PubMed

Environ Microbiome. 2024 Oct 22;19(1):78. doi: 10.1186/s40793-024-00624-y.ABSTRACTBACKGROUND: The symbiosis between arbuscular mycorrhizal fungi (AMF) and plants often stimulates plant growth, increases agricultural yield, reduces costs, thereby providing significant economic benefits. AMF can also benefit plants through affecting the rhizosphere microbial community, but the underlying mechanisms remain unclear. Using Rhizophagus intraradices as a model AMF species, we assessed how AMF influences the bacterial composition and functional diversity through 16 S rRNA gene sequencing and non-targeted metabolomics analysis in the rhizosphere of aluminum-sensitive soybean that were inoculated with pathogenic fungus Nigrospora oryzae and phosphorus-solubilizing fungus Talaromyces verruculosus in an acidic soil.RESULTS: The inoculation of R. intraradices, N. oryzae and T. verruculosus didn't have a significant influence on the levels of soil C, N, and P, or various plant characteristics such as seed weight, crude fat and protein content. However, their inoculation affected the structure, function and nutrient dynamics of the resident bacterial community. The co-inoculation of T. verruculosus and R. intraradices increased the relative abundance of Pseudomonas psychrotolerans, which was capable of N-fixing and was related to cry-for-help theory (plants signal for beneficial microbes when under stress), within the rhizosphere. R. intraradices increased the expression of metabolic pathways associated with the synthesis of unsaturated fatty acids, which was known to enhance plant resistance under adverse environmental conditions. The inoculation of N. oryzae stimulated the stress response inside the soil environment by enriching the polyene macrolide antifungal antibiotic-producing bacterial genus Streptomyces in the root endosphere and upregulating two antibacterial activity metabolic pathways associated with steroid biosynthesis pathways in the rhizosphere. Although inoculation of pathogenic fungus N. oryzae enriched Bradyrhizobium and increased soil urease activity, it had no significant effects on biomass and N content of soybean. Lastly, the host niches exhibited differences in the composition of the bacterial community, with most N-fixing bacteria accumulating in the endosphere and Rhizobium vallis only detected in the endosphere.CONCLUSIONS: Our findings demonstrate that intricate interactions between AMF, associated core fungi, and the soybean root-associated ecological niches co-mediate the regulation of soybean growth, the dynamics of rhizosphere soil nutrients, and the composition, function, and metabolisms of the root-associated microbiome in an acidic soil.PMID:39439005 | DOI:10.1186/s40793-024-00624-y

Arthritis Res Ther. 2024 Oct 22;26(1):181. doi: 10.1186/s13075-024-03414-6.ABSTRACTBACKGROUND: Abnormal oxysterol metabolism has been observed in the peripheral blood of SLE patients, but its role in systemic lupus erythematosus (SLE) skin lesions remains unclear.METHODS: Targeted oxidized lipid metabolomics analysis using liquid chromatography-mass spectrometry (LC-MS) was performed to quantify oxysterols in SLE skin lesions. Immunohistochemical staining and single-cell sequencing data analysis confirmed the upregulation of oxysterol-encoding enzymes CH25H and CYP7B1. The impact on fibroblast-mediated PBMCs chemotaxis was assessed using a transwell chamber.RESULTS: We identified aberrant oxidized cholesterol metabolism in SLE skin lesions, characterized by elevated levels of 7-ketocholesterol, 5α-6α-cholestane-3β,5α,6β-triol, and so on. Fibroblasts were the primary cells expressing oxysterol-encoding genes, with CH25H and CYP7B1 expression upregulated via the IL-1β-mediated p38 MAPK and NFκB pathways. Notably, IL-1β-stimulated fibroblasts demonstrated enhanced PBMCs recruitment, which was attenuated by a GPR183 inhibitor.CONCLUSION: Our findings reveal a potential mechanism by which fibroblasts contribute to immune cell recruitment in SLE skin lesions by expression of CH25H and CYP7B1. This study underscores the significance of oxysterol metabolism in SLE skin lesion pathogenesis and highlights potential therapeutic targets for SLE skin lesion treatment.PMID:39438997 | DOI:10.1186/s13075-024-03414-6

