PubMed

Food Microbiol. 2024 Sep;122:104569. doi: 10.1016/j.fm.2024.104569. Epub 2024 May 27.ABSTRACTHuangjiu is a spontaneously fermented alcoholic beverage, that undergoes intricate microbial compositional changes. This study aimed to unravel the flavor and quality formation mechanisms based on the microbial metabolism of Huangjiu. Here, metagenome techniques, chemometrics analysis, and headspace solid-phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS) metabolomics combined with microbial metabolic network were employed to investigate the distinctions and relationship between the microbial profiles and the quality characteristics, flavor metabolites, functional metabolic patterns of Huangjiu across three regions. Significant variations (P < 0.05) were observed in metabolic rate of physicochemical parameters and biogenic amine concentration among three regions. 8 aroma compounds (phenethyl acetate, phenylethyl alcohol, isobutyl alcohol, ethyl octanoate, ethyl acetate, ethyl hexanoate, isoamyl alcohol, and diethyl succinate) out of 448 volatile compounds were identified as the regional chemical markers. 25 dominant microbial genera were observed through metagenomic analysis, and 13 species were confirmed as microbial markers in three regions. A metabolic network analysis revealed that Saccharomycetales (Saccharomyces), Lactobacillales (Lactobacillus, Weissella, and Leuconostoc), and Eurotiales (Aspergillus) were the predominant populations responsible for substrate, flavor (mainly esters and phenylethyl alcohol) metabolism, Lactobacillales and Enterobacterales were closely linked with biogenic amine. These findings provide scientific evidence for regional microbial contributions to geographical characteristics of Huangjiu, and perspectives for optimizing microbial function to promote Huangjiu quality.PMID:38839228 | DOI:10.1016/j.fm.2024.104569

Food Microbiol. 2024 Sep;122:104557. doi: 10.1016/j.fm.2024.104557. Epub 2024 Apr 30.ABSTRACTTo investigate the potential antifungal mechanisms of rhizosphere Actinobacteria against Ceratocystis fimbriata in sweet potato, a comprehensive approach combining biochemical analyses and multi-omics techniques was employed in this study. A total of 163 bacterial strains were isolated from the rhizosphere soil of sweet potato. Among them, strain MEPS155, identified as Streptomyces djakartensis, exhibited robust and consistent inhibition of C. fimbriata mycelial growth in in vitro dual culture assays, attributed to both cell-free supernatant and volatile organic compounds. Moreover, strain MEPS155 demonstrated diverse plant growth-promoting attributes, including the production of indole-3-acetic acid, 1-aminocyclopropane-1-carboxylate deaminase, phosphorus solubilization, nitrogen fixation, and enzymatic activities such as cellulase, chitinase, and protease. Notably, strain MEPS155 exhibited efficacy against various sweet potato pathogenic fungi. Following the inoculation of strain MEPS155, a significant reduction (P < 0.05) in malondialdehyde content was observed in sweet potato slices, indicating a potential protective effect. The whole genome of MEPS155 was characterized by a size of 8,030,375 bp, encompassing 7234 coding DNA sequences and 32 secondary metabolite biosynthetic gene clusters. Transcriptomic analysis revealed 1869 differentially expressed genes in the treated group that cultured with C. fimbriata, notably influencing pathways associated with porphyrin metabolism, fatty acid biosynthesis, and biosynthesis of type II polyketide products. These alterations in gene expression are hypothesized to be linked to the production of secondary metabolites contributing to the inhibition of C. fimbriata. Metabolomic analysis identified 1469 potential differently accumulated metabolites (PDAMs) when comparing MEPS155 and the control group. The up-regulated PDAMs were predominantly associated with the biosynthesis of various secondary metabolites, including vanillin, myristic acid, and protocatechuic acid, suggesting potential inhibitory effects on plant pathogenic fungi. Our study underscores the ability of strain S. djakartensis MEPS155 to inhibit C. fimbriata growth through the production of secretory enzymes or secondary metabolites. The findings contribute to a theoretical foundation for future investigations into the role of MEPS155 in postharvest black rot prevention in sweet potato.PMID:38839221 | DOI:10.1016/j.fm.2024.104557

