PubMed

Front Plant Sci. 2024 Mar 26;15:1373975. doi: 10.3389/fpls.2024.1373975. eCollection 2024.ABSTRACTProanthocyanidins (PAs), one of the most abundant natural polymers found in plants, are gaining increasing attention because of their beneficial effects for agriculture and human health. The study of PA biosynthesis has been active for decades, and progress has been drastically accelerated since the discovery of key enzymes such as Anthocyanidin Reductase (ANR), Leucoanthocyanidin Reductase (LAR), and key transcription factors such as Transparent Testa 2 (TT2) and Transparent Testa 8 (TT8) in the early 2000s. Scientists raised some compelling questions regarding PA biosynthesis about two decades ago in the hope that addressing these questions would lead to an enhanced understanding of PA biosynthesis in plants. These questions focus on the nature of starter and extension units for PA biosynthesis, the stereochemistry of PA monomers and intermediates, and how and where the polymerization or condensation steps work subcellularly. Here, I revisit these long-standing questions and provide an update on progress made toward answering them. Because of advanced technologies in genomics, bioinformatics and metabolomics, we now have a much-improved understanding of functionalities of key enzymes and identities of key intermediates in the PA biosynthesis and polymerization pathway. Still, several questions, particularly the ones related to intracellular PA transportation and deposition, as well as enzyme subcellular localization, largely remain to be explored. Our increasing understanding of PA biosynthesis in various plant species has led to a new set of compelling open questions, suggesting future research directions to gain a more comprehensive understanding of PA biosynthesis.PMID:38595764 | PMC:PMC11002137 | DOI:10.3389/fpls.2024.1373975

RSC Adv. 2024 Apr 9;14(16):11388-11399. doi: 10.1039/d4ra01646g. eCollection 2024 Apr 3.ABSTRACTCaroxylon volkensii is a wild desert plant of the family Amaranthaceae. This study represents the first report of the metabolomic profiling of C. volkensii by liquid chromatography quadrupole-time-of-flight tandem mass spectrometry (LC-QTOF-MS/MS). The dereplication study of its secondary metabolites led to the characterization of 66 known compounds. These compounds include catecholamines, tyramine derivatives, phenolic acids, triterpenoids, flavonoids, and others. A new tyramine derivative, alongside other known compounds, was reported for the first time in the Amaranthaceae family. The new derivative and the first-reported compounds were putatively identified through MS/MS fragmentation data. Given the notorious taxonomical challenges within the genus Salsola, to which C. volkensii previously belonged, our study could offer a valuable insight into its chemical fingerprint and phylogenetic relationship to different Salsola species. The antibacterial potential of C. volkensii methanolic extract (CVM) against Pseudomonas aeruginosa was screened. The minimum inhibitory concentration (MIC) of CVM ranged from 32 to 256 μg mL-1. The anti-quorum sensing potential of CVM resulted in a decrease in the percentage of strong and moderate biofilm-forming isolates from 47.83% to 17.39%. It revealed a concentration-dependent inhibitory activity on violacein formation by Chromobacterium violaceum. Moreover, CVM exhibited an in vivo protective potential against the killing capacity of P. aeruginosa isolates. A molecular docking study revealed that the quorum-sensing inhibitory effect of CVM can be attributed to the binding of tyramine conjugates, ethyl-p-digallate, and isorhamnetin to the transcriptional global activator LasR.PMID:38595719 | PMC:PMC11002840 | DOI:10.1039/d4ra01646g

RSC Adv. 2024 Apr 9;14(16):11322. doi: 10.1039/d4ra90032d. eCollection 2024 Apr 3.ABSTRACT[This corrects the article DOI: 10.1039/D3RA00802A.].PMID:38595710 | PMC:PMC11002562 | DOI:10.1039/d4ra90032d