BMC Genomics. 2024 Oct 22;25(1):989. doi: 10.1186/s12864-024-10877-z.ABSTRACTBACKGROUND: The tea plant Camellia sinensis (L.) O. Kuntze is a perennial crop, invaded by diversity of insect pest species, and pink tea mite is one of the most devastating pests for sustainable tea production. However, molecular mechanism of defense responses against pink tea mites in tea is still unknown. In this study, metabolomics and transcriptome profiles of susceptible and resistant tea varieties were compared before and after pink tea mite infestation.RESULTS: Metabolomics analysis revealed that abundance levels of polyphenol-related compounds changed significantly before and after infestation. At the transcript level, nearly 8 GB of clean reads were obtained from each sequenced library, and a comparison of infested plants of resistant and susceptible tea varieties revealed 9402 genes with significant differential expression. An array of genes enriched in plant pathogen interaction and biosynthetic pathways of phenylpropanoids showed significant differential regulation in response to pink tea mite invasion. In particular, the functional network linkage of disease resistant proteins, phenylalanine ammonia lyase, flavanone -3-hydroxylase, hydroxycinnamoyl-CoA shikimate transferase, brassinosteroid-6-oxidase 1, and gibberellin 2 beta-dioxygenase induced dynamic defense signals to suppress prolonged pink tea mite attacks. Further integrated analyses identified a complex network of transcripts and metabolites interlinked with precursors of various flavonoids that are likely modulate resistance against to pink tea mite.CONCLUSIONS: Our results characterized the profiles of insect induced metabolic and transcript reprogramming and identified a defense regulatory network that can potentially be used to fend off pink tea mites damage.PMID:39438821 | DOI:10.1186/s12864-024-10877-z

BMC Microbiol. 2024 Oct 22;24(1):421. doi: 10.1186/s12866-024-03583-z.ABSTRACTBACKGROUND: The addition of wine lees to diets can make up for the deficiencies caused by traditional forages in beef cattle farming. However, the effects of different wine lees ratios on average daily weight, gastrointestinal microbial community structure and metabolites in Guanling crossbred cattle have been rarely studied. This study assessed the effects of feeds containing wine lees on weight gain, gastrointestinal microbial community structure, and metabolites in Guanling crossbred cattle and elucidated the metabolic responses induced by wine lees. Eighteen cows were randomly assigned to receive fed concentrate (C group), feed containing 15% wine lees (group A), or feed containing 30% wine lees (group B) for 60 days.RESULTS: The average daily weight gain of group A and group B increased by 76.75% and 57.65%, respectively, compared with group C. Microbial community analysis showed that wine lees increased the abundance of Prevotella_1 in the rumen, decreased the abundance of Ruminococcaceae UCG 011 and Lachnospiraceae_FCS020_group in the rumen, and increased the abundance of Tyzzerella_4, Family_Xlll_AD3011_group, Granulicella, and Eisenbergiella in the cecum. Metabolomics analyses showed that wine lees decreased the concentrations of indole-3-ethanol in the rumen, and complexity cecal metabolism. Notably, linoleic acid metabolism was significantly enriched in both the rumen and cecum. Mantel test analyses indicated that the adverse effects of WL were reduced by stimulating the metabolism of linoleic acid, α-linolenic acid, and tryptophan, and these changes were mediated by intestinal microorganisms. The Guanling cattle cecum was enriched for several unfavorable metabolic pathways when wine lees concentrations reached 30%, which increased the likelihood of intestinal lesions.CONCLUSION: This study shows that WL supplementation alters gut microbiota and metabolic pathways, improving cattle growth and health. Moderate WL levels (15%) enhance gut health and beneficial pathways (e.g., linoleic and alpha-linolenic acid metabolism). However, higher WL inclusion (30%) may activate adverse pathways, raising the risk of intestinal damage. To maximize benefits and minimize risks, WL levels should be carefully managed.PMID:39438796 | DOI:10.1186/s12866-024-03583-z