Food Microbiol. 2024 Sep;122:104565. doi: 10.1016/j.fm.2024.104565. Epub 2024 May 21.ABSTRACTTo evaluate the effects of bioaugmentation fermentation inoculated with one ester-producing strain (Wickerhamomyces anomalus ZX-1) and two strains of lactic acid bacteria (Lactobacillus plantarum CGMCC 24035 and Lactobacillus acidophilus R2) for improving the flavor of persimmon vinegar, microbial community, flavor compounds and metabolites were analyzed. The results of microbial diversity analysis showed that bioaugmentation fermentation significantly increased the abundance of Lactobacillus, Saccharomyces, Pichia and Wickerhamomyces, while the abundance of Acetobacter, Apiotrichum, Delftia, Komagataeibacter, Kregervanrija and Aspergillus significantly decreased. After bioaugmentation fermentation, the taste was softer, and the sensory irritancy of acetic acid was significantly reduced. The analysis of HS-SPME-GC-MS and untargeted metabolomics based on LC-MS/MS showed that the contents of citric acid, lactic acid, malic acid, ethyl lactate, methyl acetate, isocitrate, acetoin and 2,3-butanediol were significantly increased. By multivariate analysis, 33 differential metabolites were screened out to construct the correlation between the differential metabolites and microorganisms. Pearson correlation analysis showed that methyl acetate, ethyl lactate, betaine, aconitic acid, acetoin, 2,3-butanediol and isocitrate positively associated with Wickerhamomyces and Lactobacillus. The results confirmed that the quality of persimmon vinegar was improved by bioaugmentation fermentation.PMID:38839213 | DOI:10.1016/j.fm.2024.104565

JACC Heart Fail. 2024 Jun;12(6):1012-1014. doi: 10.1016/j.jchf.2024.03.018.NO ABSTRACTPMID:38839146 | DOI:10.1016/j.jchf.2024.03.018

Eur J Pharmacol. 2024 Jun 3:176703. doi: 10.1016/j.ejphar.2024.176703. Online ahead of print.ABSTRACTSystemic lupus erythematosus (SLE) is an autoimmune disease characterized by multi-organ involvement and autoantibody production. Patients with SLE face a substantial risk of developing lupus nephritis (LN), which imposes a substantial burden on both patients and their families. Protein phosphatase 2A (PP2A) is a widely distributed serine/threonine phosphatase participated in regulating multiple signaling pathways and immune responses. Inhibition of PP2A is implicated in the treatment of diseases. LB-100, a small molecule inhibitor of PP2A, is currently undergoing preclinical trials for its therapeutic potential against tumors. However, the role of PP2A and its inhibitor has been insufficiently studied in LN. In this study, we assessed the potential effects of LB-100 in both MRL/lpr mice and R848-induced BALB/c mice. Our findings indicated that LB-100 administration led to reduced spleen enlargement, decreased deposition of immune complexes, ameliorated renal damage, and improved kidney function in two distinct lupus mouse models. Importantly, we observed the formation of tertiary lymphoid structures (TLS) in the kidneys of both spontaneous and induced lupus mouse models. The levels of chemokines inducing T cell infiltration were elevated in the kidneys of lupus mice, whereas LB-100 mitigated chemokines production and inhibited TLS formation. In summary, our study identified the role of PP2A in LN and highlighted the renal protective potential of the PP2A inhibitor LB-100 in two distinct lupus mouse models, suggesting its potential as a novel strategy for LN and other autoimmune diseases.PMID:38839028 | DOI:10.1016/j.ejphar.2024.176703

Steroids. 2024 Jun 3:109451. doi: 10.1016/j.steroids.2024.109451. Online ahead of print.ABSTRACTThis paper presents the metabolomic distance between normal and obese children. Our PCA results quantitatively explain why girls are more prone to obesity than boys.PMID:38838951 | DOI:10.1016/j.steroids.2024.109451