Am J Vet Res. 2024 Apr 13:1-10. doi: 10.2460/ajvr.23.12.0285. Online ahead of print.ABSTRACTOBJECTIVE: To investigate associations between hepatic fat accumulation, fibrosis, and plasma values of primary metabolites, biochemical measurands, insulin, and lipoproteins in bearded dragons.ANIMALS: 48 adult central bearded dragons (Pogona vitticeps).METHODS: Dragons were sedated with alfaxalone, and a blood sample was collected. Plasma was submitted for untargeted primary metabolomics using gas chromatography time-of-flight mass spectrometry, a biochemistry panel, and a lipoprotein panel determined by PAGE. Hepatic lipid content was quantified by liver attenuation measurements from CT images and digital image analysis of standardized histologic sections of the liver. Fibrosis was quantified by digital image analysis on Masson's trichrome-stained histologic sections. Severity was determined from pathologic review of liver sections according to a standardized grading system. Statistical associations were investigated using serial linear models adjusted for false discovery rate and multivariate statistics.RESULTS: Both hepatic fat and fibrosis had a significant effect on CT liver attenuation values. Several oligosaccharides (maltotriose, maltose, ribose, trehalose) and alkaline phosphatase were significantly and linearly increased with hepatic lipid content (all q < .05). On partial least square-discriminant analysis, β-hydroxybutyric acid was the most important discriminatory variable between fatty liver severity grades on histology. No significant associations were found with insulin, lipoproteins, and succinic acid.CLINICAL RELEVANCE: Bearded dragons with hepatic lipid accumulation experienced multiple metabolic pathway disruptions, some being compatible with mitochondrial dysfunction. No evidence of insulin resistance or dyslipidemia was found. Hepatic biopsy and histopathology remain recommended for reliably diagnosing and staging fatty liver disease in bearded dragons.PMID:38593838 | DOI:10.2460/ajvr.23.12.0285

Neoplasia. 2024 Apr 8;52:100996. doi: 10.1016/j.neo.2024.100996. Online ahead of print.ABSTRACTPapillary thyroid carcinoma (PTC) is the most common endocrine malignancy, and its incidence has increased rapidly in recent years. The BRAF inhibitor vemurafenib is effective against BRAFV600E-positive PTC; however, acquired resistance to single agent therapy frequently leads to tumor recurrence and metastasis, underscoring the need to develop tailored treatment strategies. We previously showed that the oncogenic kinase PIM1 was associated with the malignant phenotype and prognosis of PTC. In this study, we showed that sustained expression of the PIM1 protein in PTC was affected by the BRAFV600E mutation. Based on this regulatory mechanism, we tested the synergistic effects of inhibitors of BRAF (BRAFi) and PIM1 in BRAFV600E-positive PTC cell lines and xenograft tumors. LC-MS metabolomics analyses suggested that BRAFi/PIMi therapy acted by restricting the amounts of critical amino acids and nucleotides required by cancer cells as well as modulating DNA methylation. This study elucidates the role of BRAFV600E in the regulation of PIM1 in PTC and demonstrates the synergistic effect of a novel combination, BRAFi/PIMi, for the treatment of PTC. This discovery, along with the pathways that may be involved in the powerful efficacy of BRAFi/PIMi strategy from the perspective of cell metabolism, provides insight into the molecular basis of PTC progression and offers new perspectives for BRAF-resistant PTC treatment.PMID:38593698 | DOI:10.1016/j.neo.2024.100996

Water Res. 2024 Mar 19;256:121492. doi: 10.1016/j.watres.2024.121492. Online ahead of print.ABSTRACTCyanobacterial blooms, producing toxic secondary metabolites, are becoming increasingly common phenomena in the face of rising global temperatures. They are the world's most abundant photosynthetic organisms, largely owing their success to a range of highly diverse and complex natural products possessing a broad spectrum of different bioactivities. Over 2600 compounds have been isolated from cyanobacteria thus far, and their characterisation has revealed unusual and useful chemistries and motifs including alkynes, halogens, and non-canonical amino acids. Genome sequencing of cyanobacteria lags behind natural product isolation, with only 19% of cyanobacterial natural products associated with a sequenced organism. Recent advances in meta(genomics) provide promise to narrow this gap and has also facilitated the uprise of combined genomic and metabolomic approaches, heralding a new era of discovery of novel compounds. Analyses of the datasets described within this manuscript reveal the asynchrony of current genomic and metabolomic data, highlight the chemical diversity of cyanobacterial natural products. Linked to this manuscript, we make these manually curated datasets freely accessible for the public to facilitate further research in this important area.PMID:38593604 | DOI:10.1016/j.watres.2024.121492