Pediatr Res. 2024 Oct 22. doi: 10.1038/s41390-024-03669-4. Online ahead of print.ABSTRACTBACKGROUND: Anemia in preterm infants is associated with gut dysbiosis and necrotizing enterocolitis. Our study aimed to identify the bacterial functions and metabolites that can explain the underlying mechanisms of anemia associated disease conditions.METHODS: We conducted a case control study in preterm infants with cases having a hematocrit ≤ 25%. The control infants were matched by birth gestational age and weight. Fecal samples were collected before, at the onset, and after the onset of anemia in cases and with matched postnatal age in controls for metagenomics and metabolomics analyzes.RESULTS: 18 anemic and 20 control infants with fecal samples collected at 17 days, 5 weeks, and 7 weeks postnatal age were included. Virulence factor potential, decrease in beta diversity evolution, and larger changes in metabolome were associated with severe anemia. Metabolite abundances of N-acetylneuraminate and butyrobetaine were associated with virulence factor potential. Anemic group had decreased prostaglandin and lactic acid levels.CONCLUSION: Fecal omics data showed that severe anemia is associated with a pro-inflammatory gut microbiota with more virulent and less commensal anaerobic bacterial activities. Future studies can examine the link between anemia-associated dysbiosis and clinical outcomes and predict an infant-specific hematocrit threshold that negatively affects clinical outcomes.IMPACT: Severe anemia in preterm infants contributes to a pro-inflammatory gut with greater bacterial virulence and less commensal bacterial activities. The multiomics approach using non-invasive fecal biospecimens identified functional and metabolic changes in the gut microbiota and these mechanistic changes are plausible explanations for anemia-associated disease conditions in preterm infants. Our findings identified biological changes of the gut environment in severely anemic preterm infants that can offer guidance for clinical management.PMID:39438713 | DOI:10.1038/s41390-024-03669-4

Sci Rep. 2024 Oct 22;14(1):24810. doi: 10.1038/s41598-024-75556-1.ABSTRACTThe co-occurrence of multiple chronic conditions, termed multimorbidity, presents an expanding global health challenge, demanding effective diagnostics and treatment strategies. Chronic ailments such as obesity, diabetes, and cardiovascular diseases have been linked to metabolites interacting between the host and microbiota. In this study, we investigated the impact of co-existing conditions on risk estimations for 1375 plasma metabolites in 919 individuals from population-based Estonian Biobank cohort using liquid chromatography mass spectrometry (LC-MS) method. We leveraged annually linked national electronic health records (EHRs) data to delineate comorbidities in incident cases and controls for the 14 common chronic conditions. Among the 254 associations observed across 13 chronic conditions, we primarily identified disease-specific risk factors (92%, 217/235), with most predictors (93%, 219/235) found to be related to the gut microbiome upon cross-referencing recent literature data. Accounting for comorbidities led to a reduction of common metabolite predictors across various conditions. In conclusion, our study underscores the potential of utilizing biobank-linked retrospective and prospective EHRs for the disease-specific profiling of diverse multifactorial chronic conditions.PMID:39438584 | DOI:10.1038/s41598-024-75556-1

NPJ Biofilms Microbiomes. 2024 Oct 23;10(1):112. doi: 10.1038/s41522-024-00566-w.ABSTRACTBile acids (BAs) exert a profound influence on the body's pathophysiology by intricately shaping the composition of gut bacteria. However, the complex interplay between BAs and gut microbiota has impeded a systematic exploration of their impact on intestinal bacteria. Initially, we investigated the effects of 21 BAs on the growth of 65 gut bacterial strains in vitro. Subsequently, we examined the impact of BAs on the overall composition of intestinal bacteria, both in vivo and in vitro. The results unveiled distinct effects of various BAs on different intestinal strains and their diverse impacts on the composition of gut bacteria. Mechanistically, the inhibition of intestinal strains by BAs occurs through the accumulation of these acids within the strains. The intracellular accumulation of deoxycholic acid (DCA) significantly influenced the growth of intestinal bacteria by impacting ribosome transcription and amino-acid metabolism. The metabolomic analysis underscores the pronounced impact of DCA on amino-acid profiles in both in vivo and in vitro settings. This study not only elucidates the effects of BAs on a diverse range of bacterial strains and their role in shaping the gut microbiota but also reveals underlying mechanisms essential for understanding and maintaining a healthy gut microbiota.PMID:39438471 | DOI:10.1038/s41522-024-00566-w

Nat Commun. 2024 Oct 22;15(1):9110. doi: 10.1038/s41467-024-52213-9.ABSTRACTImaging mass spectrometry is a powerful technology enabling spatial metabolomics, yet metabolites can be assigned only to a fraction of the data generated. METASPACE-ML is a machine learning-based approach addressing this challenge which incorporates new scores and computationally-efficient False Discovery Rate estimation. For training and evaluation, we use a comprehensive set of 1710 datasets from 159 researchers from 47 labs encompassing both animal and plant-based datasets representing multiple spatial metabolomics contexts derived from the METASPACE knowledge base. Here we show that, METASPACE-ML outperforms its rule-based predecessor, exhibiting higher precision, increased throughput, and enhanced capability in identifying low-intensity and biologically-relevant metabolites.PMID:39438443 | DOI:10.1038/s41467-024-52213-9

