PubMed

PLoS Genet. 2024 Dec 3;20(12):e1011346. doi: 10.1371/journal.pgen.1011346. Online ahead of print.ABSTRACTCirculating metabolite levels have been associated with type 2 diabetes (T2D), but the extent to which T2D affects metabolite levels and their genetic regulation remains to be elucidated. In this study, we investigate the interplay between genetics, metabolomics, and T2D risk in the UK Biobank dataset using the Nightingale panel composed of 249 metabolites, 92% of which correspond to lipids (HDL, IDL, LDL, VLDL) and lipoproteins. By integrating these data with large-scale T2D GWAS from the DIAMANTE meta-analysis through Mendelian randomization analyses, we find 79 metabolites with a causal association to T2D, all spanning lipid-related classes except for Glucose and Tyrosine. Twice as many metabolites are causally affected by T2D liability, spanning almost all tested classes, including branched-chain amino acids. Secondly, using an interaction quantitative trait locus (QTL) analysis, we describe four metabolites consistently replicated in an independent dataset from the Estonian Biobank, for which genetic loci in two different genomic regions show attenuated regulation in T2D cases compared to controls. The significant variants from the interaction QTL analysis are significant QTLs for the corresponding metabolites in the general population but are not associated with T2D risk, pointing towards consequences of T2D on the genetic regulation of metabolite levels. Finally, through differential level analyses, we find 165 metabolites associated with microvascular, macrovascular, or both types of T2D complications, with only a few discriminating between complication classes. Of the 165 metabolites, 40 are not causally linked to T2D in either direction, suggesting biological mechanisms specific to the occurrence of complications. Overall, this work provides a map of the consequences of T2D on Nightingale targeted metabolite levels and on their genetic regulation, enabling a better understanding of the T2D trajectory leading to complications.PMID:39625957 | DOI:10.1371/journal.pgen.1011346

Plant J. 2024 Dec 3. doi: 10.1111/tpj.17181. Online ahead of print.ABSTRACTWHIRLY1 belongs to a family of plant-specific transcription factors capable of binding DNA or RNA in all three plant cell compartments that contain genetic materials. In Arabidopsis thaliana, WHIRLY1 has been studied at the later stages of plant development, including flowering and leaf senescence, as well as in biotic and abiotic stress responses. In this study, WHIRLY1 knockout mutants of A. thaliana were prepared by CRISPR/Cas9-mediated genome editing to investigate the role of WHIRLY1 during early seedling development. The loss-of-function of WHIRLY1 in 5-day-old seedlings did not cause differences in the phenotype and the photosynthetic performance of the emerging cotyledons compared with the wild type. Nevertheless, comparative RNA sequencing analysis revealed that the knockout of WHIRLY1 affected the expression of a small but specific set of genes during this critical phase of development. About 110 genes were found to be significantly deregulated in the knockout mutant, wherein several genes involved in the early steps of aliphatic glucosinolate (GSL) biosynthesis were suppressed compared with wild-type plants. The downregulation of these genes in WHIRLY1 knockout lines led to decreased GSL contents in seedlings and in seeds. Since GSL catabolism mediated by myrosinases was not altered during seed-to-seedling transition, the results suggest that AtWHIRLY1 plays a major role in modulation of aliphatic GSL biosynthesis during early seedling development. In addition, phylogenetic analysis revealed a coincidence between the evolution of methionine-derived aliphatic GSLs and the addition of a new WHIRLY in core families of the plant order Brassicales.PMID:39625871 | DOI:10.1111/tpj.17181

Int J Syst Evol Microbiol. 2024 Dec;74(12). doi: 10.1099/ijsem.0.006560.ABSTRACTA bacterial strain was isolated from pathogenic lesions of Acer campestre tree leaves from the Teutoburg Forest in North Rhine-Westphalia, Germany, by culture on non-selective agar plates. 16S rRNA sequencing revealed 100% similarity to Sanguibacter keddieii and Sanguibacter inulinus, as well as 99% similarity to Sanguibacter gelidistatuariae and Sanguibacter antarcticus. Here, we used genome-based taxonomy with the Type (Strain) Genome Server (TYGS), which suggests the isolation of a novel prokaryotic strain. According to TYGS-analysis, using whole genome digital DNA-DNA hybridization, only 65.5% similarity to the closest relative S. inulinus was revealed, suggesting a novel species. Growth was observed at both aerobic and anaerobic conditions. Bacterial cells depicted coryneform motile rods, with a length of 1.1-3.3 µm and a constant diameter of 0.5 µm. Cells did not form spores under the tested conditions and stain Gram-positive. Growth occurred between 0.5 and 4% NaCl (optimal: 1%), at pH 5.5-9.5 (optimal: 8.0-9.0). The strain was mesophilic with an optimal growth at 25 °C. Major cellular fatty acids of the novel strain were anteiso-C15 : 0 and C16 : 0.PMID:39625746 | DOI:10.1099/ijsem.0.006560

