PubMed

Metabolomics. 2024 Jul 16;20(4):78. doi: 10.1007/s11306-024-02148-5.ABSTRACTINTRODUCTION: Amid the global health crisis, HIV/TB co-infection presents significant challenges, amplifying the burden on patients and healthcare systems alike. Metabolomics offers an innovative window into the metabolic disruptions caused by co-infection, potentially improving diagnosis and treatment monitoring.AIM: This study uses untargeted metabolomics to investigate the urinary metabolic signature of HIV/TB co-infection, enhancing understanding of the metabolic interplay between these infections.METHODS: Urine samples from South African adults, categorised into four groups - healthy controls, TB-positive, HIV-positive, and HIV/TB co-infected - were analysed using GCxGC-TOFMS. Metabolites showing significant differences among groups were identified through Kruskal-Wallis and Wilcoxon rank sum tests.RESULTS: Various metabolites (n = 23) were modulated across the spectrum of health and disease states represented in the cohorts. The metabolomic profiles reflect a pronounced disruption in biochemical pathways involved in energy production, amino acid metabolism, gut microbiome, and the immune response, suggesting a bidirectional exacerbation between HIV and TB. While both diseases independently perturb the host's metabolism, their co-infection leads to a unique metabolic phenotype, indicative of an intricate interplay rather than a simple additive effect.CONCLUSION: Metabolic profiling revealed a unique metabolic landscape shaped by HIV/TB co-infection. The findings highlight the potential of urinary differential metabolites for co-infection, offering a non-invasive tool for enhancing diagnostic precision and tailoring therapeutic interventions. Future research should focus on expanding sample sizes and integrating longitudinal analyses to build upon these foundational insights, paving the way for metabolomic applications in combating these concurrent pandemics.PMID:39014031 | DOI:10.1007/s11306-024-02148-5

Sci Data. 2024 Jul 16;11(1):780. doi: 10.1038/s41597-024-03404-y.ABSTRACTEuglena gracilis (E. gracilis), pivotal in the study of photosynthesis, endosymbiosis, and chloroplast development, is also an industrial microalga for paramylon production. Despite its importance, E. gracilis genome exploration faces challenges due to its intricate nature. In this study, we achieved a chromosome-level de novo assembly (2.37 Gb) using Illumina, PacBio, Bionano, and Hi-C data. The assembly exhibited a contig N50 of 619 Kb and scaffold N50 of 1.12 Mb, indicating superior continuity. Approximately 99.83% of the genome was anchored to 46 chromosomes, revealing structural insights. Repetitive elements constituted 58.84% of the sequences. Functional annotations were assigned to 39,362 proteins, enhancing interpretative power. BUSCO analysis confirmed assembly completeness at 80.39%. This first high-quality E. gracilis genome offers insights for genetics and genomics studies, overcoming previous limitations. The impact extends to academic and industrial research, providing a foundational resource.PMID:39013888 | DOI:10.1038/s41597-024-03404-y

Nat Commun. 2024 Jul 16;15(1):5947. doi: 10.1038/s41467-024-49585-3.ABSTRACTConversion of heterotrophic organisms into partially or completely autotrophic organisms is primarily accomplished by extensive metabolic engineering and laboratory evolution efforts that channel CO2 into central carbon metabolism. Here, we develop a directed endosymbiosis approach to introduce carbon assimilation in budding yeasts. Particularly, we engineer carbon assimilating and sugar-secreting photosynthetic cyanobacterial endosymbionts within the yeast cells, which results in the generation of yeast/cyanobacteria chimeras that propagate under photosynthetic conditions in the presence of CO2 and in the absence of feedstock carbon sources like glucose or glycerol. We demonstrate that the yeast/cyanobacteria chimera can be engineered to biosynthesize natural products under the photosynthetic conditions. Additionally, we expand our directed endosymbiosis approach to standard laboratory strains of yeasts, which transforms them into photosynthetic yeast/cyanobacteria chimeras. We anticipate that our studies will have significant implications for sustainable biotechnology, synthetic biology, and experimentally studying the evolutionary adaptation of an additional organelle in yeast.PMID:39013857 | DOI:10.1038/s41467-024-49585-3