Metabolomics. 2024 Oct 22;20(6):119. doi: 10.1007/s11306-024-02174-3.ABSTRACTINTRODUCTION: Plant hormonal mutants, which do not produce or are insensitive to hormones, are often affected in their growth and development, but other metabolic rearrangements might be involved. A trade-off between growth and stress response is necessary for the plant survival.OBJECTIVES: Here, we explore the metabolic profile and the pathogen resistance of a brassinosteroid-insensitive Hordeum vulgare L. semi-dwarf mutant, BW312.METHODS: We investigate BW312 metabolism through a chemical enrichment analysis, confirming a shifted metabolic profile towards pathogen resistance. The effective pathogen resistance of the mutant was tested in presence of Pyrenophora teres and Fusarium graminearum.RESULTS: Four compound families were increased in the mutant (pyrrolidines, basic amino acids, alkaloids, monounsaturated fatty acids), while two compound families were decreased (pyrrolidinones, anthocyanins). Dipeptides were also altered (increased and decreased). BW312 displayed a better resistance to Pyrenophora teres in the earliest stage of infection with a 21.5% decrease of the lesion length 10 days after infection. BW312 also exhibited a reduced lesion length (43.3%) and a reduced browning of the lesions (55.5%) when exposed to Fusarium graminearum at the seedling stage.CONCLUSION: The observed metabolomic shift strongly suggests that the BW312 semi-dwarf mutant is in a primed state, resulting in a standby state of alertness to pathogens.PMID:39438353 | DOI:10.1007/s11306-024-02174-3

Ann Rheum Dis. 2024 Oct 22:ard-2024-225925. doi: 10.1136/ard-2024-225925. Online ahead of print.ABSTRACTOBJECTIVES: Systemic sclerosis (SSc) is a heterogeneous disease, complicating its management. Its complexity and the insufficiency of clinical manifestations alone to delineate homogeneous patient groups further challenge this task. However, autoantibodies could serve as relevant markers for the pathophysiological mechanisms driving the disease. Identifying specific immunological mechanisms based on patients' serological statuses might facilitate a deeper understanding of the diversity of the disease.METHODS: A cohort of 206 patients with SSc enrolled in the PRECISESADS cross-sectional study was examined. Patients were stratified based on their anti-centromere (ACA) and anti-SCL70 (SCL70) antibody statuses. Comprehensive omics analyses including transcriptomic, flow cytometric, cytokine and metabolomic data were analysed to characterise the differences between these patient groups.RESULTS: Patients with SCL70 antibodies showed severe clinical features such as diffuse cutaneous sclerosis and pulmonary fibrosis and were biologically distinguished by unique transcriptomic profiles. They exhibit a pro-inflammatory and fibrotic signature associated with impaired tissue remodelling and increased carnitine metabolism. Conversely, ACA-positive patients exhibited an immunomodulation and tissue homeostasis signature and increased phospholipid metabolism.CONCLUSIONS: Patients with SSc display varying biological profiles based on their serological status. The findings highlight the potential utility of serological status as a discriminating factor in disease severity and suggest its relevance in tailoring treatment strategies and future research directions.PMID:39438128 | DOI:10.1136/ard-2024-225925

Clin Chim Acta. 2024 Oct 20:120012. doi: 10.1016/j.cca.2024.120012. Online ahead of print.NO ABSTRACTPMID:39437984 | DOI:10.1016/j.cca.2024.120012