Chem Biodivers. 2024 Dec 3:e202402334. doi: 10.1002/cbdv.202402334. Online ahead of print.ABSTRACTEstablishing a microorganism as an endophyte involves complex molecular interactions with its host plant and a broader microbial community. Precise detection methods and comprehensive metabolite annotation are essential to study these interactions. This study focused on characterizing the chemical composition of metabolites produced by two endophytic fungi, Colletotrichum siamense and Xylaria berteroi, isolated from Tibouchina granulosa leaves in axenic conditions and co-culture. We examined the fungal metabolites using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS/ MS) and analysis tools like Cytoscape and GNPS. Co-cultivation revealed unique compounds not produced in isolation, including N-acetyltriptamide. 31 compounds were identified, many with biotechnological potential due to their bioactivities. The untargeted metabolomics approach demonstrated that interactions among these T. granulosa endophytes can activate inactive metabolic pathways under axenic conditions, potentially producing novel bioactive molecules. This is the first study of the chemical profile and interaction between endophytes isolated from T. granulosa.PMID:39625367 | DOI:10.1002/cbdv.202402334

Elife. 2024 Dec 3;12:RP87120. doi: 10.7554/eLife.87120.ABSTRACTChronic high-fat feeding triggers metabolic dysfunction including obesity, insulin resistance, and diabetes. How high-fat intake first triggers these pathophysiological states remains unknown. Here, we identify an acute microglial metabolic response that rapidly translates intake of high-fat diet (HFD) to a surprisingly beneficial effect on metabolism and spatial/learning memory. High-fat intake rapidly increases palmitate levels in cerebrospinal fluid and triggers a wave of microglial metabolic activation characterized by mitochondrial membrane activation and fission as well as metabolic skewing toward aerobic glycolysis. These effects are detectable throughout the brain and can be detected within as little as 12 hr of HFD exposure. In vivo, microglial ablation and conditional DRP1 deletion show that the microglial metabolic response is necessary for the acute effects of HFD. 13C-tracing experiments reveal that in addition to processing via β-oxidation, microglia shunt a substantial fraction of palmitate toward anaplerosis and re-release of bioenergetic carbons into the extracellular milieu in the form of lactate, glutamate, succinate, and intriguingly, the neuroprotective metabolite itaconate. Together, these data identify microglia as a critical nutrient regulatory node in the brain, metabolizing away harmful fatty acids and liberating the same carbons as alternate bioenergetic and protective substrates for surrounding cells. The data identify a surprisingly beneficial effect of short-term HFD on learning and memory.PMID:39625057 | DOI:10.7554/eLife.87120

Plant J. 2024 Dec 3. doi: 10.1111/tpj.17154. Online ahead of print.ABSTRACTPlants have an amazing capacity to outcompete neighboring organisms for space and resources. Toxic metabolites are major players in these interactions, which can have a broad range of effectiveness by targeting conserved molecular mechanisms, such as protein biosynthesis. However, lack of knowledge about defensive metabolite pathways, their mechanisms of action, and resistance mechanisms limits our ability to manipulate these pathways for enhanced crop resilience. Nonproteogenic amino acids (NPAAs) are a structurally diverse class of metabolites with a variety of functions but are typically not incorporated during protein biosynthesis. Here, we investigate the mechanism of action of the NPAA azetidine-2-carboxylic acid (Aze), an analog of the amino acid proline (Pro). Using a combination of plate-based assays, metabolite feeding, metabolomics, and proteomics, we show that Aze inhibits the root growth of Arabidopsis and other plants. Aze-induced growth reduction was restored by supplementing L-, but not D-Pro, and nontargeted proteomics confirm that Aze is misincorporated for Pro during protein biosynthesis, specifically on cytosolically translated proteins. Gene expression analysis, free amino acid profiling, and proteomics show that the unfolded protein response is upregulated during Aze treatment implicating that Aze misincorporation results in accumulation of misfolded proteins triggering a global stress response. This study demonstrates the mechanism of action of Aze in plants and provides a foundation for understanding the biological functions of proteotoxic metabolites.PMID:39625042 | DOI:10.1111/tpj.17154