Int J Food Microbiol. 2024 Mar 27;417:110686. doi: 10.1016/j.ijfoodmicro.2024.110686. Online ahead of print.ABSTRACTRosa roxburghii Tratt fruits (RRT) exhibit extremely high nutritional and medicinal properties due to its unique phytochemical composition. Probiotic fermentation is a common method of processing fruits. Variations in the non-volatile metabolites and bioactivities of RRT juice caused by different lactobacilli are not well understood. Therefore, we aimed to profile the non-volatile components and investigate the impact of L. plantarum fermentation (LP) and L. paracasei fermentation (LC) on RRT juice (the control, CG). There were both similarities and differences in the effects of LP and LC on RRT juice. Both of the two strains significantly increased the content of total phenolic, total flavonoid, and some bioactive compounds such as 2-hydroxyisocaproic acid, hydroxytyrosol and indole-3-lactic acid in RRT juice. Interestingly, compared with L. paracasei, L. plantarum showed better ability to increase the content of total phenolic and these valuable compounds, as well as certain bioactivities. The antioxidant capacity and α-glucosidase inhibitory activity of RRT juice were notably enhanced after the fermentations, whereas its cholesterol esterase inhibitory activity was reduced significantly. Moreover, a total of 1466 metabolites were identified in the unfermented and fermented RRT juices. There were 278, 251 and 134 differential metabolites in LP vs CG, LC vs CG, LC vs LP, respectively, most of which were upregulated. The key differential metabolites were classified into amino acids and their derivatives, organic acids, nucleotides and their analogues, phenolic acids and alkaloids, which can serve as potential markers for authentication and discrimination between the unfermented and lactobacilli fermented RRT juice samples. The KEGG enrichment analysis uncovered that metabolic pathways, purine metabolism, nucleotide metabolism and ABC transporters contributed mainly to the formation of unique composition of fermented RRT juice. These results provide good coverage of the metabolome of RRT juice in both unfermented and fermented forms and also provide a reference for future research on the processing of RRT or other fruits.PMID:38593553 | DOI:10.1016/j.ijfoodmicro.2024.110686

Plant Physiol Biochem. 2024 Mar 19;210:108511. doi: 10.1016/j.plaphy.2024.108511. Online ahead of print.ABSTRACTTerpenoids are a vast class of plant specialized metabolites (PSMs) manufactured by plants and are involved in their interactions with environment. In addition, they add health benefits to human nutrition and are widely used as pharmaceutically active compounds. However, native plants produce a limited amount of terpenes restricting metabolite yield of terpene-related metabolites. Exponential growth in the plant metabolome data and the requirement of alternative approaches for producing the desired amount of terpenoids, has redirected plant biotechnology research to plant metabolic engineering, which requires in-depth knowledge and precise expertise about dynamic plant metabolic pathways and cellular physiology. Metabolic engineering is an assuring tool for enhancing the concentration of terpenes by adopting specific strategies such as overexpression of the key genes associated with the biosynthesis of targeted metabolites, controlling the modulation of transcription factors, downregulation of competitive pathways (RNAi), co-expression of the biosynthetic pathway genes in heterologous system and other combinatorial approaches. Microorganisms, fast-growing host plants (such as Nicotiana benthamiana), and cell suspension/callus cultures have provided better means for producing valuable terpenoids. Manipulation in the biosynthetic pathways responsible for synthesis of terpenoids can provide opportunities to enhance the content of desired terpenoids and open up new avenues to enhance their production. This review deliberates the worth of metabolic engineering in medicinal plants to resolve issues associated with terpenoid production at a commercial scale. However, to bring the revolution through metabolic engineering, further implementation of genome editing, elucidation of metabolic pathways using omics approaches, system biology approaches, and synthetic biology tactics are essentially needed.PMID:38593484 | DOI:10.1016/j.plaphy.2024.108511

Chin Neurosurg J. 2024 Apr 9;10(1):12. doi: 10.1186/s41016-024-00365-4.ABSTRACTBACKGROUND: Patients with disorders of consciousness (DoC) exhibit varied revival outcomes based on different etiologies and diagnoses, the mechanisms of which remain largely unknown. The fluctuating clinical presentations in DoC pose challenges in accurately assessing consciousness levels and prognoses, often leading to misdiagnoses. There is an urgent need for a deeper understanding of the physiological changes in DoC and the development of objective diagnostic and prognostic biomarkers to improve treatment guidance.METHODS: To explore biomarkers and understand the biological processes, we conducted a comprehensive untargeted metabolomic analysis on serum samples from 48 patients with DoC. Patients were categorized based on etiology (TBI vs. non-TBI), CRS-R scores, and prognosis. Advanced analytical techniques, including PCA and OPLS-DA models, were employed to identify differential metabolites.RESULTS: Our analysis revealed a distinct separation in metabolomic profiles among the different groups. The primary differential metabolites distinguishing patients with varying etiologies were predominantly phospholipids, with a notable decrease in glycerophospholipids observed in the TBI group. Patients with higher CRS-R scores exhibited a pattern of impaired carbohydrate metabolism coupled with enhanced lipid metabolism. Notably, serum concentrations of both LysoPE and PE were reduced in patients with improved outcomes, suggesting their potential as prognostic biomarkers.CONCLUSIONS: Our study underscores the critical role of phospholipid metabolism in the brain's metabolic alterations in patients with DoC. It identifies key biomarkers for diagnosis and prognosis, offering insights that could lead to novel therapeutic targets. These findings highlight the value of metabolomic profiling in understanding and potentially treating DoC.PMID:38594757 | DOI:10.1186/s41016-024-00365-4

