PubMed

J Transl Med. 2024 Dec 23;22(1):1138. doi: 10.1186/s12967-024-05955-5.ABSTRACTBACKGROUND: Scutellaria baicalensis Georgi, a traditional Chinese herb, is known for its various biological effects, including antibacterial, anti-inflammatory, antioxidative, and antitumor properties. However, the function and mechanisms of methanol extract of Scutellaria baicalensis Georgi (MESB) in treating hepatic fibrosis remain unclear.METHODS: This study utilized a CCl4-induced mouse model of hepatic fibrosis to assess the effects of MESB through histopathological analysis and serum tests. The anti-fibrosis mechanism of MESB was investigated using qPCR, Western blotting, RNA interference, proteomics, and metabolomics. Spatial metabolomics identified key components of MESB in liver tissue, while molecular docking determined their targets.RESULTS: Treatment with MESB alleviated hepatic pathological changes and reversed hepatic fibrosis in the CCl4-induced models, as evidenced by decreased collagen fibers deposition, reduced expression of hepatic fibrosis markers COL1A1, FN, and PAI-1, and lowered serum levels of AST and ALT. In vitro, MESB inhibited the proliferation of LX-2 cells and the expression of hepatic fibrosis markers. Furthermore, MESB intervention modulated various pathways, particularly those involved in metabolic pathways. Subsequent metabolomics analysis demonstrated that MESB disrupted glycerophospholipid metabolism and suppressed arachidonic acid metabolism. MESB downregulated the expression of cPLA2 in LX-2 cells, leading to decreased production of arachidonic acid and its downstream inflammatory mediators. Meanwhile, MESB inhibited the expression of cPLA2 and its downstream NF-κB pathway in the liver tissues of models induced by CCl4. Additionally, silencing cPLA2 markedly reduced the expressions of COL1A1, FN, and PAI-1. Spatial metabolomics analysis confirmed the penetration of baicalein, wogonin and wogonoside into liver tissue. Further results indicated that baicalein and wogonin inhibited the expression of cPLA2, while baicalin and wogonoside do not exhibit this effect. Moreover, molecular docking suggested that baicalein and wogonin possess the potential to directly interact with cPLA2.CONCLUSION: This study reveals that MESB is crucial in preventing hepatic fibrosis via the cPLA2-mediated arachidonic acid metabolic pathway, highlighting its key active components as potential drugs for fibrosis treatment.PMID:39716274 | DOI:10.1186/s12967-024-05955-5

Crit Care. 2024 Dec 24;28(1):431. doi: 10.1186/s13054-024-05216-3.ABSTRACTBACKGROUND: Lipids play a critical role in defense against sepsis. We sought to investigate gene expression and lipidomic patterns of lipid dysregulation in sepsis.METHODS: Data from four adult sepsis studies were analyzed and findings were investigated in two external datasets. Previously characterized lipid dysregulation subphenotypes of hypolipoprotein (HYPO; low lipoproteins, increased mortality) and normolipoprotein (NORMO; higher lipoproteins, lower mortality) were studied. Leukocytes collected within 24 h of sepsis underwent RNA sequencing (RNAseq) and shotgun plasma lipidomics was performed.RESULTS: Of 288 included patients, 43% were HYPO and 57% were NORMO. HYPO patients exhibited higher median SOFA scores (9 vs 5, p = < 0.001), vasopressor use (67% vs 34%, p = < 0.001), and 28-day mortality (30% vs 16%, p = 0.004). Leukocyte RNAseq identified seven upregulated lipid metabolism genes in HYPO (PCSK9, DHCR7, LDLR, ALOX5, PLTP, FDFT1, and MSMO1) vs. NORMO patients. Lipidomics revealed lower cholesterol esters (CE, adjusted p = < 0.001), lysophosphatidylcholines (LPC, adjusted p = 0.001), and sphingomyelins (SM, adjusted p = < 0.001) in HYPO patients. In HYPO patients, DHCR7 expression strongly correlated with reductions in CE, LPC, and SM (p < 0.01), while PCSK9, MSMO1, DHCR7, PLTP, and LDLR upregulation were correlated with low LPC (p < 0.05). DHCR7, ALOX5, and LDLR correlated with reductions in SM (p < 0.05). Mortality and phenotype comparisons in two external datasets (N = 824 combined patients) corroborated six of the seven upregulated lipid genes (PCSK9, DHCR7, ALOX5, PLTP, LDLR, and MSMO1).CONCLUSION: We identified a genetic lipid dysregulation signature characterized by seven lipid metabolism genes. Five genes in HYPO sepsis patients most strongly correlated with low CE, LPC, and SMs that mediate cholesterol storage and innate immunity.PMID:39716214 | DOI:10.1186/s13054-024-05216-3