Sci Total Environ. 2024 Oct 20:177071. doi: 10.1016/j.scitotenv.2024.177071. Online ahead of print.ABSTRACTThe tire antioxidant 6PPD has garnered extensive attention due to its widespread presence in the environment and the harmful effects of its transformation products on aquatic organisms. 6PPD has been detected in airborne dust, and it can enter mammals through inhalation exposure. While the toxic effects of 6PPD exposure have been reported in mammals, its effects on hepatic metabolism still remain poorly understood. Here, we collected the serum and liver samples at 1, 6, and 72 h following a single oral exposure of 100 mg/kg body weight (bw) 6PPD, respectively. We also investigated changes in serum and hepatic physiological indicators and metabolites, correspondingly. Results indicated that single time oral exposure a high dose of 6PPD did not significantly affect the physiological indexes of rats within a short time frame. However, untargeted metabolomics analysis of the metabolites in the liver at 1, 6, and 72 h revealed that the number of differential expression metabolites gradually increased over time and the most affected substances were lipids and lipid-like molecules. Interestingly, the KEGG pathway enrichment analysis indicated that 6PPD disrupted the riboflavin metabolism, leading to a significant decrease in FMN levels at all time points. In addition, the hepatic glucose metabolism was significantly affected at 6 and 72 h after oral administration. Taken together, short-term exposure to 6PPD disturbed lipid and riboflavin metabolism and gradually affected glucose metabolism in the liver of rats. These findings revealed the impacts of 6PPD on the hepatic metabolism in animals, and also offered some important insights into its toxicology and health risk.PMID:39437917 | DOI:10.1016/j.scitotenv.2024.177071

Sci Total Environ. 2024 Oct 20:177064. doi: 10.1016/j.scitotenv.2024.177064. Online ahead of print.ABSTRACTThe restoration of mangroves in urban environments can increase the risk of contaminant exposure and subsequent health effects to resident biota, yet this risk is rarely considered in mangrove restoration programs. Here we assessed the influence of sediment chemistry on contaminant bioaccumulation in shore crabs from restored and natural mangroves in urban environments compared to a reference site. The concentrations of some trace elements were several-fold higher in the sediment and crab tissues of the urban restored site compared to the natural reference site (Cd = 6×, Co = 7×, Cr = 4×, Mn = 30×, and Ni = 18× greater in sediments, while Cd = 4×, Co = 2×, Cr = 2×, Mn = 6×, and Ni = 3× greater in crab tissues). NMR-based metabolomics on crabs revealed higher abundances of proline and glutamate at urban sites, which may be indicative of physiological stress from trace element contamination. Choice experiments were used to test habitat selectivity by crabs from each population, and showed that crabs avoided sediments from the contaminated urban sites. Our results suggest that restoring mangroves in contaminated environments could create ecological sinks, where animals take residence in the new habitat but are exposed to sediment-based contaminants, with potential implications for organism and population health.PMID:39437910 | DOI:10.1016/j.scitotenv.2024.177064

Neurochem Int. 2024 Oct 20:105886. doi: 10.1016/j.neuint.2024.105886. Online ahead of print.ABSTRACTOxygen support plays a critical role in the management of preterm infants in neonatal intensive care units. On the other hand, the possible effects of oxygen supplementation on cellular functions, specifically glucose metabolism, have been less understood. PURPOSE: of the study is to investigate whether supplemental oxygen alters glucose metabolism and pentose phosphate pathway (PPP) activity in the brain tissue and its relevance with silent information regulator proteins (SIRT) pathway. For this purpose, newborn C57BL/6 pups were exposed to 90% oxygen from birth until postnatal day 7 (PN7) and metabolites of glysolysis and PPP were investigated through metabolomics analysis. SIRT1, glucose-6-phosphate dehydrogenase (G6PD) and transaldolase (TALDO) proteins were examined immunohistochemically and molecularly in the prefrontal and hippocampus regions of the brain. Later on, SIRT1 inhibition was carried out. Our results indicate that supplemental oxygen causes an increase in PPP metabolites as well as activation of G6PD enzyme in the brain tissue, which is reversed by SIRT1 inhibition. Our study underlines a connection between supplemental oxygen, glucose metabolism, PPP pathway and the SIRT signaling. Understanding these intricate relationships not only deepens our knowledge of cellular physiology but also holds promise for therapeutic interventions for creating neuroprotective strategies in preterm brain.PMID:39437895 | DOI:10.1016/j.neuint.2024.105886