Cancer Metab. 2024 Apr 9;12(1):11. doi: 10.1186/s40170-024-00341-7.ABSTRACTBACKGROUND: Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are a fatal form of brain cancer. These tumors often carry a driver mutation on histone H3 converting lysine 27 to methionine (H3K27M). DMG-H3K27M are characterized by altered metabolism and resistance to standard of care radiation (RT) but how the H3K27M mediates the metabolic response to radiation and consequent treatment resistance is uncertain.METHODS: We performed metabolomics on irradiated and untreated H3K27M isogenic DMG cell lines and observed an H3K27M-specific enrichment for purine synthesis pathways. We profiled the expression of purine synthesis enzymes in publicly available patient data and our models, quantified purine synthesis using stable isotope tracing, and characterized the in vitro and in vivo response to de novo and salvage purine synthesis inhibition in combination with RT.RESULTS: DMG-H3K27M cells activate purine metabolism in an H3K27M-specific fashion. In the absence of genotoxic treatment, H3K27M-expressing cells have higher relative activity of de novo synthesis and apparent lower activity of purine salvage demonstrated via stable isotope tracing of key metabolites in purine synthesis and by lower expression of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), the rate-limiting enzyme of purine salvage into IMP and GMP. Inhibition of de novo guanylate synthesis radiosensitized DMG-H3K27M cells in vitro and in vivo. Irradiated H3K27M cells upregulated HGPRT expression and hypoxanthine-derived guanylate salvage but maintained high levels of guanine-derived salvage. Exogenous guanine supplementation decreased radiosensitization in cells treated with combination RT and de novo purine synthesis inhibition. Silencing HGPRT combined with RT markedly suppressed DMG-H3K27M tumor growth in vivo.CONCLUSIONS: Our results indicate that DMG-H3K27M cells rely on highly active purine synthesis, both from the de novo and salvage synthesis pathways. However, highly active salvage of free purine bases into mature guanylates can bypass inhibition of the de novo synthetic pathway. We conclude that inhibiting purine salvage may be a promising strategy to overcome treatment resistance in DMG-H3K27M tumors.PMID:38594734 | DOI:10.1186/s40170-024-00341-7

BMC Psychiatry. 2024 Apr 9;24(1):262. doi: 10.1186/s12888-024-05660-z.ABSTRACTBACKGROUND: Schizophrenia (SCZ) is a profound mental disorder with a multifactorial etiology, including genetics, environmental factors, and demographic influences such as ethnicity and geography. Among these, the studies of SCZ also shows racial and regional differences.METHODS: We first established a database of biological samples for SCZ in China's ethnic minorities, followed by a serum metabolomic analysis of SCZ patients from various ethnic groups within the same region using the LC-HRMS platform.RESULTS: Analysis identified 47 metabolites associated with SCZ, with 46 showing significant differences between Miao and Han SCZ patients. These metabolites, primarily fatty acids, amino acids, benzene, and derivatives, are involved in fatty acid metabolism pathways. Notably, L-Carnitine, L-Cystine, Aspartylphenylalanine, and Methionine sulfoxide demonstrated greater diagnostic efficacy in Miao SCZ patients compared to Han SCZ patients.CONCLUSION: Preliminary findings suggest that there are differences in metabolic levels among SCZ patients of different ethnicities in the same region, offering insights for developing objective diagnostic or therapeutic monitoring strategies that incorporate ethnic considerations of SCZ.PMID:38594695 | DOI:10.1186/s12888-024-05660-z