BMC Psychiatry. 2024 Dec 23;24(1):946. doi: 10.1186/s12888-024-06413-8.ABSTRACTBACKGROUND: Antipsychotic-induced weight gain (AIWG) is a common side effect of antipsychotic drugs and may lead to cardiometabolic comorbidities. There is an urgent public health need to identify patients at high risk of AIWG and determine potential biomarkers for AIWG.METHODS: In the Sequential Multiple-Assignment Randomized Trials to Compare Antipsychotic Treatments (SMART-CAT) trail, first-episode schizophrenia patients were randomly assigned to olanzapine, risperidone, perphenazine, amisulpride or aripiprazole for 8 weeks. We applied absolute quantitative lipidomics at baseline and after 8 weeks of antipsychotic treatment in 80 patients. To evaluate the effects of AIWG on lipid profile, 25 patients with ≥ 7% weight changes (weight gain, WG) and 28 patients with <|3|% weight changes (weight stable, WS) were investigated, separately.RESULTS: We found that baseline CerP(d40:3) and PC(20:1_22:6) were positively associated with weight changes at follow-up (r > 0.4, pFDR < 0.05). Additionally, baseline CerP(d40:3) and PC(20:1_22:6) independently predicted rapid weight gain, with receiver operating curve (ROC) of 0.76 (95% CI: 0.63-0.90), and 0.75 (95% CI: 0.62-0.88), respectively. Compared with baseline, levels of 45 differential lipid metabolites (fold change > 1.2, VIP > 1 and pFDR < 0.05) were significantly higher in the WG group. Interestingly, no differential lipid metabolites were identified in the WS group. The LASSO regression model identified 18 AIWG lipid signatures, including 2 cholesterol esters (ChEs), 1 diglyceride (DG), 12 phosphatidylcholines (PCs), 1 phosphatidylglycerol (PG), 1 phosphatidylinositol (PI), and 1 sphingomyelin (SM), with the ChE(16:1) contributing the most. Furthermore, the level changes of ChE(16:1) were positively associated with weight gain(r = 0.67, pFDR < 0.05).CONCLUSION: Our findings indicate that lipid profile may serve as predictors of rapid weight gain in schizophrenia and provide useful markers for AIWG intervention.PMID:39716136 | DOI:10.1186/s12888-024-06413-8

BMC Pregnancy Childbirth. 2024 Dec 24;24(1):856. doi: 10.1186/s12884-024-07065-y.ABSTRACTOBJECTIVE: This study aimed to detect the proteins and metabolites in the cervicovaginal fluid to observe their relationship with the occurrence of placenta accreta spectrum and the potential biomarkers with predictive value.METHODS: Cervicovaginal fluid samples were collected before delivery from 6 participants of PAS and 6 controls subjects with similar gestational ages. The severity of PAS was evaluated by ultrasound and MRI scoring system and confirmed by the intraoperative findings or pathological examination. We used 4D label-free quantitative proteomics and untargeted metabolomics to identify the proteins and metabolites in cervicovaginal fluid, and analyzed the functions of differential expressed proteins or metabolites in PAS by multi-omics combined with bioinformatics analysis.RESULTS: Proteomics and metabolomics screened 127 and 12 differential expressed proteins and metabolites in CVF of PAS, respectively. Proteins and metabolites that significantly dysregulated in participants with placenta accreta spectrum were factors that regulate angiogenesis, and extracellular matrix proteins that regulate trophoblast invasion. Among them, the important difference expressed proteins/metabolites with representative significance are arginine, GAL7, uPA, MMP9 and ITGAM, that may be useful as potential biomarkers for the prediction and early diagnosis of PAS.CONCLUSION: Cervicovaginal fluid in patients with PAS presents a protein-metabolic microenvironment that promotes trophoblast invasion, endothelial activation and vascular proliferation.PMID:39716114 | DOI:10.1186/s12884-024-07065-y