J Proteome Res. 2024 Oct 22. doi: 10.1021/acs.jproteome.3c00634. Online ahead of print.ABSTRACTOrthogonal separations of data from high-resolution mass spectrometry can provide insight into sample composition and address challenges of complete annotation of molecules in untargeted metabolomics. "Molecular networks" (MNs), as used in the Global Natural Products Social Molecular Networking platform, are a prominent strategy for exploring and visualizing molecular relationships and improving annotation. MNs are mathematical graphs showing the relationships between measured multidimensional data features. MNs also show promise for using network science algorithms to automatically identify targets for annotation candidates and to dereplicate features associated with a single molecular identity. This paper introduces "molecular hypernetworks" (MHNs) as more complex MN models able to natively represent multiway relationships among observations. Compared to MNs, MHNs can more parsimoniously represent the inherent complexity present among groups of observations, initially supporting improved exploratory data analysis and visualization. MHNs also promise to increase confidence in annotation propagation, for both human and analytical processing. We first illustrate MHNs with simple examples, and build them from liquid chromatography- and ion mobility spectrometry-separated MS data. We then describe a method to construct MHNs directly from existing MNs as their "clique reconstructions", demonstrating their utility by comparing examples of previously published graph-based MNs to their respective MHNs.PMID:39437798 | DOI:10.1021/acs.jproteome.3c00634

Cell Stem Cell. 2024 Oct 14:S1934-5909(24)00328-X. doi: 10.1016/j.stem.2024.09.014. Online ahead of print.ABSTRACTSenescent neural progenitor cells have been identified in brain lesions of people with progressive multiple sclerosis (PMS). However, their role in disease pathobiology and contribution to the lesion environment remains unclear. By establishing directly induced neural stem/progenitor cell (iNSC) lines from PMS patient fibroblasts, we studied their senescent phenotype in vitro. Senescence was strongly associated with inflammatory signaling, hypermetabolism, and the senescence-associated secretory phenotype (SASP). PMS-derived iNSCs displayed increased glucose-dependent fatty acid and cholesterol synthesis, which resulted in the accumulation of lipid droplets. A 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase (HMGCR)-mediated lipogenic state was found to induce a SASP in PMS iNSCs via cholesterol-dependent transcription factors. SASP from PMS iNSC lines induced neurotoxicity in mature neurons, and treatment with the HMGCR inhibitor simvastatin altered the PMS iNSC SASP, promoting cytoprotective qualities and reducing neurotoxicity. Our findings suggest a disease-associated, cholesterol-related, hypermetabolic phenotype of PMS iNSCs that leads to neurotoxic signaling and is rescuable pharmacologically.PMID:39437792 | DOI:10.1016/j.stem.2024.09.014

Plant Physiol Biochem. 2024 Oct 18;217:109209. doi: 10.1016/j.plaphy.2024.109209. Online ahead of print.ABSTRACTBarley (Hordeum vulgare L.) is widely cultivated across diverse soil types, including acidic soils where aluminum (Al) toxicity is the major limiting factor. The relative Al sensitivity of barley highlights the need for a deeper understanding of early molecular responses in root tip (the primary target of Al toxicity) to develop Al-tolerant cultivars. Integrative N6-methyladenosine (m6A) modification, transcriptomic, and metabolomic analyses revealed that elevated auxin and jasmonic acid (JA) levels modulated Al-induced root growth inhibition by repressing genes involved in cell elongation and proliferation. Additionally, these pathways promoted pectin demethylation via up-regulation of genes encoding pectin methylesterases (PMEs). The up-regulation of citrate efflux transporter genes including Al-activated citrate transporter 1 (HvAACT1), and ATP-binding cassette (ABC) transporters like HvABCB25, facilitated Al exclusion and vacuolar sequestration. Enhanced activity within the phenylpropanoid pathway supported antioxidant defenses and internal chelation through the production of specific flavonoids and altered cell wall composition via lignin unit modulation. Notably, several Al-responsive genes, including HvABCB25 and transcription factors (TFs), exhibited m6A modification changes, with two microtubule associated protein 65 (MAP65) members displaying opposing regulatory patterns at both transcriptional and m6A levels, underscoring the crucial role of m6A modification in gene expression regulation. This comprehensive study provides valuable insights into the epitranscriptomic regulation of gene expression and metabolite accumulation in barley root tip under Al stress.PMID:39437666 | DOI:10.1016/j.plaphy.2024.109209