J Am Soc Mass Spectrom. 2024 Jul 16. doi: 10.1021/jasms.4c00146. Online ahead of print.ABSTRACTMass spectrometry is broadly employed to study complex molecular mechanisms in various biological and environmental fields, enabling 'omics' research such as proteomics, metabolomics, and lipidomics. As study cohorts grow larger and more complex with dozens to hundreds of samples, the need for robust quality control (QC) measures through automated software tools becomes paramount to ensure the integrity, high quality, and validity of scientific conclusions from downstream analyses and minimize the waste of resources. Since existing QC tools are mostly dedicated to proteomics, automated solutions supporting metabolomics are needed. To address this need, we developed the software PeakQC, a tool for automated QC of MS data that is independent of omics molecular types (i.e., omics-agnostic). It allows automated extraction and inspection of peak metrics of precursor ions (e.g., errors in mass, retention time, arrival time) and supports various instrumentations and acquisition types, from infusion experiments or using liquid chromatography and/or ion mobility spectrometry front-end separations and with/without fragmentation spectra from data-dependent or independent acquisition analyses. Diagnostic plots for fragmentation spectra are also generated. Here, we describe and illustrate PeakQC's functionalities using different representative data sets, demonstrating its utility as a valuable tool for enhancing the quality and reliability of omics mass spectrometry analyses.PMID:39013167 | DOI:10.1021/jasms.4c00146

Gut Microbes. 2024 Jan-Dec;16(1):2379566. doi: 10.1080/19490976.2024.2379566. Epub 2024 Jul 16.ABSTRACTNecrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants with no specific treatments available. We aimed to identify the molecular mechanisms underlying NEC and investigate the therapeutic effects of Bacteroides fragilis on NEC. Clinical samples of infant feces, bile acid-targeted metabolomics, pathological staining, bioinformatics analysis, NEC rat model, and co-immunoprecipitation were used to explore the pathogenesis of NEC. Taxonomic characterization of the bile salt hydrolase (bsh) gene, enzyme activity assays, 16S rRNA sequencing, and organoids were used to explore the therapeutic effects of B. fragilis on NEC-related intestinal damage. Clinical samples, NEC rat models, and in vitro experiments revealed that total bile acid increased in the blood but decreased in feces. Moreover, the levels of FXR and other bile acid metabolism-related genes were abnormal, resulting in disordered bile acid metabolism in NEC. Taurochenodeoxycholic acid accelerated NEC pathogenesis and taurodeoxycholate alleviated NEC. B. fragilis displayed bsh genes and enzyme activity and alleviated intestinal damage by restoring gut microbiota dysbiosis and bile acid metabolism abnormalities by inhibiting the FXR-NLRP3 signaling pathway. Our results provide valuable insights into the therapeutic role of B. fragilis in NEC. Administering B. fragilis may substantially alleviate intestinal damage in NEC.PMID:39013030 | DOI:10.1080/19490976.2024.2379566