BMC Genomics. 2024 Dec 23;25(1):1239. doi: 10.1186/s12864-024-11142-z.ABSTRACTCastration is widely used in poultry and livestock to enhance fat metabolism and improve the flavor, tenderness and juiciness of meat. However, the genetic regulatory mechanism underlying castration consequences have not been clarified. To investigate the key metabolites affecting the quality of capons and the key regulatory mechanisms, Qingyuan partridge roosters were subjected to castration. Metabolic profiling was used to detect differential metabolites in the breast muscle of both capon and control groups. Additionally, an integrative analysis of transcriptomics and proteomics was conducted to explore the genetic regulation mechanisms influencing meat quality. The results indicated that the muscle fiber density and shear force of capons was lower than that of normal chickens, and the fat percentage of capon group (CAM) was higher than control group (COM). The expression of the metabolite inostine-5'-monophosphate (IMP) was lower in capons, and lipid metabolites (PC (10:0/10:0), PC (6:0/13:1), LPC 22:6, LPC 18:2, LPE 18:1, LPE 20:4) were higher in capons. Metabolic pathways were found to be a common signaling pathway in all omics. Glutamate-ammonia ligase (GLUL), acetyl-CoA carboxylase beta (ACACB), 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2), 4-hydroxy-2-oxoglutarate aldolase 1 (HOGA1) and glutathione S-transferase alpha 2 (GSTA2) regulate the expression of citric acid, arachidonic acid, palmitic acid, isocitric acid, and betaine. These findings highlight the key mechanisms contributing to the meat quality differences between capons and normal chickens.PMID:39716077 | DOI:10.1186/s12864-024-11142-z

Methods Mol Biol. 2025;2884:81-98. doi: 10.1007/978-1-0716-4298-6_7.ABSTRACTShotgun proteomics can be applied to identify and study insect species in diverse research areas such as agriculture, forensics, biodiversity conservation, and food safety. In this chapter, we have provided a detailed protocol for shotgun proteomics analytical methods involving enzymatic digestion of insect proteins using trypsin, separation using high-performance liquid chromatography, and detection of separated peptides using high-resolution mass spectrometry. The protocol also covers the utilization of bioinformatics software for protein identification and spectral library building, proposing both proteomic database-dependent and independent methods. This chapter provides a valuable foundation for applying insect proteomics by discussing a step-by-step protocol.PMID:39715999 | DOI:10.1007/978-1-0716-4298-6_7

Nature. 2024 Dec 23. doi: 10.1038/s41586-024-08555-x. Online ahead of print.NO ABSTRACTPMID:39715925 | DOI:10.1038/s41586-024-08555-x

NPJ Vaccines. 2024 Dec 23;9(1):255. doi: 10.1038/s41541-024-01042-4.ABSTRACTFiloviruses, including Ebola, Marburg, Sudan, and Taï Forest viruses, are zoonotic pathogens that can cause severe viral hemorrhagic fever and death. Developing vaccines that provide durable, broad immunity against multiple filoviruses is a high global health priority. In this Phase 1 trial, we enrolled 60 healthy U.S. adults and evaluated the safety, reactogenicity and immunogenicity of homologous and heterologous MVA-BN®-Filo and Ad26.ZEBOV prime-boost schedules followed in select arms by MVA-BN®-Filo boost at 1 year (NCT02891980). We found that all vaccine regimens had acceptable safety and reactogenicity. The heterologous prime-boost strategy elicited superior Ebola binding and neutralizing antibody, antibody-dependent cellular cytotoxicity (ADCC), and cellular responses compared to homologous prime-boost. The MVA-BN®-Filo boost administered at 1 year resulted in robust humoral and cellular responses that persisted through 6-month follow-up. Overall, our data demonstrated that a heterologous Ad26.ZEBOV/MVA-BN®-Filo prime-boost was safe and immunogenic and established immunologic memory primed to respond after re-exposure. Clinicaltrials.gov, NCT02891980, registered September 1, 2016.PMID:39715748 | DOI:10.1038/s41541-024-01042-4