Genes Cells. 2024 Dec 3:e13182. doi: 10.1111/gtc.13182. Online ahead of print.ABSTRACTAbnormalities in spermatogenesis, a fundamental component of male reproductive function, can cause male infertility. Somatic cells constituting the testis microenvironment are essential for controlling normal spermatogenesis. Although testicular somatic cells are thought to sense and respond to germ cells to ensure proper spermatogenesis, the details of this signaling mechanism are unknown. Here, we investigated somatic cell dynamics in testicular tissue lacking spermatogenesis using the mice with deletion of the testis-specific histone H3 variant gene H3t. Testicular tissue sections of H3tΔ/Δ mice exhibited an increased interstitial area compared with those of wild-type mice, which was primarily attributed to an increase in Leydig cell numbers. Furthermore, this increase in Leydig cells led to increased testosterone synthesis, which occurred alongside cellular senescence-associated β-galactosidase activity. These findings suggest that Leydig cells monitor the progress of spermatogenesis and possess a mechanism to promote functional germ cell formation.PMID:39624989 | DOI:10.1111/gtc.13182

Front Pharmacol. 2024 Nov 18;15:1453447. doi: 10.3389/fphar.2024.1453447. eCollection 2024.ABSTRACTProstate cancer has the second highest incidence among male malignancies. Only a few studies exist on the inhibitory effects of maslinic acid (MA) on prostate cancer. Herein we found that MA inhibits prostate cancer cell proliferation by decreasing CDK2, CDK4, and CDK6 expression and concurrently increasing p27, Rb, p-Rb expression. Further, MA was observed to induce prostate cancer cell autophagy by increasing the expression of p53, p-p53, ULK1, Beclin1, Atg7, and Atg5 and the ratio of LC3-II/I and concurrently decreasing the expression of ERK1/2 and mTOR. In addition, MA induced RM-1 cell ferroptosis by regulating glutathione, glutamate, and oxidized glutathione concentrations, inhibiting SLC7A11 activity, and downregulating GPX4 expression. Integrated metabolome and transcriptome analysis led to the identification of key pathways (e.g., pathways in cancer and glutathione metabolism). Real-time quantitative PCR confirmed that MA regulates the expression of ABCA1, JUN, and NFKBIA. In vivo, we demonstrated that 50 mg/kg MA significantly inhibited the growth of tumors established using RM-1 cells. To summarize, we report that MA inhibits prostate cancer cell growth both in vitro and in vivo by inducing autophagy and ferroptosis via transcriptomic and metabolomic reprogramming.PMID:39624845 | PMC:PMC11608986 | DOI:10.3389/fphar.2024.1453447

Curr Dev Nutr. 2024 Sep 26;8(11):104462. doi: 10.1016/j.cdnut.2024.104462. eCollection 2024 Nov.ABSTRACTBACKGROUND: Dietary quality has been linked to better glycemic control, but the precise molecular mechanisms giving rise to these associations are not fully understood.OBJECTIVES: To examine the association of metabolites associated with the intake of a healthy diet with measures of insulin/glucose homeostasis.METHODS: Using cross-sectional data from 295 United States adults, the associations between 3 diet pattern scores and metabolome-wide metabolites were estimated via linear regression models, which controlled for demographic factors and health behaviors. Subsequently, the associations between the diet-related metabolites with 6 measures of glucose/insulin homeostasis were examined in similar models. A Bonferroni correction was applied to control the family-wise error rate at 5%.RESULTS: Fifty-five metabolites were significantly associated with ≥1 diet score (all P < 1.7∗10-5). When these were summed into each of the 3 diet-specific metabolite summary scores, all 3 aggregate measures showed strong associations with 5 out of 6 measures of glucose/insulin homeostasis (P = 9.7∗10-5-4.1∗10-13).CONCLUSIONS: Adherence to a priori-defined "healthy diet" is associated with the plasma metabolites that, in turn, are associated with better glycemia. If the associations between replicated in future studies and examined using large-scale longitudinal data, the identified molecules could yield insights into mechanisms by which diet may support glucose and insulin homeostasis.PMID:39624807 | PMC:PMC11609643 | DOI:10.1016/j.cdnut.2024.104462