BMC Plant Biol. 2024 Apr 9;24(1):258. doi: 10.1186/s12870-024-04986-w.ABSTRACTBACKGROUND: Weed control is essential for agricultural floor management in vineyards and the inter-row mulching is an eco-friendly practice to inhibit weed growth via filtering out photosynthetically active radiation. Besides weed suppression, inter-row mulching can influence grapevine growth and the accumulation of metabolites in grape berries. However, the complex interaction of multiple factors in the field challenges the understanding of molecular mechanisms on the regulated metabolites. In the current study, black geotextile inter-row mulch (M) was applied for two vintages (2016-2017) from anthesis to harvest. Metabolomics and transcriptomics analysis were conducted in two vintages, aiming to provide insights into metabolic and molecular responses of Cabernet Sauvignon grapes to M in a semi-arid climate.RESULTS: Upregulation of genes related to photosynthesis and heat shock proteins confirmed that M weakened the total light exposure and grapes suffered heat stress, resulting in lower sugar-acid ratio at harvest. Key genes responsible for enhancements in phenylalanine, glutamine, ornithine, arginine, and C6 alcohol concentrations, and the downward trend in ε-viniferin, anthocyanins, flavonols, terpenes, and norisoprenoids in M grapes were identified. In addition, several modules significantly correlated with the metabolic biomarkers through weighted correlation network analysis, and the potential key transcription factors regulating the above metabolites including VviGATA11, VviHSFA6B, and VviWRKY03 were also identified.CONCLUSION: This study provides a valuable overview of metabolic and transcriptomic responses of M grapes in semi-arid climates, which could facilitate understanding the complex regulatory network of metabolites in response to microclimate changes.PMID:38594637 | DOI:10.1186/s12870-024-04986-w

BMC Plant Biol. 2024 Apr 9;24(1):257. doi: 10.1186/s12870-024-04948-2.ABSTRACTBACKGROUND: Sulfur (S) is a mineral nutrient essential for plant growth and development, which is incorporated into diverse molecules fundamental for primary and secondary metabolism, plant defense, signaling, and maintaining cellular homeostasis. Although, S starvation response is well documented in the dicot model Arabidopsis thaliana, it is not clear if the same transcriptional networks control the response also in the monocots.RESULTS: We performed series of physiological, expression, and metabolite analyses in two model monocot species, one representing the C3 plants, Oryza sativa cv. kitaake, and second representing the C4 plants, Setaria viridis. Our comprehensive transcriptomic analysis revealed twice as many differentially expressed genes (DEGs) in S. viridis than in O. sativa under S-deficiency, consistent with a greater loss of sulfur and S-containing metabolites under these conditions. Surprisingly, most of the DEGs and enriched gene ontology terms were species-specific, with an intersect of only 58 common DEGs. The transcriptional networks were different in roots and shoots of both species, in particular no genes were down-regulated by S-deficiency in the roots of both species.CONCLUSIONS: Our analysis shows that S-deficiency seems to have different physiological consequences in the two monocot species and their nutrient homeostasis might be under distinct control mechanisms.PMID:38594609 | DOI:10.1186/s12870-024-04948-2

Eur Radiol Exp. 2024 Apr 10;8(1):46. doi: 10.1186/s41747-024-00445-1.ABSTRACTBACKGROUND: Monitoring pyruvate metabolism in the spleen is important for assessing immune activity and achieving successful radiotherapy for cervical cancer due to the significance of the abscopal effect. We aimed to explore the feasibility of utilizing hyperpolarized (HP) [1-13C]-pyruvate magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to evaluate pyruvate metabolism in the human spleen, with the aim of identifying potential candidates for radiotherapy in cervical cancer.METHODS: This prospective study recruited six female patients with cervical cancer (median age 55 years; range 39-60) evaluated using HP [1-13C]-pyruvate MRI/MRS at baseline and 2 weeks after radiotherapy. Proton (1H) diffusion-weighted MRI was performed in parallel to estimate splenic cellularity. The primary outcome was defined as tumor response to radiotherapy. The Student t-test was used for comparing 13C data between the groups.RESULTS: The splenic HP [1-13C]-lactate-to-total carbon (tC) ratio was 5.6-fold lower in the responders than in the non-responders at baseline (p = 0.009). The splenic [1-13C]-lactate-to-tC ratio revealed a 1.7-fold increase (p = 0.415) and the splenic [1-13C]-alanine-to-tC ratio revealed a 1.8-fold increase after radiotherapy (p = 0.482). The blood leukocyte differential count revealed an increased proportion of neutrophils two weeks following treatment, indicating enhanced immune activity (p = 0.013). The splenic apparent diffusion coefficient values between the groups were not significantly different.CONCLUSIONS: This exploratory study revealed the feasibility of HP [1-13C]-pyruvate MRS of the spleen for evaluating baseline immune potential, which was associated with clinical outcomes of cervical cancer after radiotherapy.TRIAL REGISTRATION: ClinicalTrials.gov NCT04951921 , registered 7 July 2021.RELEVANCE STATEMENT: This prospective study revealed the feasibility of using HP 13C MRI/MRS for assessing pyruvate metabolism of the spleen to evaluate the patients' immune potential that is associated with radiotherapeutic clinical outcomes in cervical cancer.KEY POINTS: • Effective radiotherapy induces abscopal effect via altering immune metabolism. • Hyperpolarized 13C MRS evaluates patients' immune potential non-invasively. • Pyruvate-to-lactate conversion in the spleen is elevated following radiotherapy.PMID:38594558 | DOI:10.1186/s41747-024-00445-1