Proc Natl Acad Sci U S A. 2024 Jul 23;121(30):e2303642121. doi: 10.1073/pnas.2303642121. Epub 2024 Jul 16.ABSTRACTGlutamyl-prolyl-tRNA synthetase (EPRS1) is a bifunctional aminoacyl-tRNA-synthetase (aaRS) essential for decoding the genetic code. EPRS1 resides, with seven other aaRSs and three noncatalytic proteins, in the cytoplasmic multi-tRNA synthetase complex (MSC). Multiple MSC-resident aaRSs, including EPRS1, exhibit stimulus-dependent release from the MSC to perform noncanonical activities distinct from their primary function in protein synthesis. Here, we show EPRS1 is present in both cytoplasm and nucleus of breast cancer cells with constitutively low phosphatase and tensin homolog (PTEN) expression. EPRS1 is primarily cytosolic in PTEN-expressing cells, but chemical or genetic inhibition of PTEN, or chemical or stress-mediated activation of its target, AKT, induces EPRS1 nuclear localization. Likewise, preferential nuclear localization of EPRS1 was observed in invasive ductal carcinoma that were also P-Ser473-AKT+. EPRS1 nuclear transport requires a nuclear localization signal (NLS) within the linker region that joins the catalytic glutamyl-tRNA synthetase and prolyl-tRNA synthetase domains. Nuclear EPRS1 interacts with poly(ADP-ribose) polymerase 1 (PARP1), a DNA-damage sensor that directs poly(ADP-ribosyl)ation (PARylation) of proteins. EPRS1 is a critical regulator of PARP1 activity as shown by markedly reduced ADP-ribosylation in EPRS1 knockdown cells. Moreover, EPRS1 and PARP1 knockdown comparably alter the expression of multiple tumor-related genes, inhibit DNA-damage repair, reduce tumor cell survival, and diminish tumor sphere formation by breast cancer cells. EPRS1-mediated regulation of PARP1 activity provides a mechanistic link between PTEN loss in breast cancer cells, PARP1 activation, and cell survival and tumor growth. Targeting the noncanonical activity of EPRS1, without inhibiting canonical tRNA ligase activity, provides a therapeutic approach potentially supplementing existing PARP1 inhibitors.PMID:39012819 | DOI:10.1073/pnas.2303642121

Ann Clin Transl Neurol. 2024 Jul;11(7):1897-1908. doi: 10.1002/acn3.52112. Epub 2024 Jun 21.ABSTRACTOBJECTIVE: Differentiating forms of autoimmune encephalitis (AE) from other causes of seizures helps expedite immunotherapies in AE patients and informs studies regarding their contrasting pathophysiology. We aimed to investigate whether and how Nuclear Magnetic Resonance (NMR)-based metabolomics could differentiate AE from drug-resistant epilepsy (DRE), and stratify AE subtypes.METHODS: This study recruited 238 patients: 162 with DRE and 76 AE, including 27 with contactin-associated protein-like 2 (CASPR2), 29 with leucine-rich glioma inactivated 1 (LGI1) and 20 with N-methyl-d-aspartate receptor (NMDAR) antibodies. Plasma samples across the groups were analyzed using NMR spectroscopy and compared with multivariate statistical techniques, such as orthogonal partial least squares discriminant analysis (OPLS-DA).RESULTS: The OPLS-DA model successfully distinguished AE from DRE patients with a high predictive accuracy of 87.0 ± 3.1% (87.9 ± 3.4% sensitivity and 86.3 ± 3.6% specificity). Further, pairwise OPLS-DA models were able to stratify the three AE subtypes. Plasma metabolomic signatures of AE included decreased high-density lipoprotein (HDL, -(CH2)n-, -CH3), phosphatidylcholine and albumin (lysyl moiety). AE subtype-specific metabolomic signatures were also observed, with increased lactate in CASPR2, increased lactate, glucose, and decreased unsaturated fatty acids (UFA, -CH2CH=) in LGI1, and increased glycoprotein A (GlycA) in NMDAR-antibody patients.INTERPRETATION: This study presents the first non-antibody-based biomarker for differentiating DRE, AE and AE subtypes. These metabolomics signatures underscore the potential relevance of lipid metabolism and glucose regulation in these neurological disorders, offering a promising adjunct to facilitate the diagnosis and therapeutics.PMID:39012808 | DOI:10.1002/acn3.52112