EBioMedicine. 2024 Oct 21;109:105375. doi: 10.1016/j.ebiom.2024.105375. Online ahead of print.ABSTRACTBACKGROUND: SLC7A9 is responsible for the exchange of dibasic amino acids and cystine (influx) for neutral amino acids (efflux). Cystine/cysteine transport is related to ferroptosis.METHODS: Sanger sequencing detected TP53 status of cancer cells. Transcriptomic sequencing and untargeted metabolome profiling were used to identify differentially expressed genes and metabolites, respectively, upon SLC7A9 overexpression. CCK8, cell clonality, and EdU assays were used to observe cell proliferation. Cystine probes, glutathione (GSH) probes, and lipid ROS probes were used to examine cystine, GSH, and lipid ROS levels. 13C metabolic flow assays were used to monitor cellular cystine and GSH metabolism. Patient-derived organoids (PDO), immunocompetent MFC mice allograft models and patient-derived xenograft (PDX) models were used to evaluate SLC7A9 impact on chemotherapeutic response and to observe therapeutic effect of SLC7A9 knockdown.FINDINGS: Elevated SLC7A9 expression levels in gastric cancer cells were attributed to p53 loss. SLC7A9 knockdown suppressed the proliferation and increased the chemotherapy sensitivity of the cells. Chemotherapy was more effective in PDX and immunocompetent mice models upon SLC7A9 knockdown. Differentially expressed genes and metabolites between the SLC7A9 overexpression and control groups were associated with ferroptosis and GSH metabolism. SLC7A9 knockdown reduced cystine transport into cells, hampered intracellular cystine and GSH metabolic flow, decreased GSH synthesis, and increased lipid ROS levels in gastric cancer cells. Erastin was more effective at inducing ferroptosis in PDO and PDX models upon SLC7A9 knockdown.INTERPRETATION: SLC7A9 promotes gastric cancer progression by acting as a suppressor of ferroptosis, independent of SLC7A11, which is negatively regulated by p53.FUNDING: This work was supported by National Natural Science Foundation of China, Innovation Promotion Program of NHC and Shanghai Key Labs SIBPT, and Shanghai Academy of Science & Technology.PMID:39437660 | DOI:10.1016/j.ebiom.2024.105375

Physiol Genomics. 2024 Oct 22. doi: 10.1152/physiolgenomics.00011.2024. Online ahead of print.ABSTRACTThe availability of large scale multi-omics data requires development of computational models to infer valuable biological insights for the implementation of precision medicine. Artificial intelligence (AI) refers to a host of computational algorithms that is becoming a major tool capable of integrating large genomic, transcriptomic, proteomic, and metabolomic data. Machine learning (ML) is the most significant AI algorithm in health sciences have exploded, specifically due to the recent progress made by deep learning. Although the use of AI/ML tools in GBM-omics is still at an early stage, a comprehensive discussion of how AI can be used to unravel various aspects of GBM (intratumor heterogeneity, biomarker discovery, survival prediction, and treatment optimization) would be highly relevant to both researchers and clinicians. Here, we aim to review the different AI-based techniques that have been used to study GBM pathogenesis using multi-omics data over the last decade. We first summarize different types of GBM related omics resources that can be used to develop AI models. We then discuss various AI applications for multi-omics data in order to enhance GBM precision medicine. Finally, we discuss the technical and ethical challenges that limit its application and ways to improve its implementation in clinics.PMID:39437552 | DOI:10.1152/physiolgenomics.00011.2024

J Proteome Res. 2024 Oct 22. doi: 10.1021/acs.jproteome.4c00646. Online ahead of print.ABSTRACTRecent advancements in single-cell (sc) resolution analyses, particularly in sc transcriptomics and sc proteomics, have revolutionized our ability to probe and understand cellular heterogeneity. The study of metabolism through small molecules, metabolomics, provides an additional level of information otherwise unattainable by transcriptomics or proteomics by shedding light on the metabolic pathways that translate gene expression into functional outcomes. Metabolic heterogeneity, critical in health and disease, impacts developmental outcomes, disease progression, and treatment responses. However, dedicated approaches probing the sc metabolome have not reached the maturity of other sc omics technologies. Over the past decade, innovations in sc metabolomics have addressed some of the practical limitations, including cell isolation, signal sensitivity, and throughput. To fully exploit their potential in biological research, however, remaining challenges must be thoroughly addressed. Additionally, integrating sc metabolomics with orthogonal sc techniques will be required to validate relevant results and gain systems-level understanding. This perspective offers a broad-stroke overview of recent mass spectrometry (MS)-based sc metabolomics advancements, focusing on ongoing challenges from a biologist's viewpoint, aimed at addressing pertinent and innovative biological questions. Additionally, we emphasize the use of orthogonal approaches and showcase biological systems that these sophisticated methodologies are apt to explore.PMID:39437423 | DOI:10.1021/acs.jproteome.4c00646