Ophthalmol Sci. 2024 Oct 1;5(1):100629. doi: 10.1016/j.xops.2024.100629. eCollection 2025 Jan-Feb.ABSTRACTOBJECTIVE: Our objectives were to identify correlation patterns between complement and lipid pathways using a multiomics data integration approach and to determine how these interconnections affect age-related macular degeneration (AMD).DESIGN: Nested case-control study.SUBJECTS AND CONTROLS: The analyses were performed in a subset of the Singapore Indian Eye Study. We randomly selected 155 AMD cases and age- and sex-matched them with 155 controls.METHODS: Firstly, a multiomics data integration method was used to identify correlation patterns between the omics data. Then, we tested possible interactions between the lipids and complement proteins using logistic regression models.MAIN OUTCOME MEASURES: Age-related macular degeneration was determined according to the Beckman classification system. We measured in serum samples 35 complement proteins and 66 lipids, and used 9 genetic variants.RESULTS: Among the 155 AMD cases, 93 (60.0%) had early and 62 (40.0%) intermediate AMD. Firstly, we identified 2 clusters between complement proteins and lipids involving (1) mannan-binding lectin serine protease 1 and several different high-density lipoprotein particles, and (2) complement factor H-related protein 1, carboxypeptidase N subunit 2 and complement component C8 gamma chain, and sphingomyelin and different cholesterol. Secondly, we identified 1 interaction between complement protein 1R and sphingomyelin with an odds of AMD 2 times higher for individuals with low levels of sphingomyelin and complement protein 1R (odds ratio = 2.13 [1.09, 4.17]).CONCLUSIONS: We report here, using a cutting-edge multiomics integration approach, the complex interconnections between genetic, metabolomics, and proteomic data. This method permitted us to obtain a holistic picture and identify multiomics signature of AMD pathophysiology. These results advocate for a personalized therapeutic approach that accounts for multiple pathways. However, these results need to be validated in larger studies with different ethnic groups.FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.PMID:39624796 | PMC:PMC11609548 | DOI:10.1016/j.xops.2024.100629

Biomed Rep. 2024 Nov 13;22(1):12. doi: 10.3892/br.2024.1890. eCollection 2025 Jan.ABSTRACTThe aim of the present study was to examine the effects of Astragalus polysaccharide (APS) on gut microbiota and serum metabolites in asthmatic mice. For this purpose, a total of 36 BALB/c female mice were selected and randomly classified into the following groups: i) The normal control group sensitized with phosphate-buffered saline; ii) the asthma group sensitized and challenged with ovalbumin (OVA); iii) the OVA + APS (2.5 g/kg) treatment group; iv) the OVA + APS (5.0 g/kg) treatment group; v) the OVA + APS (10 g/kg) treatment group; and vi) the OVA + dexamethasone (2 mg/kg) treatment group, with 6 mice in each group. OVA was used to establish the mouse model of asthma. In the APS group, the asthmatic mice were intragastrically administered APS at various doses at 1 h prior to each OVA stimulation. The airway hyperreactivity (AHR) was measured, and hematoxylin and eosin staining was employed to evaluate pulmonary inflammatory infiltration. In addition, 16S rRNA sequencing and ultra-performance liquid chromatography-tandem mass spectrometry were used to detect the changes in the mouse gut microbiota and serum metabolites. The results revealed that compared with the asthma model group, APS improved airway inflammation and eosinophil infiltration in asthmatic mice. In asthmatic mice, the gut microbial imbalance mainly manifested as a low abundance of Bacteroidetes and a high abundance of Firmicutes, yielding an increased F/B ratio. In the high-dose APS group, the abundance of Firmicutes was reduced, and the abundance of Bacteroidetes was increased, which thereby decreased the F/B ratio and corrected the gut microbial imbalance. Through blood metabolomics, 145 and 105 significantly differential metabolites were detected in the medium- and high-dose APS groups, respectively. Moreover, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis demonstrated that the metabolic pathways in the medium-dose APS group included the biosynthesis of unsaturated fatty acids and the biosynthesis of arginine. On the other hand, the metabolic pathways enriched in high-dose APS group were the biosynthesis of unsaturated fatty acids, and pyrimidine metabolism. On the whole, the present study demonstrates that APS may regulate the gut microbiota and the metabolites to improve airway inflammation and AHR in asthmatic mice.PMID:39624784 | PMC:PMC11609611 | DOI:10.3892/br.2024.1890