Shock. 2024 Jul 16. doi: 10.1097/SHK.0000000000002419. Online ahead of print.ABSTRACTBACKGROUND: Trauma and blood loss are frequently associated with organ failure, immune dysfunction, and a high risk of secondary bacterial lung infections. We aim to test if plasma metabolomic flux and monocyte bioenergetics are altered in association with trauma and related secondary infections.METHODS: Plasma samples were collected from trauma patients at three time points: days 0, 3, and 7 post-admission. Metabolites (140) were measured in plasma from trauma survivors (n = 24) and healthy control individuals (HC, n = 10). Further analysis within the trauma cohort included subsets of trauma/infection-negative (TIneg, n = 12) and trauma/infection-positive patients (TIpos, n = 12). The bioenergetic profile in monocytes was determined using mitochondrial and glycolytic stress tests.RESULTS: In the trauma cohort, significant alterations were observed in 29 metabolites directly affecting 11 major metabolic pathways, while 34 metabolite alterations affected 8 pathways in TIpos, versus TIneg patients. The most altered metabolic pathways included protein synthesis, the urea cycle/arginine metabolism, phenylalanine, tyrosine, tryptophan biosynthesis, and carnitine compound family. In monocytes from trauma patients, reduced mitochondrial indices and loss of glycolytic plasticity were consistent with an altered profile of plasma metabolites in the TCA cycle and glycolysis.CONCLUSIONS: Our study highlights that the metabolic profile is significantly and persistently affected by trauma and related infections. Among trauma survivors, metabolic alterations in plasma were associated with reduced monocyte bioenergetics. These exploratory findings establish a groundwork for future clinical studies aimed at enhancing our understanding of the interplay between metabolic/bioenergetic alterations associated with trauma and secondary bacterial infections.PMID:39012766 | DOI:10.1097/SHK.0000000000002419

Aging Dis. 2024 Jul 23. doi: 10.14336/AD.2024.0434. Online ahead of print.ABSTRACTCardiovascular risk factors and established cardiovascular disease (CVD) increase the risk of suffering dementia of the Alzheimer's type (DAT). Here, we set out to define specific molecular profiles of CVD in patients with DAT to better understand its relationship, to unravel the mechanisms underlying the high risk of developing DAT in CVD patients and to define new markers of early disease. Plasma samples from patients with DAT, with and without CVD, were analyzed through a multiomics approach, with integration of metabolomics and proteomics datasets using the OmicsNet web-based tool. Metabolomics results showed an enrichment in lipids and lipid-like molecules. Similarly, the most significant cluster identified through proteomics was formed by 5 proteins related to lipoprotein and cholesterol metabolism. After integration and functional enrichment, glycerolipid metabolism, fatty acid degradation and sphingolipid metabolism were among the most significant functions. Finally, differential expression of ABCA1 and APOH proteins was verified, in an independent cohort also including controls and patients with CVD alone. Both proteins positively correlated with phospho-Tau (181), a classical hallmark of DAT. Different molecular profiles exist in patients with DAT, with and without CVD, with exacerbated alterations in patients in which DAT and CVD co-exist. This information may help to define biomarkers like ABCA1 and APOH that identify patients with cardiovascular dysfunction that are at high risk of developing DAT. Such markers will allow more personalized interventions to be selected, a further step towards precision medicine for individuals whose molecular profiles indicate a distinct response to the same management strategies.PMID:39012677 | DOI:10.14336/AD.2024.0434

Am J Physiol Gastrointest Liver Physiol. 2024 Jul 16. doi: 10.1152/ajpgi.00301.2023. Online ahead of print.ABSTRACTGut metabolites via the portal vein affect several liver functions, including regeneration. Here, we investigated gut microbiota-derived metabolites in portal and peripheral serum during liver regeneration. We developed rat models of 70% partial hepatectomy (PHx) with and without prior gut microbiota modulation by three-week antibiotic (Abx) treatment. Sham without Abx were used as controls and compared to sham with Abx. Liver regeneration at day 2 following PHx was assessed by expression of proliferating cell nuclear antigen (PCNA) protein in liver tissues and cyclin genes in primary hepatocytes. High pressure liquid chromatography-mass spectrometry (HPLC-MS) based portal and peripheral venous serum metabolomics was performed to identify differentially altered metabolites (DAMs). Compared to controls, rat livers at day 2 post-PHx showed significant upregulation in the average number of PCNA-positive cells, which positively correlated with the expression of cell cycle genes in hepatocytes. In Abx-treated PHx, we observed reduced PCNA-positivity and downregulation in gene expression of various cyclins in hepatocytes compared to PHx. We identified 224 DAMs between controls vs PHx and 189 DAMs between Abx-treated PHx vs PHx in portal serum. Many common DAMs showed opposite expression trends in PHx vs controls and then Abx+PHx vs PHx in portal serum, such as sphingosine-1-phosphate and deoxycholic acid. In vitro studies with deoxycholic acid demonstrated that it enhanced the viability and proliferation of primary hepatocytes and hepatocyte organoids. The study underscores the critical role of deoxycholic acid in portal blood in enhancing hepatocyte proliferation and subsequently, liver regeneration.PMID:39012497 | DOI:10.1152/ajpgi.00301.2023