J Ethnopharmacol. 2024 Jun 3:118406. doi: 10.1016/j.jep.2024.118406. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Haematitum, a time-honored mineral-based Chinese medicine, has been used medicinally in China for over 2,000 years. It is now included in the Chinese Pharmacopoeia and used clinically for treating digestive and respiratory diseases. The Chinese Materia Medica records that it is toxic and should not be taken for a long period, but there are few research reports on the toxicity of Haematitum and its potential toxicity mechanisms.AIM OF THE STUDY: This study aimed to evaluate the toxicity of Haematitum and calcined Haematitum, including organ toxicity, neurotoxicity, and reproductive toxicity. Further, it is also necessary to explore the mechanism of Haematitum toxicity and to provide a reference for the safe clinical use of the drug.MATERIALS AND METHODS: The samples of Haematitum and calcined Haematitum decoctions were prepared. KM mice were treated with samples by gavage for 10 days, and lung damage and apoptosis were assessed by HE staining and TUNEL staining of lung tissues respectively. Metabolomics analysis was performed by HPLC-MS. Metallomics analysis was performed by ICP-MS. In addition, C. elegans was used as a model for 48 h exposure to examine the neurotoxicity and reproductive toxicity-related indices of Haematitum, including locomotor behaviors, growth and development, reproductive behaviors, AChE activities, sensory behaviors, apoptosis, and ROS levels.RESULTS: The use of large doses of Haematitum decoction caused lung damage in mice. Neither calcined Haematitum decoction nor Haematitum decoction at clinically used doses showed organ damage. Metabolomics results showed that disorders in lipid metabolic pathways such as sphingolipid metabolism and glycerophospholipid metabolism may be important factors in Haematitum-induced pulmonary toxicity. High doses of Haematitum decoction caused neurological damage to C. elegans, while low doses of Haematitum decoction and calcined Haematitum decoction showed no significant neurotoxicity. Decoction of Haematitum and calcined Haematitum did not show reproductive toxicity to C. elegans. Toxicity was also not observed in the control group of iron (Ⅱ) and iron (Ⅲ) ions in equal amounts with high doses of Haematitum.CONCLUSIONS: Haematitum is relatively safe for routine doses and short-term use. Calcination can significantly reduce Haematitum toxicity, and this study provides a reference for safe clinical use.PMID:38838923 | DOI:10.1016/j.jep.2024.118406

Chemosphere. 2024 Jun 3:142415. doi: 10.1016/j.chemosphere.2024.142415. Online ahead of print.ABSTRACTMicroplastics are difficult to degrade and widespread environmental pollutants. Coastal areas are hardest hit of microplastic pollution as they receive significant amounts of microplastics discharged from inland sources. Golden pompano (Trachinotus blochii) is a high commercial valuable marine aquaculture fish species, most of the golden pompano are raised in coastal areas, which means they are at significant risk of exposure to microplastics. Therefore, we exposed golden pompano to 10μg/L, 100μg/L and 1000μg/L of 5μm spherical polystyrene microplastics and conducted a 14-day stress experiment. Histopathology results showed the intestinal villi shrank. The 16s sequencing analysis revealed that microplastics significantly impacted the abundance and community structure of intestinal microorganisms, which may affect the metabolic function of the gastrointestinal tract. Metabolomics sequencing of the intestinal contents showed that microplastics caused disruptions in lipid, glucose, and amino acid metabolism, thus compromising the normal digestion and absorption functions in the intestinal system. In addition, the activation of various pathways, including the intestinal endocrine system, proline metabolism, and signal transduction, which can lead to the occurrence of several diseases. This study combined various methods to investigate the adverse effects of microplastics on intestinal digestion and absorption, and provided new insights into the toxic mechanisms of microplastics.PMID:38838870 | DOI:10.1016/j.chemosphere.2024.142415