Front Microbiol. 2024 Nov 13;15:1468365. doi: 10.3389/fmicb.2024.1468365. eCollection 2024.ABSTRACTOBJECTIVE: This study investigated the differences in oral saliva microbiota composition and metabolic products among Han Chinese populations living at different altitudes, as well as their correlations.METHOD: The analysis was conducted using the 16S rRNA gene sequencing method and untargeted metabolomics.RESULTS: 16S gene sequencing results showed significant differences in bacterial diversity and composition between HH (High altitude Han) group and LH (Low altitude Han) group. LEfSe analysis showed that Selenomonas, Leptotrichia, Veillonella, Prevotella relatively abundant are higher in HH group, Haemophilus, Neisseria, Actinobacillus, Aggregatibacter are higher in LH group (p<0.05). Furthermore, as depicted in the phylogenetic tree, there are differences observed between the two groups at all taxonomic levels: 4 phyla, 6 classes, 6 orders, 9 families, 9 genera and 8 species (p<0.05). After conducting PICRUSt functional prediction analysis, we identified 11 significantly different KEGG categories (level 2) between the two groups. These categories primarily encompass energy metabolism, amino acid metabolism, and carbohydrate metabolism. Furthermore, non-targeted metabolomics analysis revealed a total of 997 distinct metabolites in the two groups. These differentiated metabolites can be classified into 13 Class I categories including amino acids and their metabolites, benzene and its derivatives, organic acids and their derivatives, heterocyclic compounds, aldehydes, ketones and esters, nucleotides and their metabolites among others. Additionally, fatty acyl compounds, alcohols and amines as well as glycerophospholipids are present along with carbohydrates and other physiologically active components such as hormones. Finally, Pearson correlation analysis of the top 20 differential metabolites with microorganisms demonstrated an interaction between them; however further experimental verification is required to elucidate the specific mechanism of action.CONCLUSION: Therefore, this study revealed the effect of altitude on oral saliva microbes and metabolites, as well as their correlations.PMID:39624722 | PMC:PMC11610449 | DOI:10.3389/fmicb.2024.1468365

Heliyon. 2024 Oct 26;10(22):e39753. doi: 10.1016/j.heliyon.2024.e39753. eCollection 2024 Nov 30.ABSTRACTCalcium phosphate (CaP) biomaterials have been widely used in hard tissue engineering, but their impact on cell metabolism is unclear. We synthesized and characterized hydroxyapatite, β-tricalcium phosphate, and biphasic calcium phosphate composites to investigate material effects on NIH/3T3 cell metabolism. The intracellular metabolites were analyzed employing LC-MS metabolomics, and cell metabolic status was assessed comparatively. Our results revealed that CaPs adsorb metabolites, particularly amino acids. Furthermore, CaP biomaterials significantly influence amino acid and energy metabolism pathways. Specifically, we observed glycolysis and TCA cycle activity stimulation, resulting in higher energy consumption in cells adhered to CaP surfaces. Our findings suggest that CaPs composed of different ratios of hydroxyapatite (HAp) and β-tricalcium phosphate (β-TCP) have a similar impact on cell metabolism alterations. Moreover, we observed that the metabolism alterations gradually decreased over time. Our study enhances understanding of cell-CaP interplay, paving the way for metabolic regulation biomaterials and improving efficacy in tissue engineering and regenerative medicine.PMID:39624315 | PMC:PMC11609662 | DOI:10.1016/j.heliyon.2024.e39753