Appl Physiol Nutr Metab. 2024 Jul 16. doi: 10.1139/apnm-2023-0573. Online ahead of print.ABSTRACTThis report describes the knowledge mobilization and translation outcomes of the Canadian-funded portion of a large, international project called the Food Biomarker Alliance (FoodBAll), which ran from 2015 to 2019. This remarkably successful project led to a large number of important findings, outputs, and impacts. In particular, FoodBAll unequivocally demonstrated that metabolomics could be used to not only discover biomarkers of food intake (BFIs), but also to measure diet in a more objective manner. FoodBAll also created standards for assessing and validating BFIs, papers and databases describing BFIs, and kits for measuring BFIs and it laid the groundwork for many global studies exploring food composition and precision nutrition.PMID:39011902 | DOI:10.1139/apnm-2023-0573

Food Funct. 2024 Jul 16. doi: 10.1039/d4fo01489h. Online ahead of print.ABSTRACTThis study was designed to verify the anti-obesity effect of dietary turmeric powder (TP) as a traditional cooking spice and its underlying mechanism. The HFD-fed C57BL/6J mice were supplemented with or without TP (8%) for 12 weeks. The results indicated that the glucolipid metabolism disorder of high-fat diet (HFD)-fed mice was significantly ameliorated through the supplementation of TP. The consumption of TP also induced beige-fat development and brown adipose tissue (BAT)-derived nonshivering thermogenesis in HFD-fed obese mice. 16S rDNA-based microbiota or targeted metabolomics analysis indicated that TP ameliorated the intestinal microbiota dysbiosis and microbial metabolism abnormality caused by HFD, reflected by dramatically increasing the relative abundance of Muribaculaceae, Candidatus_Saccharimonas, and Bifidobacterium and production of short-chain fatty acids (SCFAs) and succinate. Interestingly, TP-induced BAT thermogenesis and iWAT browning were highly correlated with the reconstruction of the gut microbiome and formation of SCFAs and succinate. Collectively, these findings manifest beneficial actions of TP on the promotion of adipose browning and thermogenesis in association with gut microbiota reconstruction, and our findings may provide a promising way for preventing obesity.PMID:39011866 | DOI:10.1039/d4fo01489h

J Sci Food Agric. 2024 Jul 16. doi: 10.1002/jsfa.13741. Online ahead of print.ABSTRACTBACKGROUND: Chemical fortification and dose supplementation of vitamin B12 are widely implemented to combat deficiency symptoms. However, in situ, fortification of vitamin B12 in food matrixes can be a promising alternative to chemical fortification. The present study aimed to produce vitamin B12-rich, probiotic guava juice fermented with Levilactobacillus brevis strain KU15152. Pasteurized fresh guava juice was inoculated with 7.2 log CFU mL-1 L. brevis strain KU15152 and incubated for 72 h at 37 °C anaerobically. The antioxidants, total phenolic compounds, vitamin B12 production, sugars, organic acids, pH and viable count were analyzed at 24, 48 and 72 h of incubation. The fermented juice was stored at 4 °C, and the changes in its functional properties were analyzed at 7-day intervals up to 28 days of storage.RESULTS: During fermentation, the bacteria cell count was increased from 7.01 ± 0.06 to 9.76 ± 0.42 log CFU mL-1 after 72 h of fermentation and was decreased to 6.94 ± 0.34 CFU mL-1 during storage at 4 °C after 28 days. The pH, total soluble solids, crude fiber, citric acid and total sugars decreased, while titratable acidity, total protein, antioxidants, phenolic compounds and lactic acid contents increased during fermentation. The fermented guava juice exhibited higher 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS)) radical scavenging activities (85.97% and 75.97%, respectively) at 48 h of fermentation. The concentration of active vitamin B12 in the sample reached 109.5 μg L-1 at 72 h of fermentation. However, this concentration gradually decreased to 70.2 μg L-1 during the storage period. During storage for 28 days at 4 °C, both the fermented and control guava juices exhibited a decline in antioxidant and phenolic compound concentrations. Furthermore, the addition of 20% honey and guava flavor enhanced the organoleptic properties and acceptability of fermented guava juice.CONCLUSION: The value-added fermented guava juice could be a novel functional food product to combat vitamin B12 deficiency. © 2024 The Author(s). Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.PMID:39011860 | DOI:10.1002/jsfa.13741