Phytomedicine. 2024 Apr 19;130:155655. doi: 10.1016/j.phymed.2024.155655. Online ahead of print.ABSTRACTBACKGROUND: The study of cardiotoxicity of drugs has become an important part of clinical safety evaluation of drugs. It is commonly known that podophyllotoxin (PPT) and its many derivatives and congeners are broad-spectrum pharmacologically active substances. Clinical cardiotoxicity of PPT and its derivatives has been raised, basic research on the mechanism of cardiotoxicity remains insufficient.PURPOSE: In present study, our group's innovative concept of toxicological evidence chain (TEC) was applied to reveal the cardiac toxicity mechanism of PPT by targeted metabolomics, TMT-based quantitative proteomics and western blot.METHODS: The injury phenotype evidence (IPE) acquired from the toxicity manifestations, such as weight and behavior observation of Sprague-Dawley rat. The damage to rat hearts were assessed through histopathological examination and myocardial enzymes levels, which were defined as Adverse Outcomes Evidence (AOE). The damage to rat hearts was assessed through histopathological examination and myocardial enzyme levels, which were defined as evidence of adverse outcomes.Overall measurements of targeted metabolomics based on energy metabolism and TMT-based quantitative proteomics were obtained after exposure to PPT to acquire the Toxic Event Evidence (TEE). The mechanism of cardiac toxicity was speculated based on the integrated analysis of targeted metabolomics and TMT-based quantitative proteomics, which was verified by western blot.RESULTS: The results indicated that exposure to PPT could result in significant elevation of myocardial enzymes and pathological alterations in rat hearts. In addition, we found that PPT caused disorders in cardiac energy metabolism, characterized by a decrease in energy metabolism fuels. TMT-based quantitative proteomics revealed that the PPAR (Peroxisome proliferators-activated receptor) signaling pathway needs further study. It is worth noting that PPT may suppress the expression of SIRT1, subsequently inhibiting AMPK, decreasing the expression of PGC-1α, PPARα and PPARγ. This results in disorders of glucose oxidation, glycolysis and ketone body metabolism. Additionally, the increase in the expression of p-IKK and p-IκBα, leads to the nuclear translocation of NF-κB p65 from the cytosol, thus triggering inflammation.CONCLUSION: This study comprehensively evaluated cardiac toxicity of PPT and initially revealed the mechanism of cardiotoxicity,suggesting that PPT induced disorders of energy metabolism and inflammation via SIRT1/PPAR/NF-κB axis, potentially contributing to cardiac injury.PMID:38838636 | DOI:10.1016/j.phymed.2024.155655

Food Chem. 2024 May 31;455:139917. doi: 10.1016/j.foodchem.2024.139917. Online ahead of print.ABSTRACTCrocus sativus L. is a both medicinal and food bulbous flower whose qualities are geographically characterized. However, identification involving different places of origin of such substances is currently limited to single-omics mediated content analysis. Integrated metabolomics and proteomics, 840 saffron samples from six countries (Spain, Greece, Iran, China, Japan, and India) were analyzed using the QuEChERS extraction method. A total of 77 differential metabolites and 14 differential proteins were identified. The limits of detection of the method were 1.33 to 8.33 μg kg-1, and the recoveries were 85.56% to 105.18%. Using homology modeling and molecular docking, the Gln84, Lys195, Val182 and Pro184 sites of Crocetin glucosyltransferase 2 were found to be the targets of crocetin binding. By multivariate statistical analysis (PCA and PLS-DA), different saffron samples were clearly distinguished. The results provided the basis for the selection and identification of high quality saffron from different producing areas.PMID:38838622 | DOI:10.1016/j.foodchem.2024.139917

Talanta. 2024 Jun 1;277:126347. doi: 10.1016/j.talanta.2024.126347. Online ahead of print.ABSTRACTSilver nanoparticles are used in laser mass spectrometry to replace organic matrices. Thanks to their unique properties, they enable effective desorption/ionization of samples of various polarities and ionization abilities. This review presents new methods for the synthesis of monoisotopic silver nanoparticles and the use of targets coated with these nanoparticles for qualitative and quantitative analyses of various small-molecule compounds. Additionally, the results of progress in the application of AgNPs for metabolomics analyses were presented.PMID:38838565 | DOI:10.1016/j.talanta.2024.126347

Water Res. 2024 May 24;259:121805. doi: 10.1016/j.watres.2024.121805. Online ahead of print.ABSTRACTUnderstanding the structure and activity of activated sludge (AS) microbiome is key to ensuring optimal operation of wastewater treatment processes. While high-throughput metagenomics offers a comprehensive view of AS microbiome, its cost and time demands warrant alternative approaches. This study employed machine learning methods to integrate metabolomic and metagenomic data, enabling predictions of selected microbial abundances from metabolite profiling. Model training relied on rich microbial and metabolite abundance data collected in an intensively sampled AS system, including a period of filamentous bulking, as well as a few other AS systems. Multiple linear regression out-competed other three algorithms in achieving relatively high prediction accuracy (R2 = 0.70±0.02) for the abundances of 10 selected, either keystone or core metagenome-assembled genomes (MAGs). The model predicted the abundances of filamentous Microtrichaceae and Thiotrichaceae during bulking with an error range of 14-17.8 %. This predictive power extends beyond the specific system studied, showcasing potentials for broader applications across other AS systems. Aspartate, glycine, and folate were the most influential metabolite features contributing to model performance, which were also effective indicators for filamentous bulking, with up to one week of early warning potential. This study pioneers the application of metabolomics for fast, relatively accurate and cost-effective prediction of AS community composition, enabling proactive management of AS systems towards improved efficiency and stability.PMID:38838481 | DOI:10.1016/j.watres.2024.121805