PLoS One. 2024 Dec 23;19(12):e0314599. doi: 10.1371/journal.pone.0314599. eCollection 2024.ABSTRACTBACKGROUND: Chronic prostatitis may be a risk factor for developing proliferative changes in the prostate, although the underlying mechanisms are not entirely comprehended.MATERIALS AND METHODS: Fifty individual prostate tissues were examined in this study, consisting of 25 patients diagnosed with prostatic hyperplasia combined with histologic chronic inflammation and 25 patients diagnosed with prostatic hyperplasia alone. We employed UPLC-Q-TOF-MS-based untargeted metabolomics using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry to identify differential metabolites that can reveal the mechanisms that underlie the promotion of prostate hyperplasia by histologic chronic inflammation. Selected differential endogenous metabolites were analyzed using bioinformatics and subjected to metabolic pathway studies.RESULTS: Nineteen differential metabolites, consisting of nine up-regulated and ten down-regulated, were identified between the two groups of patients. These groups included individuals with combined histologic chronic inflammation and those with prostatic hyperplasia alone. Glycerolipids, glycerophospholipids, and sphingolipids were primarily the components present. Metabolic pathway enrichment was conducted on the identified differentially expressed metabolites. Topological pathway analysis revealed the differential metabolites' predominant involvement in sphingolipid, ether lipid, and glycerophospholipid metabolism. The metabolites involved in sphingolipid metabolism were Sphingosine, Cer (d18:1/24:1), and Phytosphingosine. The metabolites involved in ether lipid metabolism were Glycerophosphocholine and LysoPC (O-18:0/0:0). The metabolites involved in glycerophospholipid metabolism were LysoPC (P-18:0/0:0) and Glycerophosphocholine. with Impact > 0. 1 and FDR < 0. 05, the most important metabolic pathway was sphingolipid metabolism.CONCLUSIONS: In conclusion, our findings suggest that patients with prostate hyperplasia and combined histologic chronic inflammation possess distinctive metabolic profiles. These differential metabolites appear to play a significant role in the pathogenesis of histologic chronic inflammation-induced prostate hyperplasia, primarily through the regulation of sphingolipids and glycerophospholipids metabolic pathways. The mechanism by which histologic chronic inflammation promotes prostate hyperplasia was elucidated through the analysis of small molecule metabolites. These findings support the notion that chronic prostatitis may contribute to an increased risk of prostate hyperplasia.PMID:39715183 | DOI:10.1371/journal.pone.0314599

J Proteome Res. 2024 Dec 23. doi: 10.1021/acs.jproteome.4c00410. Online ahead of print.ABSTRACTThe identification of peptides is a cornerstone of mass spectrometry-based proteomics. Spectral library-based algorithms are well-established methods to enhance the identification efficiency of peptides during database searches in proteomics. However, these algorithms are not specifically tailored for tandem mass tag (TMT)-based proteomics due to the lack of high-quality TMT spectral libraries. Here, we introduce JUMPlib, a computational tool for a TMT-based spectral library search. JUMPlib comprises components for generating spectral libraries, conducting library searches, filtering peptide identifications, and quantifying peptides and proteins. Fragment ion indexing in the libraries increases the search speed and utilizing the experimental retention time of precursor ions improves peptide identification. We found that methionine oxidation is a major factor contributing to large shifts in peptide retention time. To test the JUMPlib program, we curated two comprehensive human libraries for the labeling of TMT6/10/11 and TMT16/18 reagents, with ∼286,000 precursor ions and ∼304,000 precursor ions, respectively. Our analyses demonstrate that JUMPlib, employing the fragment ion index strategy, enhances search speed and exhibits high sensitivity and specificity, achieving approximately a 25% increase in peptide-spectrum matches compared to other search tools. Overall, JUMPlib serves as a streamlined computational platform designed to enhance peptide identification in TMT-based proteomics. Both the JUMPlib source code and libraries are publicly available.PMID:39715016 | DOI:10.1021/acs.jproteome.4c00410