FEBS J. 2024 Jul 16. doi: 10.1111/febs.17227. Online ahead of print.ABSTRACTUpregulation of nuclear factor κB (NFκB) signaling is a hallmark of aging and a major cause of age-related chronic inflammation. However, its effect on cellular senescence remains unclear. Here, we show that alteration of NFκB nuclear dynamics from oscillatory to sustained by depleting a negative feedback regulator of NFκB pathway, NFκB inhibitor alpha (IκBα), in the presence of tumor necrosis factor α (TNFα) promotes cellular senescence. Sustained NFκB activity enhanced inflammatory gene expression through increased NFκB-DNA binding and slowed the cell cycle. IκBα protein was decreased under replicative or oxidative stress in vitro. Furthermore, a decrease in IκBα protein and an increase in DNA-NFκB binding at the transcription start sites of age-associated genes in aged mouse hearts suggested that nuclear NFκB dynamics may play a critical role in the progression of aging. Our study suggests that nuclear NFκB dynamics-dependent epigenetic changes regulated over time in a living system, possibly through a decrease in IκBα, enhance the expression of inflammatory genes to advance the cells to a senescent state.PMID:39011799 | DOI:10.1111/febs.17227

Hum Mol Genet. 2024 Jul 16:ddae110. doi: 10.1093/hmg/ddae110. Online ahead of print.ABSTRACTUnlike other cancers with widespread screening (breast, colorectal, cervical, prostate, and skin), lung nodule biopsies for positive screenings have higher morbidity with clinical complications. Development of non-invasive diagnostic biomarkers could thereby significantly enhance lung cancer management for at-risk patients. Here, we leverage Mendelian Randomization (MR) to investigate the plasma proteome and metabolome for potential biomarkers relevant to lung cancer. Utilizing bidirectional MR and co-localization analyses, we identify novel associations, highlighting inverse relationships between plasma proteins SFTPB and KDELC2 in lung adenocarcinoma (LUAD) and positive associations of TCL1A with lung squamous cell carcinoma (LUSC) and CNTN1 with small cell lung cancer (SCLC). Additionally, our work reveals significant negative correlations between metabolites such as theobromine and paraxanthine, along with paraxanthine-related ratios, in both LUAD and LUSC. Conversely, positive correlations are found in caffeine/paraxanthine and arachidonate (20:4n6)/paraxanthine ratios with these cancer types. Through single-cell sequencing data of normal lung tissue, we further explore the role of lung tissue-specific protein SFTPB in carcinogenesis. These findings offer new insights into lung cancer etiology, potentially guiding the development of diagnostic biomarkers and therapeutic approaches.PMID:39011643 | DOI:10.1093/hmg/ddae110