Commun Biol. 2024 Apr 9;7(1):430. doi: 10.1038/s42003-024-06087-8.ABSTRACTDespite recent advances in cancer immunotherapy, pancreatic ductal adenocarcinoma (PDAC) remains unresponsive due to an immunosuppressive tumor microenvironment, which is characterized by the abundance of cancer-associated fibroblasts (CAFs). Once identified, CAF-mediated immune inhibitory mechanisms could be exploited for cancer immunotherapy. Siglec receptors are increasingly recognized as immune checkpoints, and their ligands, sialic acids, are known to be overexpressed by cancer cells. Here, we unveil a previously unrecognized role of sialic acid-containing glycans on PDAC CAFs as crucial modulators of myeloid cells. Using multiplex immunohistochemistry and transcriptomics, we show that PDAC stroma is enriched in sialic acid-containing glycans compared to tumor cells and normal fibroblasts, and characterized by ST3GAL4 expression. We demonstrate that sialic acids on CAF cell lines serve as ligands for Siglec-7, -9, -10 and -15, distinct from the ligands on tumor cells, and that these receptors are found on myeloid cells in the stroma of PDAC biopsies. Furthermore, we show that CAFs drive the differentiation of monocytes to immunosuppressive tumor-associated macrophages in vitro, and that CAF sialylation plays a dominant role in this process compared to tumor cell sialylation. Collectively, our findings unravel sialic acids as a mechanism of CAF-mediated immunomodulation, which may provide targets for immunotherapy in PDAC.PMID:38594506 | DOI:10.1038/s42003-024-06087-8

Nature. 2024 Apr 9. doi: 10.1038/s41586-024-07392-2. Online ahead of print.NO ABSTRACTPMID:38594341 | DOI:10.1038/s41586-024-07392-2

Sci Rep. 2024 Apr 9;14(1):8329. doi: 10.1038/s41598-024-57747-y.ABSTRACTPatients with advanced cancer are frequently burdened with a severe sensation of fatigue called cancer-related fatigue (CRF). CRF is induced at various stages and treatments, such as cachexia and chemotherapy, and reduces the overall survival of patients. Objective and quantitative assessment of CRF could contribute to the diagnosis and prediction of treatment efficacy. However, such studies have not been intensively performed, particularly regarding metabolic profiles. Here, we conducted plasma metabolomics of 15 patients with urological cancer. The patients with and without fatigue, including those with cachexia or chemotherapy-induced fatigue, were compared. Significantly lower concentrations of valine and tryptophan were observed in fatigued patients than in non-fatigued patients. In addition, significantly higher concentrations of polyamine pathway metabolites were observed in patients with fatigue and cachexia than in those without cachexia. Patients with exacerbated fatigue due to chemotherapy showed significantly decreased cysteine and methionine metabolism before chemotherapy compared with those without fatigue exacerbation. These findings suggest that plasma metabolic profiles could help improve the diagnosis and monitoring of CRF.PMID:38594321 | DOI:10.1038/s41598-024-57747-y