Chembiochem. 2024 Dec 23:e202400852. doi: 10.1002/cbic.202400852. Online ahead of print.ABSTRACTThe importance of the protein-metabolite interaction network extends beyond its relevance to life sciences focused on proteins, it also profoundly influences its mechanisms related to disease targets, drug screening, and clinical diagnosis and treatment. Research methods targeting protein-metabolite interaction focus on enhancing the detectable signals of specific interactions by examining the structural characteristics of both proteins and metabolites in conjunction with chemical molecules, playing a crucial role in elucidating the protein-metabolite interaction network. Consequently, this article outlines several chemical targeting strategies developed in recent years and provides examples of their applications in the discovery and interpretation of new protein-metabolite interaction pathways. Finally, a brief summary will be presented regarding technological advances, research prospects, and current challenges of protein-metabolite interaction research.PMID:39715006 | DOI:10.1002/cbic.202400852

Mol Biotechnol. 2024 Dec 23. doi: 10.1007/s12033-024-01346-9. Online ahead of print.ABSTRACTStaphylococcus warneri is a gram-positive mesophilic bacterium, resilient to extreme environmental conditions. To unravel its Osmotic Tolerance Response (OTR), we conducted proteomic and metabolomic analyses under drought (PEG) and salt (NaCl) stresses. Our findings revealed 1340 differentially expressed proteins (DEPs) across all treatments. Interestingly, majority of these DEPs were part of common pathways activated by S. warneri. CPD1 in response to osmotic stress. Notably, the bacterial isolate exhibited increased expression of lysophospholipases associated with biofilm formation and protection from environmental stresses, transglycosylases involved in peptidoglycan biosynthesis, and acetoin reductase linked to acetoin metabolism. The upregulation of global ion transporters, including ABC transporters, potassium ion transport, and glutamate transport, indicated the bacterium's ability to maintain ionic balance under stress conditions. Protein-protein docking analysis revealed highest interactions with thioredoxin and alpha-acetolactate decarboxylase, highlighting their crucial roles in the mechanisms of osmotic stress tolerance in S. warneri CPD1. Metabolomic results demonstrated significant alterations in fatty acids and amino acids. In the greenhouse experiment, the bacterial isolate significantly enhanced wheat biomass, nutrient content, photosynthesis, and proline levels under stress conditions, making it a promising bacterial inoculant and biostimulant for improving crop productivity in challenging environments.PMID:39714746 | DOI:10.1007/s12033-024-01346-9

Anal Bioanal Chem. 2024 Dec 23. doi: 10.1007/s00216-024-05706-x. Online ahead of print.ABSTRACTCoronavirus disease 2019 is a highly contagious respiratory illness caused by the coronavirus SARS-CoV-2. Symptoms can range from mild to severe and typically appear 2-14 days after virus exposure. While vaccination has significantly reduced the incidence of severe complications, strategies for the identification of new biomarkers to assess disease severity remains a critical area of research. Severity biomarkers are essential for personalizing treatment strategies and improving patient outcomes. This study aimed to identify sex-specific biomarkers for COVID-19 severity in a Chilean population (n = 123 female, n = 115 male), categorized as control, mild, moderate, or severe. Data were collected using clinical biochemistry parameters and mass spectrometry-based metabolomics and lipidomics to detect alterations in plasma cytokines, metabolites, and lipid profiles related to disease severity. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were performed to select significant characteristic features for each group. The results revealed distinct biomarkers for males and females. In males, COVID-19 severity of was associated with inflammation parameters, triglycerides content, and phospholipids profiles. For females, liver damage parameters, triglycerides content, cholesterol derivatives, and phosphatidylcholine were identified as severity biomarkers. For both sexes, most of the biomarker combinations evaluated got areas under the ROC curve greater than 0.8 and low prediction errors. These findings suggest that sex-specific biomarkers can help differentiate the levels of COVID-19 severity, potentially aiding in the development of tailored treatment approaches.PMID:39714519 | DOI:10.1007/s00216-024-05706-x