JHEP Rep. 2024 Sep 4;6(12):101208. doi: 10.1016/j.jhepr.2024.101208. eCollection 2024 Dec.ABSTRACTBACKGROUND & AIMS: Porto-sinusoidal vascular disorder (PSVD) is a rare and diagnostically challenging vascular liver disease. This study aimed to identify distinct metabolomic signatures in patients with PSVD or cirrhosis to facilitate non-invasive diagnosis and elucidate perturbed metabolic pathways.METHODS: Serum samples from 20 healthy volunteers (HVs), 20 patients with histologically confirmed PSVD or 20 patients with cirrhosis were analyzed. Metabolites were measured using liquid chromatography-mass spectrometry. Differential abundance was evaluated with Limma's moderated t-statistics. Artificial neural network and support vector machine models were developed to classify PSVD against cirrhosis or HV metabolomic profiles. An independent cohort was used for validation.RESULTS: A total of 283 metabolites were included for downstream analysis. Clustering effectively separated PSVD from HV metabolomes, although a subset of patients with PSVD (n = 5, 25%) overlapped with those with cirrhosis. Differential testing revealed significant PSVD-linked metabolic perturbations, including pertubations in taurocholic and adipic acids, distinguishing patients with PSVD from both HVs and those with cirrhosis. Alterations in pyrimidine, glycine, serine, and threonine pathways were exclusively associated with PSVD. Machine learning models utilizing selected metabolic signatures reliably differentiated the PSVD group from HVs or patients with cirrhosis using only 4 to 6 metabolites. Validation in an independent cohort demonstrated the high discriminative ability of taurocholic acid (AUROC 0.899) for patients with PSVD vs. HVs and the taurocholic acid/aspartic acid ratio (AUROC 0.720) for PSVD vs. cirrhosis.CONCLUSIONS: High-throughput metabolomics enabled the identification of distinct metabolic profiles that differentiate between PSVD, cirrhosis, and healthy individuals. Unique alterations in the glycine, serine, and threonine pathways suggest their potential involvement in PSVD pathogenesis.IMPACT AND IMPLICATIONS: Porto-sinusoidal vascular disorder (PSVD) is a vascular liver disease that can lead to pre-sinusoidal portal hypertension in the absence of cirrhosis, with poorly understood pathophysiology and no established treatment. Our study demonstrates that analyzing the serum metabolome could reveal distinct metabolic signatures in patients with PSVD, including alterations in the pyrimidine, glycine, serine and threonine pathways, potentially shedding light on the disease's underlying pathways. These findings could enable earlier and non-invasive diagnosis of PSVD, potentially reducing reliance on invasive procedures like liver biopsy and guiding diagnostic pathways.PMID:39624234 | PMC:PMC11609546 | DOI:10.1016/j.jhepr.2024.101208

Cancer Drug Resist. 2024 Nov 16;7:44. doi: 10.20517/cdr.2024.101. eCollection 2024.ABSTRACTAim: Gastric cancer (GC) is one of the common malignant tumors, and most patients with advanced GC often develop chemotherapy resistance, resulting in poor chemotherapy efficacy. Therefore, it is crucial to clarify the specific mechanisms of their chemotherapy resistance. Methods: In this study, we analyzed the correlation between fos-related antigen-1 (Fra-1) and chemotherapy resistance in GC using bioinformatics, cell counting kit-8 (CCK8), and 5-ethynyl-2'-deoxyuridine (EDU) combined with flow cytometry; furthermore, we used energy metabolomics sequencing, combined with ChIP-qPCR technology, to elucidate the specific role of Fra-1 in chemotherapy resistance of GC cells and its related mechanisms. Results: We found that high Fra-1 expression was closely related to chemotherapeutic drugs in GC cells, as demonstrated by bioinformatics analysis combined with EDU and CCK8 experiments. Energy metabolomics combined with in vitro cellular experimental analysis revealed that the pentose phosphate pathway (PPP) was activated in GC cells with high Fra-1 expression, along with an increase in the synthesis of metabolites such as nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), a decrease in the level of reactive oxygen species (ROS), and the inhibition of their ferroptosis. In addition, ChIP-qPCR experiments confirmed that Fra-1 binds to the promoter of glucose-6-phosphate dehydrogenase (G6PD), a key rate-limiting enzyme of the PPP, and transcriptionally regulates its expression, which in turn activates the PPP and promotes chemotherapy resistance in GC cells. Conclusion: Our research findings suggest that Fra-1 activates the PPP by upregulating G6PD transcriptional activity and inhibiting its ubiquitination level, inhibiting ferroptosis in GC cells and inducing chemoresistance. This provides an experimental basis for screening potential molecular targets for chemotherapy resistance in GC patients.PMID:39624082 | PMC:PMC11609144 | DOI:10.20517/cdr.2024.101