J Inflamm Res. 2024 Jul 11;17:4587-4610. doi: 10.2147/JIR.S463067. eCollection 2024.ABSTRACTPURPOSE: Zhixiao Tang (ZXT), a traditional Chinese compound prescription, has been used clinically to treat pneumonia in China. However, the underlying mechanism of ZXT treatment in pneumonia is still unclear. The present study aimed to reveal the potential mechanism of ZXT in pneumonia using a strategy combining metabolomics and network pharmacology.METHODS: Initially, the chemical compositions were identified by UPLC-QE-Orbitrap-MS, while the prediction of potential signal pathways was performed through network pharmacology. To assess the anti-inflammatory properties of ZXT in the context of pneumonia, models of 16HBE cells induced by LPS and zebrafish induced by CuSO4 were established to measure levels of inflammatory markers and apoptosis. Subsequently, the differential changes of endogenous metabolites in cells caused by ZXT were examined using metabolomics technology, and the molecular docking analysis of key targets was carried out using Autodock Vina software. Ultimately, the validation of the primary pathways and targets was conducted through quantitative RT-PCR and Western blot techniques.RESULTS: A total of 75 compounds were identified through UPLC-QE-Orbitrap-MS analyses. Network pharmacological analysis shows that it plays an anti-inflammatory role in C-type lectin receptor signaling pathway. After ZXT intervention, the inflammatory factors and apoptosis in cells were significantly reduced. Metabonomics analysis showed that 18 metabolites changed significantly. Four key genes were identified, which exhibited partial compatibility with the findings of network pharmacology. Molecular docking analysis confirmed the substantial affinity of the primary targets for ZXT. Furthermore, ZXT exerted a suppressive effect on neutrophil migration, down-regulated the expression of pro-inflammatory cytokine genes, and inhibited the up-regulation of the Dectin-1/SYK/NF-κB signaling pathway. In vivo cell experiments also yielded consistent experimental outcomes.CONCLUSION: This study enhances comprehension of the pharmacological mechanism underlying ZXT's efficacy in pneumonia treatment, thereby establishing a scholarly basis for future research and clinical utilization of ZXT in pneumonia management.PMID:39011417 | PMC:PMC11249118 | DOI:10.2147/JIR.S463067

Front Genet. 2024 Jun 19;15:1405468. doi: 10.3389/fgene.2024.1405468. eCollection 2024.ABSTRACTGenomic sequencing offers an untargeted, data-driven approach to genetic diagnosis; however, variants of uncertain significance often hinder the diagnostic process. The discovery of rare genomic variants without previously known functional evidence of pathogenicity often results in variants being overlooked as potentially causative, particularly in individuals with undifferentiated phenotypes. Consequently, many neurometabolic conditions, including those in the GABA (gamma-aminobutyric acid) catabolism pathway, are underdiagnosed. Succinic semialdehyde dehydrogenase deficiency (SSADHD, OMIM #271980) is a neurometabolic disorder in the GABA catabolism pathway. The disorder is due to bi-allelic pathogenic variants in ALDH5A1 and is usually characterized by moderate-to-severe developmental delays, hypotonia, intellectual disability, ataxia, seizures, hyperkinetic behavior, aggression, psychiatric disorders, and sleep disturbances. In this study, we utilized an integrated approach to diagnosis of SSADHD by examining molecular, clinical, and metabolomic data from a single large commercial laboratory. Our analysis led to the identification of 16 patients with likely SSADHD along with three novel variants. We also showed that patients with this disorder have a clear metabolomic signature that, along with molecular and clinical findings, may allow for more rapid and efficient diagnosis. We further surveyed all available pathogenic/likely pathogenic variants and used this information to estimate the global prevalence of this disease. Taken together, our comprehensive analysis allows for a global approach to the diagnosis of SSADHD and provides a pathway to improved diagnosis and potential incorporation into newborn screening programs. Furthermore, early diagnosis facilitates referral to genetic counseling, family support, and access to targeted treatments-taken together, these provide the best outcomes for individuals living with either GABA-TD or SSADHD, as well as other rare conditions.PMID:39011401 | PMC:PMC11247174 | DOI:10.3389/fgene.2024.1405468