Chem Biodivers. 2024 Dec 23:e202402311. doi: 10.1002/cbdv.202402311. Online ahead of print.ABSTRACTBlanchetia heterotricha is a species popularly used for its medicinal properties. However, few scientific records report the investigation of its chemical composition and biological activity. Herein, a metabolomics and multivariate statistical analysis approach was used to assess the chemical composition, antioxidant, and antimicrobial activity of B. heterotricha essential oil and fixed extracts (non-volatile). Thirty-six metabolites were identified in the essential oil by GC-MS, whereas 59 metabolites were identified in the fixed extracts by HPLC-HRMS. The essential oil and fixed extracts showed varying degrees of antioxidant and antimicrobial activities. The antioxidant activity varied from 7.27 ± 0.95 μg.mL-1 for the root methanolic extract extract to 513.25 ± 7.77 μg.mL-1 for the seed hexane extract. Extracts obtained with ethyl acetate showed the most promising antimicrobial activity, followed by extracts obtained with methanol and hexane. Multivariate statistical analysis allowed the identification of possible contributors to the observed activities within the extracts. This is the first study to assess the antimicrobial activity in any Blanchetia species. The combination of metabolomics and multivariate statistical analysis was a powerful tool to identify bioactive compounds, highlighting the potential of B. heterotricha essential oil and fixed extracts as sources of metabolites with antioxidant and antimicrobial properties.PMID:39714403 | DOI:10.1002/cbdv.202402311

Mol Omics. 2024 Dec 23. doi: 10.1039/d4mo00187g. Online ahead of print.ABSTRACTCancer remains the second leading cause of death worldwide, surpassed only by cardiovascular disease. From the different types of cancer, pancreatic cancer (PaC) has one of the lowest survival rates, with a survival rate of about 20% after the first year of diagnosis and about 8% after 5 years. The lack of highly sensitive and specific biomarkers, together with the absence of symptoms in the early stages, determines a late diagnosis, which is associated with a decrease in the effectiveness of medical intervention, regardless of its nature - surgery and/or chemotherapy. This review provides an updated overview of recent studies combining multi-OMICs approaches (e.g., proteomics, metabolomics) with analytical tools, highlighting the synergy between high-throughput molecular data generation and precise analytical tools such as LC-MS, GC-MS and MALDI-TOF MS. This combination significantly improves the detection, quantification and identification of biomolecules in complex biological systems and represents the latest advances in understanding PaC management and the search for effective diagnostic tools. Large-scale data analysis coupled with bioinformatics tools enables the identification of specific genetic mutations, gene expression patterns, pathways, networks, protein modifications and metabolic signatures associated with PaC pathogenesis, progression and treatment response through the integration of multi-OMICs data.PMID:39714229 | DOI:10.1039/d4mo00187g

mSystems. 2024 Dec 23:e0045224. doi: 10.1128/msystems.00452-24. Online ahead of print.ABSTRACTDietary fiber confers multiple health benefits originating from the expansion of beneficial gut microbial activity. However, very few studies have established the metabolic consequences of interactions among specific fibers, microbiome composition, and function in either human or representative animal models. In a study design reflective of realistic population dietary variation, fecal metagenomic and metabolomic profiles were analyzed from healthy dogs fed 12 test foods containing different fiber sources and quantities (5-13% as-fed basis). Taxa and functions were identified whose abundances were associated either with overall fiber intake or with specific fiber compositions. Fourteen microbial species were significantly enriched in response to ≥1 specific fiber source; enrichment of fiber-derived metabolites was more pronounced in response to these fiber sources. Positively associated fecal metabolites, including short-chain fatty acids, acylglycerols, fiber bound sugars, and polyphenols, co-occurred with microbes enriched in specific food groups. Critically, the specific metabolite pools responsive to differential fiber intake were dependent on differences both in individual microbial community membership and in overall ecological configuration. This helps to explain, for the first time, differences in microbiome-diet associations observed in companion animal epidemiology. Thus, our study corroborates findings in human cohorts and reinforces the role of personalized microbiomes even in seemingly phenotypically homogeneous subjects.IMPORTANCE: Consumption of dietary fiber changes the composition of the gut microbiome and, to a larger extent, the associated metabolites. Production of health-relevant metabolites such as short-chain fatty acids from fiber depends both on the consumption of a specific fiber and on the enrichment of beneficial metabolite-producing species in response to it. Even in a seemingly homogeneous population, the benefit received from fiber consumption is personalized and emphasizes specific fiber-microbe-host interactions. These observations are relevant for both population-wide and personalized nutrition applications.PMID:39714168 | DOI:10.1128/msystems.00452-24