Epigenomics. 2024 Dec 2:1-16. doi: 10.1080/17501911.2024.2435257. Online ahead of print.ABSTRACTAIM: Diabetic cardiomyopathy (DbCM), a complex metabolic disease, greatly threatens human health due to therapeutic limitations. Multi-omics approaches facilitate the elucidation of its intrinsic pathological changes.METHODS: Metabolomics, RNA-seq, proteomics, and assay of transposase-accessible chromatin (ATAC-seq) were utilized to elucidate multidimensional molecular alterations in DbCM.RESULTS: In the heart and plasma of mice with DbCM, metabolomic analysis demonstrated significant differences in branched-chain amino acids (BCAAs) and lipids. Subsequent RNA-seq and proteomics showed that the key genes, including BCKDHB, PPM1K, Cpt1b, Fabp4, Acadm, Acadl, Acadvl, HADH, HADHA, HADHB, Eci1, Eci2, PDK4, and HMGCS2, were aberrantly regulated, contributing to the disorder of BCAAs and fatty acids. ATAC-seq analysis underscored the pivotal role of epigenetic regulation by revealing dynamic shifts in chromatin accessibility and a robust positive correlation with gene expression patterns in diabetic cardiomyopathy mice. Furthermore, motif analysis identified that KLF15 as a critical transcription factor in DbCM, regulating the core genes implicated with BCAAs metabolism.CONCLUSION: Our research delved into the metabolic alterations and epigenetic landscape and revealed that KLF15 may be a promising candidate for therapeutic intervention in DbCM.PMID:39623870 | DOI:10.1080/17501911.2024.2435257

Plant Cell Environ. 2024 Dec 2. doi: 10.1111/pce.15303. Online ahead of print.ABSTRACTMany plant viruses modify the phenotype of their hosts, which may influence the behaviour of their vectors and facilitate transmission. Among them is the turnip yellows virus (TuYV), which can modify the orientation, feeding, and performance of its main aphid vector, Myzus persicae. However, the virus factors driving these mechanisms have not been elucidated. In this study, we compared the feeding behaviour and fecundity of aphids on TuYV-infected and transgenic Arabidopsis thaliana expressing individual TuYV proteins (CP, RT and P0) to define the role of these proteins in aphid-plant interactions. Aphids on TuYV-infected plants had shorter pathway phases and ingested phloem sap for longer times, which is expected to promote the acquisition of the phloem-limited TuYV. No change in aphid fecundity was observed on TuYV-infected plants. The transmission-conducive feeding behaviour changes could be fully reproduced by phloem-specific expression of the capsid protein (CP) in transgenic plants, whereas expression of P0 had minor and RT had no effects on aphid feeding behaviour. We then carried out a metabolomic analysis to determine plant compounds that could be involved in the modification of the aphid behaviour. A few metabolites were specific for TuYV-infected or CP-transgenic A. thaliana, and are good candidates for inducing behavioural changes.PMID:39623721 | DOI:10.1111/pce.15303