Microbiome. 2024 Jun 5;12(1):101. doi: 10.1186/s40168-024-01814-z.ABSTRACTBACKGROUND: Plant microbiota contributes to plant growth and health, including enhancing plant resistance to various diseases. Despite remarkable progress in understanding diseases resistance in plants, the precise role of rhizosphere microbiota in enhancing watermelon resistance against soil-borne diseases remains unclear. Here, we constructed a synthetic community (SynCom) of 16 core bacterial strains obtained from the rhizosphere of grafted watermelon plants. We further simplified SynCom and investigated the role of bacteria with synergistic interactions in promoting plant growth through a simple synthetic community.RESULTS: Our results demonstrated that the SynCom significantly enhanced the growth and disease resistance of ungrafted watermelon grown in non-sterile soil. Furthermore, analysis of the amplicon and metagenome data revealed the pivotal role of Pseudomonas in enhancing plant health, as evidenced by a significant increase in the relative abundance and biofilm-forming pathways of Pseudomonas post-SynCom inoculation. Based on in vitro co-culture experiments and bacterial metabolomic analysis, we selected Pseudomonas along with seven other members of the SynCom that exhibited synergistic effects with Pseudomonas. It enabled us to further refine the initially constructed SynCom into a simplified SynCom comprising the eight selected bacterial species. Notably, the plant-promoting effects of simplified SynCom were similar to those of the initial SynCom. Furthermore, the simplified SynCom protected plants through synergistic effects of bacteria.CONCLUSIONS: Our findings suggest that the SynCom proliferate in the rhizosphere and mitigate soil-borne diseases through microbial synergistic interactions, highlighting the potential of synergistic effects between microorganisms in enhancing plant health. This study provides a novel insight into using the functional SynCom as a promising solution for sustainable agriculture. Video Abstract.PMID:38840214 | DOI:10.1186/s40168-024-01814-z

BMC Plant Biol. 2024 Jun 5;24(1):499. doi: 10.1186/s12870-024-05066-9.ABSTRACTBACKGROUND: Murraya tetramera Huang is a traditional Chinese woody medicine. Its leaves contain flavonoids, alkaloids, and other active compounds, which have anti-inflammatory and analgesic effects, as well as hypoglycemic and lipid-lowering effects, and anti-tumor effects. There are significant differences in the content of flavonoids and alkaloids in leaves during different growth cycles, but the synthesis mechanism is still unclear.RESULTS: In April 2021, new leaves (one month old) and old leaves (one and a half years old) of M. tetramera were used as experimental materials to systematically analyze the changes in differentially expressed genes (DEGs) and differentially accumulated metabolites (DAMs) with transcriptomics and metabolomics technology. This was done to identify the signaling pathways of flavonoid and alkaloid synthesis. The results showed that the contents of total alkaloids and flavonoids in old leaves were significantly higher than those in new leaves. Thirteen flavonoid compounds, three isoflavone compounds, and nineteen alkaloid compounds were identified, and 125 and 48 DEGs related to flavonoid and alkaloid synthesis were found, respectively. By constructing the KEGG (Kyoto Encyclopedia of Genes and Genomes) network of DEGs and DAMs, it was shown that the molecular mechanism of flavonoid biosynthesis in M. tetramera mainly focuses on the "flavonoid biosynthetic pathway" and the "flavonoid and flavonol biosynthetic pathway". Among them, p-Coumaryl alcohol, Sinapyl alcohol, Phloretin, and Isoquercitrin were significantly accumulated in old leaves, the up-regulated expression of CCR (cinnamoyl-CoA reductase) might promote the accumulation of p-Coumaryl alcohol, upregulation of F5H (ferulate-5-hydroxylase) might promote Sinapyl alcohol accumulation. Alkaloids, including indole alkaloids, pyridine alkaloids, imidazole alkaloids, and quinoline alkaloids, were significantly accumulated in old leaves, and a total of 29 genes were associated with these substances.CONCLUSIONS: These data are helpful to better understand the biosynthesis of flavonoids and alkaloids in M. tetramera and provide a scientific basis for the development of medicinal components in M. tetramera.PMID:38840069 | DOI:10.1186/s12870-024-05066-9