mSystems. 2024 Dec 23:e0118924. doi: 10.1128/msystems.01189-24. Online ahead of print.ABSTRACTOnions are well-known vegetables that offer various health benefits. This study explores the impact of onion extracts on gut microbiome using an in vitro fecal incubation model and metabolome analysis. Fecal samples were collected from 19 healthy donors and incubated in the presence or absence of onion extracts for 24 h. To reduce inter-individual variability in the gut microbiome, we employed enterotyping based on baseline fecal microbiota: 14 subjects with a Bacteroides-dominant type (enterotype B) and 5 subjects with Prevotella-dominant type (enterotype P). Alpha diversity was significantly reduced in the onion-treated group compared to the non-treated control group in both Bacteroides- and Prevotella-dominant types. However, significant structural differences in bacterial communities were observed based on weighted UniFrac distance. Notably, short-chain fatty acid (SCFA)-producing bacteria, such as Bifidobacterium_388775, Feacalibacterium, and Fusicatenibacter, were overrepresented in response to onion extracts in enterotype B. Furthermore, genes related to butyrate production were significantly overrepresented in the onion-treated group within enterotype B. Consistent with the enriched taxa and the predicted metabolic pathways, SCFAs and their related metabolites were significantly enriched in the onion-treated group. Additionally, tryptophan metabolism-derived metabolites, including indolelactate (ILA) and indolepropionate (IPA), were elevated by 4- and 32-fold, respectively, in the onion-treated group compared to the control group. In vitro growth assays showed an increase in lactobacilli strains in the presence of onion extracts. These results provide evidence that onion extracts could serve as promising prebiotics by altering gut microbial structure and promoting the production of beneficiary metabolites, including SCFAs and indole derivatives, and enhancing the growth of probiotics.IMPORTANCEThis study is significant as it provides compelling evidence that onion extracts have the potential to serve as effective prebiotics. Utilizing an in vitro fecal incubation model and enterotyping to reduce inter-individual variability, the research demonstrates how onion extracts can alter gut microbial structure and promote the production of beneficial metabolites, including SCFAs and indole derivatives like ILA and IPA. Additionally, onion extract treatment enhances the growth of beneficial probiotics. The findings underscore the potential of onion extracts to improve gut health by enriching specific beneficial bacteria and metabolic pathways, thereby supporting the development of functional foods aimed at improving gut microbiota composition and metabolic health.PMID:39714164 | DOI:10.1128/msystems.01189-24

Front Nutr. 2024 Dec 6;11:1509341. doi: 10.3389/fnut.2024.1509341. eCollection 2024.ABSTRACTGiven the abundance of beneficial properties and enzymes secreted by edible oyster mushrooms, their mycelium could serve as a starter for fermented foods to enhance their nutritional and bioactive quality. This study aimed to investigate the effects on the nutritional ingredients, antioxidant activity, and non-volatile metabolites during solid-state fermentation (SSF) of soybeans by Pleurotus ostreatus mycelium. The results indicated that the contents of dietary fiber and starch in fermented soybeans decreased, while the amounts of protein and lipid increased after SSF (P < 0.05). Analysis of the total phenolic content (TPC) and antioxidant activities of the fermented soybeans revealed that the methanolic extracts significantly increased TPC and antioxidant activities against intracellular reactive oxygen species (ROS) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, as well as against DPPH and ABTS radicals in vitro. A total 154 differential metabolites were identified after SSF, and a Spearman correlation study revealed a direct relationship between antioxidant activities and certain metabolites including phenolic compounds, oligopeptides, and free fatty acids etc. Among these metabolites, phenolic compounds produced by the shikimic acid pathway were diverse in variety and had the greatest multiple differences. The study discovered that a potential mechanism involving SSF with P. ostreatus mycelium increased the antioxidant activity of soybeans.PMID:39713777 | PMC:PMC11660803 | DOI:10.3389/fnut.2024.1509341