Cancer Commun (Lond). 2024 Dec 2. doi: 10.1002/cac2.12633. Online ahead of print.ABSTRACTBACKGROUND: Recurrence and metastasis remain significant challenges in lung adenocarcinoma (LUAD) after radical resection. The mechanisms behind the recurrence and metastasis of LUAD remain elusive, and deregulated cellular metabolism is suspected to play a significant role. This study explores the metabolic and epigenetic regulation mediated by nicotinamide N-methyl transferase (NNMT) in LUAD.METHODS: Untargeted metabolomic analyses were performed to detect metabolism irregularities. Single-cell RNA sequencing (RNA-seq) databases and multiplex immunofluorescence analysis were used to identify the location of NNMT within the tumor microenvironment. The biological functions of NNMT were investigated both in vitro and in vivo, with RNA-seq and chromatin immunoprecipitation-PCR providing insights into underlying mechanisms. Finally, single-cell RNA-seq data and immunohistochemistry of primary tumors were analyzed to validate the main findings.RESULTS: Untargeted metabolomic analyses revealed metabolic aberrations in amino acids, organic acids, lipids, and nicotinamide pathways, which are linked to metastasis of non-small cell lung cancer. NNMT is a key enzyme in nicotinamide metabolism, and we found the bulk tissue mRNA level of NNMT gene was inversely associated with LUAD metastasis. NNMT was proved to be predominantly expressed in cancer-associated fibroblasts (CAFs) within the stromal regions of LUAD, and a low stromal NNMT expression was identified as a predictor of poor disease-free survival following radical resection of LUAD. The isolation and primary culture of CAFs from LUAD enabled in vitro and in vivo experiments, which confirmed that NNMT negatively regulated the metastasis-promoting properties of CAFs in LUAD. Mechanistically, the downregulation of NNMT led to an increase in intracellular methyl groups by reducing the activity of the methionine cycle, resulting in heightened methylation at H3K4me3. This alteration triggered the upregulation of genes involved in extracellular matrix remodeling in CAFs, including those encoding collagens, integrins, laminins, and matrix metalloproteinases, thereby facilitating cancer cell invasion and metastasis. Reanalysis of single-cell RNA-seq data and immunohistochemistry assays of primary LUAD tissues substantiated NNMT's negative regulation of these genes in CAFs.CONCLUSIONS: This study provides novel insights into the metabolic and epigenetic regulatory functions of NNMT in CAFs, expanding the current understanding of LUAD metastasis regulation and suggesting potential avenues for future research and therapeutic development.PMID:39623600 | DOI:10.1002/cac2.12633

Zhonghua Gan Zang Bing Za Zhi. 2024 Nov 20;32(11):1053-1056. doi: 10.3760/cma.j.cn501113-20240223-00088.ABSTRACTThe activation of hepatic stellate cells (HSCs) and excessive deposition of extracellular matrix are the keys to the occurrence and development of liver fibrosis. Metabolic reprogramming supports the activation process of HSCs, which requires substantial energy to meet the corresponding energy requirements for liver fibrosis formation. This review focuses on the effect of metabolomic changes characterized by metabolic reprogramming on HSC activation and summarizes the characteristics of HSC energy metabolism reprogramming during the formation of liver fibrosis, with the aim to summarize research evidence for exploring the mechanism and developing strategies for the prevention and treatment of liver fibrosis.PMID:39623584 | DOI:10.3760/cma.j.cn501113-20240223-00088

Hum Vaccin Immunother. 2024 Dec 31;20(1):2430087. doi: 10.1080/21645515.2024.2430087. Epub 2024 Dec 2.ABSTRACTSome patients may develop adverse events during neoadjuvant chemoradiotherapy combined with immunotherapy, influencing response rates. The roles of intestinal microbiome and its metabolites in therapeutic adverse events remain unclear. We collected baseline fecal samples from 21 patients with adverse events (AE group) and 11 patients without adverse events (Non-AE group). Their microbiota and metabolome were characterized using metagenomic shotgun sequencing and untargeted metabolomics. At the species level, the gut microbiota in the Non-AE group exhibits significantly higher abundance of Clostridium sp. Alistipes sp. and lower abundance of Lachnoclostridium sp. Weissella cibaria, Weissella confusa, compared to the AE group (p < .05). A total of 58 discriminative metabolites were identified between groups. Beta-alanine metabolism was scattered. Boc-beta-cyano-L-alanine and CoQ9 were significantly increased in patients without adverse events, while linoleic acid increased in patients with adverse events. The increased Alistipes sp. in the Non-AE group was positively correlated with Boc-beta-cyano-L-alanine and negatively correlated with linoleic acid (p < .05). We constructed a combined microbiome-metabolite model to distinguish Non-AE and AE patients with an AUC of 0.963 via the random forest algorithm. Our findings provided a novel insight into the interplay of multispecies microbial cluster and metabolites of rectal patients with adverse events in neoadjuvant chemoradiotherapy combined with immunotherapy. These microbiota and metabolites deserve further investigations to reveal their roles in adverse events, providing clues for better treatment scenarios.Trial registration number: ClinicalTrials.gov identifier: NCT05368051.PMID:39623529 | DOI:10.1080/21645515.2024.2430087