Nat Microbiol. 2024 Apr 9. doi: 10.1038/s41564-024-01665-2. Online ahead of print.ABSTRACTPseudomonas aeruginosa is a leading cause of hospital-acquired infections for which the development of antibiotics is urgently needed. Unlike most enteric bacteria, P. aeruginosa lacks enzymes required to scavenge exogenous thymine. An appealing strategy to selectively target P. aeruginosa is to disrupt thymidine synthesis while providing exogenous thymine. However, known antibiotics that perturb thymidine synthesis are largely inactive against P. aeruginosa.Here we characterize fluorofolin, a dihydrofolate reductase (DHFR) inhibitor derived from Irresistin-16, that exhibits significant activity against P. aeruginosa in culture and in a mouse thigh infection model. Fluorofolin is active against a wide range of clinical P. aeruginosa isolates resistant to known antibiotics. Metabolomics and in vitro assays using purified folA confirm that fluorofolin inhibits P. aeruginosa DHFR. Importantly, in the presence of thymine supplementation, fluorofolin activity is selective for P. aeruginosa. Resistance to fluorofolin can emerge through overexpression of the efflux pumps MexCD-OprJ and MexEF-OprN, but these mutants also decrease pathogenesis. Our findings demonstrate how understanding species-specific genetic differences can enable selective targeting of important pathogens while revealing trade-offs between resistance and pathogenesis.PMID:38594311 | DOI:10.1038/s41564-024-01665-2

Small Methods. 2024 Apr 9:e2301644. doi: 10.1002/smtd.202301644. Online ahead of print.ABSTRACTSurface-assisted laser desorption/ionization (SALDI) mass spectrometry imaging (MSI) holds great value in spatial metabolomics and tumor diagnosis. Tissue imprinting on the SALDI target can avoid laser-induced tissue ablation and simplifies the sample preparation. However, the tissue imprinting process always causes lateral diffusion of biomolecules, thereby losing the fidelity of metabolite distribution on tissue. Herein, a membrane-mediated imprinting mass spectrometry imaging (MMI-MSI) strategy is proposed using isoporous nuclepore track-etched membrane as a mediating imprinting layer to selectively transport metabolites through uniform and vertical pores onto silicon nanowires (SiNWs) array. Compared with conventional direct imprinting technique, MMI-MSI can not only exclude the adsorption of large biomolecules but also avoid the lateral diffusion of metabolites. The whole time for MMI-based sample preparation can be reduced to 2 min, and the lipid peak number can increase from 46 to 113 in kidney tissue detection. Meanwhile, higher resolution of MSI can be achieved due to the confinement effect of the pore channel in the diffusion of metabolites. Based on MMI-MSI, the tumor margins of liver cancer can be clearly discriminated and their different subtypes can be precisely classified. This work demonstrates MMI-MSI is a rapid, highly sensitive, robust and high-resolution technique for spatially-resolved metabolomics and pathological diagnosis.PMID:38593356 | DOI:10.1002/smtd.202301644

Plant J. 2024 Apr 9. doi: 10.1111/tpj.16751. Online ahead of print.ABSTRACTPlant acclimation to an ever-changing environment is decisive for growth, reproduction, and survival. Light availability limits biomass production on both ends of the intensity spectrum. Therefore, the adjustment of plant metabolism is central to high-light (HL) acclimation, and the accumulation of photoprotective anthocyanins is commonly observed. However, mechanisms and factors regulating the HL acclimation response are less clear. Two Arabidopsis mutants of spliceosome components exhibiting a pronounced anthocyanin overaccumulation in HL were isolated from a forward genetic screen for new factors crucial for plant acclimation. Time-resolved physiological, transcriptome, and metabolome analysis revealed a vital function of the spliceosome components for rapidly adjusting gene expression and metabolism. Deficiency of INCREASED LEVEL OF POLYPLOIDY1 (ILP1), NTC-RELATED PROTEIN1 (NTR1), and PLEIOTROPIC REGULATORY LOCUS1 (PRL1) resulted in a marked overaccumulation of carbohydrates and strongly diminished amino acid biosynthesis in HL. While not generally limited in N-assimilation, ilp1, ntr1, and prl1 showed higher glutamate levels and reduced amino acid biosynthesis in HL. The comprehensive analysis reveals a function of the spliceosome components in the conditional regulation of the carbon:nitrogen balance and the accumulation of anthocyanins during HL acclimation. The importance of gene expression, metabolic regulation, and re-direction of carbon towards anthocyanin biosynthesis for HL acclimation are discussed.PMID:38593295 | DOI:10.1111/tpj.16751