthy growth in the CHM group were increased compared with the CK group. And there was a close correlation between hindgut microbiota and metabolic differentials. In general, LE has a promoting effect on the growth performance and health status of beef cattle over a period (30 to 60 days).PMID:39195810 | DOI:10.3390/vetsci11080356