Front Genet. 2024 Jul 1;15:1398165. doi: 10.3389/fgene.2024.1398165. eCollection 2024.ABSTRACTBACKGROUND: Prevalent urological cancers, including kidney, prostate, bladder, and testicular cancers, contribute significantly to global cancer incidence and mortality. Metabolomics, focusing on small-molecule intermediates, has emerged as a tool to understand cancer etiology. Given the knowledge gap in this field, we employ a two-sample Mendelian randomization (MR) analysis to investigate the causal relationships between genetically determined metabolites (GDMs) and the susceptibility to four common urological cancers.METHODS: The study employs genome-wide association studies (GWAS) data from European populations, featuring the most extensive case count available for both blood metabolites and four prevalent urological cancers. Preliminary and secondary MR analyses were separately conducted, employing inverse variance weighted (IVW) as the primary method. Multiple statistical analyses, including the MR-Steiger test, Cochran's Q test, leave-one-out analysis, MR-Egger intercept analysis, and MR-PRESSO analysis, were executed to ensure robustness. Additionally, a meta-analysis was carried out to consolidate findings. The weighted median (WM) method was utilized for a relatively lenient correction (PWM < 0.05).RESULTS: After rigorous genetic variation filtering, 645 out of 1,400 metabolites were included in both preliminary and secondary MR analyses. Preliminary MR analysis identified 96 potential causal associations between 94 distinct metabolites and four urological cancers. Secondary analysis based on Finnish outcome data revealed 93 potential causal associations. Cross-database meta-analysis identified 68 blood metabolites associated with four urological cancers. Notably, 31 metabolites remained significant after using WM for correction, with additional 37 suggestive causal relationships. Reverse MR analysis revealed a significant causal association between genetically predicted prostate cancer and elevated 4-hydroxychlorothalonil levels (IVW, combined OR: 1.039, 95% CI 1.014-1.064, p = 0.002; WM, combined OR: 1.052, 95% CI 1.010-1.095, p = 0.014).CONCLUSION: This comprehensive MR study provides insights into the causal relationships between blood metabolites and urological cancers, revealing potential biomarkers and therapeutic targets, thereby addressing gaps in understanding and laying the foundation for targeted interventions in urological cancer research and treatment.PMID:39011400 | PMC:PMC11246892 | DOI:10.3389/fgene.2024.1398165

Biol Methods Protoc. 2024 Jul 2;9(1):bpae048. doi: 10.1093/biomethods/bpae048. eCollection 2024.ABSTRACTMetabolic rewiring allows cells to adapt their metabolism in response to evolving environmental conditions. Traditional metabolomics techniques, whether targeted or untargeted, often struggle to interpret these adaptive shifts. Here, we introduce MetaboLiteLearner, a lightweight machine learning framework that harnesses the detailed fragmentation patterns from electron ionization (EI) collected in scan mode during gas chromatography/mass spectrometry to predict changes in the metabolite composition of metabolically adapted cells. When tested on breast cancer cells with different preferences to metastasize to specific organs, MetaboLiteLearner predicted the impact of metabolic rewiring on metabolites withheld from the training dataset using only the EI spectra, without metabolite identification or pre-existing knowledge of metabolic networks. Despite its simplicity, the model learned captured shared and unique metabolomic shifts between brain- and lung-homing metastatic lineages, suggesting cellular adaptations associated with metastasis to specific organs. Integrating machine learning and metabolomics paves the way for new insights into complex cellular adaptations.PMID:39011352 | PMC:PMC11249387 | DOI:10.1093/biomethods/bpae048

Metabol Open. 2024 May 31;22:100290. doi: 10.1016/j.metop.2024.100290. eCollection 2024 Jun.ABSTRACTMetabolomics, a cutting-edge omics technique, is a rapidly advancing field in biomedical research, concentrating on the elucidation of pathogenetic mechanisms and the discovery of novel metabolite signatures predictive of disease risk, aiding in earlier disease detection, prognosis and prediction of treatment response. The capacity of this omics approach to simultaneously quantify thousands of metabolites, i.e. small molecules less than 1500 Da in samples, positions it as a promising tool for research and clinical applications in personalized medicine. Clinical metabolomics studies have proven valuable in understanding cardiometabolic disorders, potentially uncovering diagnostic biomarkers predictive of disease risk. Liquid chromatography-mass spectrometry is the predominant analytical method used in metabolomics, particularly untargeted. Metabolomics combined with extensive genomic data, proteomics, clinical chemistry data, imaging, health records, and other pertinent health-related data may yield significant advances beneficial for both public health initiatives, clinical applications and precision medicine, particularly in rare disorders and multimorbidity. This special issue has gathered original research articles in topics related to clinical metabolomics as well as research articles, reviews, perspectives and highlights in the broader field of translational and clinical metabolic research. Additional research is necessary to identify which metabolites consistently enhance clinical risk prediction across various populations and are causally linked to disease progression.PMID:39011161 | PMC:PMC11247213 | DOI:10.1016/j.metop.2024.100290