BMC Genomics. 2024 Jun 5;25(1):564. doi: 10.1186/s12864-024-10329-8.ABSTRACTMesenchymal Stem Cells are ideal seed cells for tissue repair and cell therapy and have promising applications in regenerative medicine and tissue engineering. Using Platelet-Rich Plasma as an adjuvant to create and improve the microenvironment for Mesenchymal Stem Cells growth can enhance the biological properties of Mesenchymal Stem Cells and improve the efficacy of cell therapy. However, the mechanism by which Platelet-Rich Plasma improves the biological performance of Mesenchymal Stem Cells is still unknown. In this study, by examining the effects of Platelet-Rich Plasma on the biological performance of Mesenchymal Stem Cells, combined with multiomics analysis (Transcriptomics, Proteomics and Metabolomics) and related tests, we analyzed the specific pathways, related mechanisms and metabolic pathways of Platelet-Rich Plasma to improve the biological performance of Mesenchymal Stem Cells. In an in vitro cell culture system, the biological performance of Mesenchymal Stem Cells was significantly improved after replacing Foetal Bovine Serum with Platelet-Rich Plasma, and the genes (ESM1, PDGFB, CLEC7A, CCR1 and ITGA6 et al.) related to cell proliferation, adhesion, growth, migration and signal transduction were significantly upregulated. Platelet-Rich Plasma can enhance the secretion function of MSC exosomes, significantly upregulate many proteins related to tissue repair, immune regulation and anti-infection, and enhance the repair effect of exosomes on skin injury. After replacing Foetal Bovine Serum with Platelet-Rich Plasma, Mesenchymal Stem Cells underwent metabolic reprogramming, the metabolism of amino acids and fatty acids and various signaling pathways were changed, the anabolic pathways of various proteins were enhanced. These results provide a theoretical and technical reference for optimizing the Mesenchymal Stem Cells culture system, improving the biological characteristics and clinical application effects of Mesenchymal Stem Cells.PMID:38840037 | DOI:10.1186/s12864-024-10329-8

Pediatr Res. 2024 Jun 5. doi: 10.1038/s41390-024-03291-4. Online ahead of print.ABSTRACTBACKGROUND: Female infants with congenital heart disease (CHD) face significantly higher postoperative mortality rates after adjusting for cardiac complexity. Sex differences in metabolic adaptation to cardiac stressors may be an early contributor to cardiac dysfunction. In adult diseases, hypoxic/ischemic cardiomyocytes undergo a cardioprotective metabolic shift from oxidative phosphorylation to glycolysis which appears to be regulated in a sexually dimorphic manner. We hypothesize sex differences in cardiac metabolism are present in cyanotic CHD and detectable as early as the infant period.METHODS: RNA sequencing was performed on blood samples (cyanotic CHD cases, n = 11; controls, n = 11) and analyzed using gene set enrichment analysis (GSEA). Global plasma metabolite profiling (UPLC-MS/MS) was performed using a larger representative cohort (cyanotic CHD, n = 27; non-cyanotic CHD, n = 11; unaffected controls, n = 12).RESULTS: Hallmark gene sets in glycolysis, fatty acid metabolism, and oxidative phosphorylation were significantly enriched in cyanotic CHD females compared to male counterparts, which was consistent with metabolomic differences between sexes. Minimal sex differences in metabolic pathways were observed in normoxic patients (both controls and non-cyanotic CHD cases).CONCLUSION: These observations suggest underlying differences in metabolic adaptation to chronic hypoxia between males and females with cyanotic CHD.IMPACT: Children with cyanotic CHD exhibit sex differences in utilization of glycolysis vs. fatty acid oxidation pathways to meet the high-energy demands of the heart in the neonatal period. Transcriptomic and metabolomic results suggest that under hypoxic conditions, males and females undergo metabolic shifts that are sexually dimorphic. These sex differences were not observed in neonates in normoxic conditions (i.e., non-cyanotic CHD and unaffected controls). The involved metabolic pathways are similar to those observed in advanced heart failure, suggesting metabolic adaptations beginning in the neonatal period may contribute to sex differences in infant survival.PMID:38839995 | DOI:10.1038/s41390-024-03291-4