J Inflamm Res. 2024 Dec 18;17:11197-11209. doi: 10.2147/JIR.S495512. eCollection 2024.ABSTRACTINTRODUCTION: Sepsis-induced acute lung injury (ALI), a critical sequela of systemic inflammation, often progresses to acute respiratory distress syndrome, conferring high mortality. Although UMI-77 has demonstrated efficacy in mitigating lung injury in sepsis, the molecular mechanisms underlying its action have not yet been fully elucidated.METHODS: This study aimed to delineate the mechanism by which UMI-77 counteracts sepsis-induced ALI using comprehensive transcriptomic and metabolomic analyses.RESULTS: UMI-77 significantly ameliorated histopathological changes in the lungs of mice with sepsis-induced ALI Transcriptomic analysis revealed that 124 differentially expressed genes were modulated by UMI-77 and were predominantly implicated in chemokine-mediated signaling pathways, apoptosis regulation, and inflammatory responses. Integrated metabolomic analysis identified Atp4a, Ido1, Ctla4, and Cxcl10 as key genes, and inosine 5'-monophosphate (IMP), thiamine monophosphate, thymidine 3',5'-cyclic monophosphate (dTMP) as key differential metabolites. UMI-77 may regulate key genes (Atp4a, Ido1, Ctla4, and Cxcl10) to affect key metabolites (IMP, thiamine monophosphate, and dTMP) and their target genes (Entpd2, Entpd1, Nt5e, and Hprt) involved in cytokine-cytokine receptor interaction, gastric acid secretion, pyrimidine, and purine metabolism in the treatment of sepsis-induced ALI.CONCLUSION: UMI-77 exerts its therapeutic effect in sepsis-induced ALI through intricate modulation of pivotal genes and metabolites, thereby influencing critical biological pathways. This study lays the groundwork for further development and clinical translation of UMI-77 as a potential therapeutic agent for sepsis-associated lung injuries.PMID:39713715 | PMC:PMC11663390 | DOI:10.2147/JIR.S495512

bioRxiv [Preprint]. 2024 Dec 14:2024.12.13.628212. doi: 10.1101/2024.12.13.628212.ABSTRACTProteolysis of hydrophobic helices is required for complete breakdown of every transmembrane protein trafficked to the lysosome and sustains high rates of endocytosis. However, the lysosomal mechanisms for degrading hydrophobic domains remain unknown. Combining lysosomal proteomics with functional genomic data mining, we identify Lysosomal Leucine Aminopeptidase (LyLAP; formerly Phospholipase B Domain-Containing 1) as the hydrolase most tightly associated with elevated endocytic activity. Untargeted metabolomics and biochemical reconstitution demonstrate that LyLAP is not a phospholipase, but a processive monoaminopeptidase with strong preference for N-terminal leucine - an activity necessary and sufficient for breakdown of hydrophobic transmembrane domains. LyLAP is upregulated in pancreatic ductal adenocarcinoma (PDA), which relies on macropinocytosis for nutrient uptake, and its ablation led to buildup of undigested hydrophobic peptides, which compromised lysosomal membrane integrity and inhibited PDA cell growth. Thus, LyLAP enables lysosomal degradation of membrane proteins, and may represent a vulnerability in highly endocytic cancer cells.ONE SENTENCE SUMMARY: LyLAP degrades transmembrane proteins to sustain high endocytosis and lysosomal membrane stability in pancreatic cancer.PMID:39713462 | PMC:PMC11661280 | DOI:10.1101/2024.12.13.628212