Nat Cell Biol. 2024 Jun 5. doi: 10.1038/s41556-024-01436-5. Online ahead of print.ABSTRACTThe lysosomal degradation of macromolecules produces diverse small metabolites exported by specific transporters for reuse in biosynthetic pathways. Here we deorphanized the major facilitator superfamily domain containing 1 (MFSD1) protein, which forms a tight complex with the glycosylated lysosomal membrane protein (GLMP) in the lysosomal membrane. Untargeted metabolomics analysis of MFSD1-deficient mouse lysosomes revealed an increase in cationic dipeptides. Purified MFSD1 selectively bound diverse dipeptides, while electrophysiological, isotope tracer and fluorescence-based studies in Xenopus oocytes and proteoliposomes showed that MFSD1-GLMP acts as a uniporter for cationic, neutral and anionic dipeptides. Cryoelectron microscopy structure of the dipeptide-bound MFSD1-GLMP complex in outward-open conformation characterized the heterodimer interface and, in combination with molecular dynamics simulations, provided a structural basis for its selectivity towards diverse dipeptides. Together, our data identify MFSD1 as a general lysosomal dipeptide uniporter, providing an alternative route to recycle lysosomal proteolysis products when lysosomal amino acid exporters are overloaded.PMID:38839979 | DOI:10.1038/s41556-024-01436-5

Nature. 2024 Jun 5. doi: 10.1038/s41586-024-07501-1. Online ahead of print.ABSTRACTIncreasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis3-6-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.PMID:38839969 | DOI:10.1038/s41586-024-07501-1

Nat Commun. 2024 Jun 5;15(1):4775. doi: 10.1038/s41467-024-49049-8.ABSTRACTThe metal ion transporter SLC39A8 is associated with physiological traits and diseases, including blood manganese (Mn) levels and inflammatory bowel diseases (IBD). The mechanisms by which SLC39A8 controls Mn homeostasis and epithelial integrity remain elusive. Here, we generate Slc39a8 intestinal epithelial cell-specific-knockout (Slc39a8-IEC KO) mice, which display markedly decreased Mn levels in blood and most organs. Radiotracer studies reveal impaired intestinal absorption of dietary Mn in Slc39a8-IEC KO mice. SLC39A8 is localized to the apical membrane and mediates 54Mn uptake in intestinal organoid monolayer cultures. Unbiased transcriptomic analysis identifies alkaline ceramidase 1 (ACER1), a key enzyme in sphingolipid metabolism, as a potential therapeutic target for SLC39A8-associated IBDs. Importantly, treatment with an ACER1 inhibitor attenuates colitis in Slc39a8-IEC KO mice by remedying barrier dysfunction. Our results highlight the essential roles of SLC39A8 in intestinal Mn absorption and epithelial integrity and offer a therapeutic target for IBD associated with impaired Mn homeostasis.PMID:38839750 | DOI:10.1038/s41467-024-49049-8

J Agric Food Chem. 2024 Jun 5. doi: 10.1021/acs.jafc.4c00365. Online ahead of print.ABSTRACTInflammatory bowel disease (IBD) is a recurrent inflammatory condition affecting the gastrointestinal tract, and its clinical treatment remains suboptimal. Probiotics have shown effectiveness in alleviating dextran sulfate sodium salt (DSS)-induced colitis, exhibiting strain-specific anti-inflammatory properties. In this study, we compared the therapeutic effects of five strains of Bifidobacterium bifidum isolated from healthy adult feces on DSS-induced colitis in mice. Additionally, we investigated the underlying mechanisms by examining gut microbiota composition and microbial metabolome. Our findings highlighted the superior efficacy of B. bifidum M1-3 compared to other strains. It significantly improved colitis symptoms, mitigated gut barrier disruption, and reduced colonic inflammation in DSS-treated mice. Moreover, gut microbiota composition analysis revealed that B. bifidum M1-3 treatment increased the abundance and diversity of gut microbiota. Specifically, it significantly increased the abundance of Muribaculaceae, Lactobacillus, Bacteroides, and Enterorhabdus, while decreasing the abundance of Escherichia-Shigella. Furthermore, our nontargeted metabolomics analysis illustrated that B. bifidum M1-3 treatment had a regulatory effect on various metabolic pathways, including tyrosine metabolism, lysine degradation, and tryptophan metabolism. Importantly, we confirmed that the therapeutic efficiency of B. bifidum M1-3 was dependent on the gut microbiota. These results are conducive to the development of probiotic products for alleviating colitis.PMID:38838169 | DOI:10.1021/acs.jafc.4c00365